Vitamin A (Retinol)

BACKGROUND & AIMS: The association between dietary vitamin A, retinol intake and blood retinol level and gastric cancer risk has been investigated by many studies. However, the results of these studies were controversial. The aim of our study was to systematically assess this issue. METHODS: PUBMED and EMBASE were searched, supplemented with manual-screening for relevant publications. Meta-analyses were performed to evaluate the association between vitamin A, retinol dietary intake or blood retinol level and gastric cancer risk. RESULTS: Thirty-one studies were included in this meta-analysis. Comparing the highest with the lowest categories, vitamin A intake significantly reduced gastric cancer risk (pooled RR = 0.66, 95% CI: 0.52-0.84), whereas a marginally inverse association was found between retinol intake (pooled RR = 0.94, 95% CI: 0.87-1.03) or blood retinol level (pooled RR = 0.87, 95% CI: 0.73-1.05) and gastric cancer risk. Interestingly, the results of subgroup analysis indicated that high vitamin A intake and blood retinol level were associated with reduced gastric cancer risk in Western countries, while a marginally inverse association was found between retinol and gastric cancer risk in Western countries. CONCLUSIONS: Vitamin A intake was inversely associated with gastric cancer risk, while no significant association was found with retinol intake or blood retinol level.

PURPOSE: The aim of the MultiVeg study, a double-blind, randomised controlled trial (RCT), was to investigate the nutritional status of healthy vegans following 4 months of multinutrient supplementation. METHODS: A double-blind, RCT was conducted with 72 vegan adults (19-57 years) in Germany. Data on anthropometric parameters, dietary nutrient intake, and nutritional status were collected. The nutritional status of the participants was assessed at baseline and after 4 months. The results were compared between groups using ANCOVA. The results for vitamins and choline are presented here. RESULTS: After adjustment for baseline values, age, sex, and multiple testing, no significant between-group differences in biomarker concentration changes from baseline to 4 months were observed for vitamin A, retinol-binding protein, transthyretin, beta-carotene, methylmalonic acid, homocysteine, choline, total osteocalcin, carboxylated and undercarboxylated osteocalcin, and folate. In contrast, significant between-group differences in changes were observed for flavin adenine dinucleotide (FAD), serum vitamin B12, holotranscobalamin, and the combined vitamin B12 status indicator (cB12) after adjustment. CONCLUSION: A multinutrient supplement containing 82 µg of vitamin B12 per day significantly positively affected vitamin B12 blood biomarkers in healthy vegans. REGISTRATION: This study was registered in the German Clinical Trials Register (DRKS00028151). © 2025. The Author(s).

FGF21 is a hormone secreted from the liver in response to various nutritional stressors, suggested to act to balance dietary intake through negative feedback regulation. This meal study aimed to investigate two different potential nutrient interactions on postprandial FGF21 secretion in healthy human participants: 1) between intake of alcohol and protein, and 2) between intake of alcohol and vitamin A (retinol). In a 4-arm, randomized, double-blinded, cross-over meal study (NCT06105476), postprandial circulating concentrations of FGF21, glucose, insulin, ethanol, and acetate were compared after intake of four different test drinks containing alcohol, alcohol + protein, alcohol + retinol, or retinol in 27 healthy humans. The postprandial FGF21 response to the alcohol + protein drink was severely attenuated compared with the alcohol drink. The FGF21 response to the alcohol + retinol drink was similar to the alcohol drink, whereas there was no FGF21 response to the drink with retinol only. In conclusion, intake of protein inhibited the secretory FGF21 response to alcohol intake, whereas retinol intake did not appear to influence FGF21 secretion.NEW & NOTEWORTHY The hepatic hormone FGF21 is regulated by dietary intake. The results of this human meal study suggest that coconsumption of protein inhibits alcohol-induced FGF21 secretion in humans, similar to how protein intake previously has been shown to inhibit sugar-induced FGF21 secretion. This indicates that dietary protein is a consistent downregulator of FGF21. We found no indication that intake of retinol influences FGF21 regulation.

INTRODUCTION: Maternal nutritional and vitamin status during pregnancy may have long-term effects on offspring health and disease. The aim of this study was to examine the associations between maternal vitamin A and D status in pregnancy and offspring bone mineral content (BMC) at nine years of age. METHODS: This is a post-hoc study of a randomized control trial including 855 pregnant women from two Norwegian cities; Trondheim and Stavanger. The women were randomized into an exercise intervention or standard antenatal care. Mother and child pairs for the present study were recruited from those still living in Trondheim after 8-10 years. Serum vitamin A (retinol) and vitamin D (25(OH)D) were measured in the 2nd and 3rd trimesters of pregnancy, and active vitamin D (1,25(OH)2D) in serum was measured in a subgroup. Spine BMC and trabecular bone score were measured in the children at nine years of age. Associations were analyzed with linear regression models. RESULTS: A total of 119 mother and child pairs were included in the analyses. Vitamin A insufficiency (retinol< 1.05 µmol/L) and vitamin D deficiency (25(OH)D< 50 mmol/L) increased from ~7% to ~43% and from ~28% to ~33%, respectively, from the 2nd to the 3rd trimester. An increase in serum 1,25(OH)2D from the 2nd to the 3rd trimester was observed in the subgroup. There was a negative association between serum retinol in the 2nd trimester and spine BMC in the boys, but not in the girls, when adjusted for maternal and child confounders. No other associations between maternal serum vitamin A or D and BMC in the children were found. CONCLUSION: We observed a high prevalence of vitamin A insufficiency and vitamin D deficiency during pregnancy. A negative association between mid-pregnancy vitamin A status and spine BMC was observed in boys, but not girls, while no associations were found between maternal vitamin D status and child BMC. The implications of optimal vitamin A and D status in pregnancy for offspring bone health, remains a subject for further investigations.

OBJECTIVES: Multidrug-resistant (MDR) superbugs, including Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), are a challenge for healthcare professionals. In this study, the synergistic activity of vitamins with antibiotics against resistant bacterial strains was evaluated. METHODS: Synergistic effects between antibiotics and stock solutions of vitamins were evaluated by the Kirby-Bauer disk diffusion assay. Distilled water and propylene glycol were used as solvent for water-soluble and fat-soluble vitamins, respectively. Final concentrations of 10mg/mL for each water-soluble vitamin [B1 (thiamine), B2 (riboflavin), B6 (pyridoxine), B12 (methylcobalamin) and C (ascorbic acid)] and 0.1mg/mL for each fat-soluble vitamin [A (retinol), D (cholecalciferol), E (α-tocopherol) and K (menadione)] were used in combination with the antibiotics. RESULTS: The results demonstrated that vitamins K and E had good synergistic activity with piperacillin/tazobactam, imipenem and doripenem against A. baumannii, whilst vitamins B1, B2 and B12 showed remarkable synergistic activity with linezolid against MRSA. Vitamin B1 was further shown to have better synergism with oxacillin, tetracycline, rifampicin and linezolid against MRSA. The fat-soluble vitamins E and K showed good synergism against Gram-negative A. baumannii, whilst the water-soluble vitamins B1, B2 and B12 were effective against MRSA but not against A. baumannii. CONCLUSIONS: This synergistic action of vitamins with antibiotics may be used as a tool to treat MDR superbugs, with further evaluation required at a molecular level.

BACKGROUND: Retinyl esters (REs), the major storage form of vitamin A (retinol), provide substrates for the production of bioactive retinoids, including retinoic acid (RA), which are known to promote lung development and maturation. We previously showed that the nutrient-metabolite combination VARA (molar ratio 10 vitamin A to 1 RA), synergistically increased REs in the lungs of 1-week-old rats, compared to vitamin A or RA alone. OBJECTIVES: To test the hypotheses, first, that VARA is more effective in increasing lung RE than is vitamin A in newborn rats prior to alveolarization, and, second, that the effect of VARA is maintained during concurrent treatment with the glucocorticoid, dexamethasone (Dex). METHODS: Newborn rats were treated with VARA, vitamin A alone, or oil (C) on postnatal days (P) 1-3, and RE in the lungs was quantified on P4, and again on P8 to assess retention. Additionally, neonatal rats were treated on P5-7 with VARA with and without Dex, and the lung and liver REs were quantified on P8. RESULTS AND CONCLUSIONS: Lung RE was nearly 8-fold higher in VARA compared to vitamin A-treated rats on P4 (p < 0.01) and 2.5-fold higher on P8. In neonates co-treated with Dex and VARA on P5-7, the elevation in lung RE on P8 by VARA was not antagonized by Dex, although Dex reduced growth. Lung morphology and development were not significantly altered. The VARA combination may significantly increase lung RE content even during concurrent Dex therapy. Because lung retinoids are important for lung maturation and repair, increasing lung RE may possibly have clinical benefit.

Pretreatment of rats with large doses of vitamin A (retinol) dramatically increased the hepatotoxicity of carbon tetrachloride (CCl4). Experiments were performed to elucidate the mechanism of this potentiation. Hypervitaminosis A was produced by oral administration of retinol, 250,000 IU/kg for seven days. CCl4 was then administered at a dose of 0.15 ml/kg, ip. This large dose of vitamin A did not enhance the biotransformation of CCl4, but did produce a 4-fold increase in CCl4-induced lipid peroxidation, as assessed by ethane exhalation. Because vitamin A has been shown to activate macrophages, it was hypothesized that this increased lipid peroxidation and liver injury resulted from the release of reactive oxygen species from activated Kupffer cells. By using a chemiluminescence assay, an enhanced release of free radicals was detected in Kupffer cells isolated from vitamin A pretreated rats. In addition, Kupffer cells from vitamin A pretreated rats displayed enhanced phagocytic activity in vitro, towards sheep red blood cells. In vivo, vitamin A pretreated rats cleared carbon particles from the blood 2-3 times faster than non-pretreated rats. In vivo administration of superoxide dismutase (SOD) 2 hr after CCl4 exposure did not influence CCl4 toxicity in control rats but did block the enhanced ethane exhalation and also the potentiation of CCl4 liver injury in vitamin A treated rats. Administration of methyl palmitate, an inhibitor of Kupffer cell function, did not inhibit CCl4 toxicity in control rats, but did effectively block enhanced ethane exhalation and potentiation of CCl4 injury in vitamin A treated rats. We conclude that potentiation of CCl4 hepatotoxicity by hypervitaminosis A is mediated in part by reactive oxygen species released from activated Kupffer cells.

Vitamin A (retinol) and five retinoids were tested for their ability to enhance epidermal growth factor (EGF) stimulation of adult human skin fibroblast growth in vitro. The retinoids utilized in this study were RO-1-5488 (all-trans-retinoic acid), RO-4-3780 (13-cis-retinoic acid), RO-10-9359, RO-10-1670, and RO-21-6583. Retinol and each retinoid were capable of stimulating fibroblast growth alone (0-86%), while 13-cis and all-trans-retinoic acid were the most potent in potentiating the EGF promotion of fibroblast growth. Other growth factors tested in addition to EGF were nerve growth factor (NGF), fibroblast growth factor (FGF), and thrombin. While EGF and FGF stimulated fibroblast growth to the same degree (2.3-fold), only growth stimulated by EGF was potentiated by retinoic acid. Since retinoic acid might enhance the EGF stimulation of cell growth by increasing either EGF receptor number or binding affinity, the binding of 125I-labeled EGF was carried out in the presence of retinoic acid and the data were subjected to a Scatchard-type analysis. No change in EGF receptor number or affinity was seen in the presence of retinoic acid. The data indicate a specific interaction between retinoid acid and EGF which results in the potentiation of the EGF-stimulated cell growth. Furthermore, the mechanism of this interaction does not seem to involve the initial binding of EGF to its plasma membrane receptor or the available number of EGF receptors located on the cell surface.

9. Arch Toxicol. 1982 Jan;49(2):169-74. doi: 10.1007/BF00332364. Retinol (vitamin A) as a modifier of 2-aminofluorene and 2-acetyl-aminofluorene mutagenesis in the Salmonella/microsome assay. Busk L, Ahlborg UG. Vitamin A (retinol)has been demonstrated to modify the mutagenic activity of the aromatic amines, 2-aminofluorene (2AF) and 2-acetylaminofluorene (2AAF) when added to the Ames Salmonella/mammalian microsome assay. Low amounts of retinol(2-20 micrograms/plate) increased the mutagenicity of both 2AF and 2AAF. At higher doses (50-150 micrograms/plates) the mutagenicity of 2AAF remained unchanged while the mutagenicity of 2AF gradually decreased. The present data do not support the hypothesis that retinol generally acts as an inhibitor of in vitro metabolic activation of procarcinogens.

BACKGROUND: Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. OBJECTIVE: This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. DESIGN: Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. RESULTS: Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P < 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 ± 0.52 (n = 28) vs. 2.32 ± 0.44 ng/mL (n = 13)], NAFLD [1.61 ± 0.37 (n = 29) vs. 1.28 ± 0.41 ng/mL (n = 16)], and NASH [1.35 ± 0.34 (n = 24) vs. 1.07 ± 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRα mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P < 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRα protein was lower in more severe grades in patients with NAFLD. CONCLUSION: These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263. © 2015 American Society for Nutrition.

OBJECTIVE: To conduct a systematic review with meta-analysis of studies assessing the association of vitamin A (retinol, carotene and other carotenoids) intake or blood (serum or plasma) levels of vitamin A (retinol and carotene) with risk of cervical cancer. METHODS: We evaluated the studies published in English and Chinese on diet or blood vitamin A for the risk of cervical cancer. We also reviewed reference lists from retrieved articles. Meta-analysis was applied to calculate the combined effect values and their 95% confidence intervals. The risk of bias was assessed by the Egger regression asymmetry test. RESULTS: As many as 11 articles on dietary vitamin A and 4 articles on blood vitamin A were selected according to the eligibility criteria and were included in the meta-analysis, for a total of 12,136 participants. The pooled odds ratios (ORs) of cervical cancer were 0.59 (95% CI, 0.49-0.72) for total vitamin A intake and 0.60 (95% CI, 0.41-0.89) for blood vitamin A levels. The combined ORs of cervical cancer were 0.80 (95% CI, 0.64-1.00), 0.51 (95% CI, 0.35-0.73) and 0.60 (95% CI, 0.43-0.84) for retinol, carotene and other carotenoid intake, and 1.14 (95% CI, 0.83-1.56) and 0.48 (95% CI, 0.30-0.77) for blood retinol and carotene. CONCLUSIONS: Vitamin A intake and blood vitamin A levels were inversely associated with the risk of cervical cancer in this meta-analysis.

The contribution of liver sinusoidal endothelial cell (LSEC) zonation to metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis remains undefined. We identified selective lipid deposition in the pericentral zone during early MASLD. Multiomics analyses confirmed enhanced pericentral lipid metabolism in both hepatocytes and LSECs. Mechanistically, pericentral LSEC marker c-Kit transcriptionally activated FGF1 via nuclear receptor RXRG, which suppressed hepatocellular lipid accumulation through FGFR4 signaling. Retinoic acid (RXRG's endogenous ligand and active vitamin A metabolite) phenocopied FGF1's antisteatotic effects. Clinical data revealed an inverse correlation between dietary vitamin A and MASLD severity, suggesting therapeutic potential of vitamin A supplementation for early intervention.

Update of bioRxiv. 2025 Sep 10:2025.09.08.674524. doi: 10.1101/2025.09.08.674524. The intestinal microbiota shapes adaptive immunity, but the mechanisms remain incompletely defined. Here, we show that the microbiota initiates movement of retinoids-dietary vitamin A derivatives including retinol and retinoic acid-through a sequential pathway from epithelial cells to myeloid cells and ultimately to T cells in the mesenteric lymph nodes (mLNs). This cellular axis is traversed over three days. Microbe-associated molecular patterns initiate retinoid flux by inducing expression of serum amyloid A proteins. These epithelial retinol-binding proteins are necessary and sufficient for epithelial-to-myeloid retinoid transfer and myeloid cell migration to the mLNs. In the mLNs, microbial antigen drives retinoid transfer from myeloid cells to developing T cells, culminating in T cell retinoid uptake and transcriptional programming. This pathway is activated during postnatal development, when gut adaptive immunity is established. These findings reveal that the microbiota programs intestinal adaptive immunity by regulating immune cell access to a nutrient-derived developmental signal.

Persistent infection with High-Risk Human Papillomavirus (HR-HPV), particularly HPV-16, is the main driver of cervical intraepithelial neoplasia (CIN) and cervical cancer (CC). However, HR-HPV infection alone is insufficient for malignant progression and nutritional cofactors such as Vitamin A deficiency, may influence cervical neoplasia progression through immune dysregulation. This study aimed to explore the interaction between HPV-16 E7 oncoprotein expression and severe Vitamin A Deficiency (VAD), as well as the effects of a Vitamin A-Normal Diet Reintegration (NDR) on adaptive immune regulation in cervical neoplasia using the K14E7 preclinical murine model. We found that VAD worsening cervical epithelial changes and impairs the cytotoxic ability of CD8+ T cells, which is marked by lower levels of granzyme B and increased expression of PI-9. These changes were accompanied by increase F4/80+ macrophage infiltration and elevated Foxp3 expression, suggesting enhanced Tregs immunosuppressor activity. Distinctly, NDR induced partial recovery of cervical epithelium architecture and the effector function of CD8+ T cells. Our results highlight Vitamin A as a key immunomodulator that influences the balance between immune surveillance and immune evasion of HPV-associated cervical carcinogenesis and suggests its potential relevance for preventive or adjuvant treatments in populations at high risk of CC. © 2026 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.

BACKGROUND: The combination of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) has dramatically improved the cure rate of acute promyelocytic leukemia (APL). However, differentiation syndrome (DS) remains a significant cause of early mortality in APL patients. This severe complication typically occurs during induction therapy with ATRA and/or ATO. Early prediction and timely intervention are crucial to reducing DS-related mortality. This study aimed to identify risk factors for DS and develop a predictive model tailored to children with non-high-risk (NHR) APL. METHODS: We conducted a multicenter retrospective analysis of 166 pediatric NHR-APL patients treated between 2011 and 2024. Clinical characteristics were compared between DS and non-DS groups. Logistic regression was used to identify independent predictors, and a nomogram was developed based on these variables. The model was evaluated using the area under the curve (AUC) and decision curve analysis (DCA). RESULTS: Seventeen patients (10.2%) developed DS during induction. Multivariate analysis identified five independent risk factors: female sex, non-chemotherapy group, BCR subtype 3, elevated peripheral promyelocyte proportion (≥ 44%), and platelet count (≥ 20 × 109/L). The predictive nomogram achieved an AUC of 0.89 in the training set and 0.75 in the validation set. DCA demonstrated favorable clinical utility of the model. CONCLUSIONS: We developed and validated the first nomogram for predicting DS in pediatric NHR-APL. This tool enables early risk stratification and may guide clinical decision-making to reduce early mortality. © 2026 John Wiley & Sons Ltd.

Liver fibrosis is a major contributor to global mortality due to its progressive disruption of hepatic architecture and function, and it remains a critical unmet medical need. Hepatic stellate cells (HSCs) are considered a key therapeutic target owing to their central role in fibrosis progression, primarily mediated through the TGF-β1/Smad2/3 signaling pathway. Pirfenidone (PFD), a clinically approved broad-spectrum antifibrotic agent, shows potential for repurposing in liver fibrosis therapy. However, its clinical translation is limited by poor aqueous solubility and a lack of cellular targeting specificity. To address these limitations, we developed a vitamin A-conjugated liposomal delivery system (P@GB-Lipo-VA) to enhance the liver-specific accumulation of PFD. In vitro studies demonstrated that P@GB-Lipo-VA significantly increased cellular uptake in TGF-β1-stimulated LX-2 cells and reduced oxidative stress. In a bile duct ligation (BDL)-induced mouse model of liver fibrosis, P@GB-Lipo-VA effectively alleviated collagen deposition, improved liver function, and suppressed activation of the TGF-β1/Smad signaling pathway. These findings support P@GB-Lipo-VA as a promising targeted nanotherapeutic platform for enhancing the efficacy and safety of PFD in the treatment of liver fibrosis. © 2026. The Author(s).

Autism spectrum disorders (ASD) affect approximately 1.0% of children worldwide with still increasing global prevalence. The fact that genetic factors contribute to less than 50% of ASD suggests some critical yet enigmatic roles of non-genetic factors in ASD etiology. Here, we reported that montelukast (MTK), a cysteinyl leukotriene receptor antagonist and one of the most commonly prescribed anti-asthma drugs, potently disrupted neuronal retinoic acid (RA) signaling and altered synaptic plasticity of the primary neurons from rat pre-frontal cortex (PFC). Prenatal or early postnatal exposure to MTK induced autistic-like behaviors in wild-type rats, which could be significantly alleviated by supplementing all-trans retinoic acid (atRA). MTK altered neuronal RA signaling and forebrain patterning in brain organoids derived from human embryonic stem cells through antagonizing RA in RA signaling. Meanwhile, molecular docking followed by biochemical validation strongly indicated that MTK could physically interact with RA receptors (RARs), e.g. RA receptor α (RARA). Furthermore, multi-center survey with a large Chinese ASD cohort suggested that MTK administration during early childhood might indeed increase the risk of ASD in children. Altogether, our findings have not only established MTK use as a yet unrecognized risk factor for human ASD, but highlighted the key importance of safer use of medicines to prevent ASD. © 2026. The Author(s).

Glycosylation is essential for hematopoietic cell homeostasis and malignant transformation. Dysregulated expression of glycosylation genes in leukemia cells accelerates disease progression and fosters drug resistance. Therefore, targeting these genes offers a promising avenue for anti-leukemic therapy. In this study, we explore the roles of N-glycans in acute promyelocytic leukemia (APL) differentiation using the ATRA-induced wild-type NB4 (WT/ATRA) or HL-60 cell model. We found that expression of N-acetylglucosaminyltransferase IVa (GnT-IVa, encoded by the MGAT4A gene) and its product (β1,4-GlcNAc-branched N-glycan) increased significantly during differentiation, as evaluated by lectin blot, real-time PCR, and flow cytometry. Interestingly, analysis of the Gene Expression Omnibus (GEO) public data showed that MGAT4A expression is significantly lower in APL patients, and higher MGAT4A expression was associated with favorable survival in AML cohorts. To address the role of GnT-IVa in differentiation, we established MGAT4A- and MGAT4B-knockout (KO) NB4 cell lines using CRISPR/Cas9. Compared to WT/ATRA cells, MGAT4A KO, but not MGAT4B KO, markedly suppressed ATRA-induced differentiation, as evidenced by reduced expression of CD11b and CD11c. We found that CD11b is a major glycoprotein carrying β1,4-GlcNAc-branched N-glycans. This modification enhanced CD11b stability, as CD11b expression declined more rapidly in MGAT4A KO cells in the presence of cycloheximide. In addition, MGAT4A KO suppressed ERK/MAPK signaling, which contributed to differentiation. Our study highlights the critical role of GnT-IVa in regulating APL differentiation, which may provide a basis for developing new differentiation therapies for APL.

PURPOSE: Anti-inflammatory diets, such as the Mediterranean Diet (MedDiet) have shown positive effects on disease activity in Rheumatoid Arthritis (RA). The Dietary Inflammatory Index (DII) has been associated with RA risk. However, the effect of improving diet quality with a MedDiet and impact on the DII and patient-reported outcome measures (PROMs) has not been investigated. OBJECTIVES: To assess the effects of a MedDiet and adherence to the Irish Healthy Eating Guidelines (HEG) on change in DII and to determine whether change in DII and energy-adjusted DII (e-DII) scores is associated with improvements in PROMs in adults with RA in Ireland. METHODS: 40 Participants were randomised to a MedDiet (n = 20) or a HEG intervention (n = 20) for 12 weeks. DII was calculated based on food diaries collected. Between and within group data was analysed in SPSS. RESULTS: Baseline e-DII was 0.99 ± 2.37, 0.79 ± 2.60, 1.20 ± 2.16 for total cohort (n = 40), MedDiet, and HEG groups, respectively (p = 0.588). e-DII significantly improved for the cohort following the MedDiet (p = 0.022) and HEG (p = 0.004) groups. Differences in PROMs across tertiles of e-DII change were not statistically significant, irrespective of diet assignment. Participants in the most anti-inflammatory e-DII tertile group had significantly greater intakes of omega-3 fatty acids, dietary fibre, vitamin A, vitamin E, folic acid, and beta-carotene compared to those in the pro-inflammatory tertile group (p < 0.05). CONCLUSIONS: Improving dietary quality with either a MedDiet or the Irish HEG improved e-DII scores in a cohort of people living with RA, however, no statistically significant change in PROMs were observed. © 2026. The Author(s).

How HOX transcription factors play a role in the stem cell (SC) origin of cancer is unclear. Our goal is to determine how dysregulation of HOX gene expression promotes colorectal cancer (CRC) development through aberrant SC regulatory mechanisms. We investigated retinoic acid (RA) and WNT signaling because they regulate HOX expression and both pathways are dysregulated in cancer. Previously, we reported WNT and RA pathways are functionally linked, and in CRC, APC mutation generates a WNT:RA imbalance leading to incomplete differentiation and SC overpopulation. We hypothesize that aberrant WNT- and RA-signaling dysregulates HOX expression that contributes to the SC origin of CRC. We discovered a HOX expression signature of eight genes (six-upregulated, two-downregulated) that are significantly altered in CRC, and that predict poor CRC patient survival. NanoString profiling of fluorescence activated cell sorted SC subpopulations, bioinformatics studies, and RNA-seq analysis of fresh colon tissues revealed: (1). The six-upregulated genes are regulated by RA signaling; (2). ATRA-treatment of CRC cells, but not wt-APC induction or RARA knockout, leads to a HOX expression pattern matching the HOX signature; (3). Mid-cluster (group 3) HOXB gene expression characterizes normal colon, but increased group 3 HOXC expression occurs in CRC; (4). LGR5+ SCs selectively express group 3 HOXB genes while ALDH+ SCs express group 3 HOXC genes; (5). HOXA13 and HOXB13 which are downregulated and predict poor patient survival likely possess tumor-suppressor activity and function by retro-inhibition of earlier HOX genes. Given HOX expression predicts survival and identifies SC phenotype, this indicates dysregulated HOX expression contributes to SC origin of CRC. © The Author(s) 2026. Published by Oxford University Press.

BACKGROUND: Micronutrients, dietary phytochemicals, and lipid metabolism influence mammary gland growth, lactation efficiency, and breast cancer incidence. The present retrospective investigation evaluated these aspects using clinical, dietary, and biochemical data from women with established lactation and breast cancer outcomes. METHODS: This retrospective analysis involved 800 women found through hospital electronic medical data. Dietary consumption of micronutrients and phytochemicals was evaluated via food frequency questionnaires and dietary recalls. Lipid metabolism was assessed via serum lipid parameters and fatty acid indicators. Outcomes involved mammary gland growth markers, lactation history and efficiency, mammographic density, breast cancer risk, and tumor features. Multivariable regression analysis corrected for demographic, reproductive, lifestyle, and clinical variables were applied. RESULTS: Vitamin D deficiency was noted in 48.5% of subjects and was related with higher breast cancer incidence (adjusted OR = 1.68; 95% CI: 1.21-2.33). Breast cancer instances had decreased intakes of vitamin D, folate, selenium, zinc, and vitamin A compared with controls. Increased dietary phytochemical index (DPI) was linked with reduced breast cancer incidence (adjusted OR = 0.48; 95% CI: 0.32-0.71). Dyslipidemia was observed in 60.8% of individuals and was linked with elevated tumor grade and advanced stage. Extended periods of exclusive breastfeeding have been linked to a lower incidence of breast cancer. CONCLUSION: Micronutrient consumption, dietary phytochemical concentrations, lipid metabolism indicators, and lactation history show substantial relation with breast cancer probability, mammographic density, and tumor features in this population highlighting the importance of nutritional and metabolic markers in breast health outcomes.

In solid cancer, the tumor microenvironment (TME) poses significant challenges to chimeric antigen receptor (CAR) T cell therapy due to its dense physical barrier, abnormal metabolism, and immunosuppressive factors. This study addresses these limitations using a synergistic approach involving all-trans retinoic acid (ATRA) and lansoprazole (LPZ) to target fibrosis and acidity, respectively. In vitro, ATRA reversed activated cancer-associated fibroblasts to a quiescent state, reducing α-SMA production, while LPZ increased tumor-site pH (Δ pH = 0.54) by inhibiting V-ATPase expression. In a triple-negative breast cancer (TNBC) model, a temperature-sensitive hydrogel delivering ATRA and LPZ was administered prior to drug-loaded NKG2D-CAR T (N-CAR T) cell injection, achieving a tumor inhibition rate of 72.08%. Notably, co-culture with ATRA and LPZ enhanced N-CAR T activity, cytokine secretion, and promoted differentiation into more lethal CD8+ subtypes (p < 0.0001), amplifying the immune response. These findings establish a targeted, potent, and low-toxicity preconditioning strategy to enhance CAR T cell efficacy in solid tumors, supporting further validation in more complex models and human-relevant systems.

INTRODUCTION: Whether retinoids and carotenoids impact on graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (ASCT) is unknown. METHODS: We conducted a 1:1 randomized controlled trial with extracorporeal photopheresis for GVHD-prophylaxis as the intervention. The plasma levels of retinoids and carotenoids were determined at randomization and 3 months after ASCT. RESULTS: We found no significant difference in GVHD occurrence and levels of retinoids between the intervention and control groups at either of the two time points. CONCLUSION: Whether routine vitamin A supplementation is warranted for GVHD prevention, needs further study. Our exploratory study highlights the complex role of retinoid homeostasis in immune function during ASCT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03204721. © 2026 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

BACKGROUND: All-trans retinoic acid (ATRA), a derivative of vitamin A, potently induces cell maturation in acute promyelocytic leukemia (APL). However, this therapeutic effect is attenuated or absent in non-APL acute myeloid leukemia (AML) and solid tumors. This study aims to elucidate the mechanisms underlying ATRA resistance and identify strategies to overcome it. METHODS: Integrated high-throughput sequencing-including single-cell multiomics, digital RNA with pertUrbation of genes (DRUG)-seq, bulk RNA-seq, ATAC-seq and CUT&Tag-was performed on AML and solid tumor cell lines treated with ATRA and the mTOR inhibitor PP242. Functional validation was conducted using flow cytometry, siRNA transfection, morphological assessment, Western Blotting and cell line derived xenografts (CDX). Pan-cancer analysis leveraged the Tahoe-100 M pharmacological perturbation dataset to assess metabolic responses across 50 cancer cell lines. RESULTS: ATRA simultaneously activates myeloid differentiation programs and a hyperactive metabolic state that impedes terminal maturation in non-APL AML cells. Pharmacological inhibition of the mechanistic target of the mTOR pathway with PP242 suppresses this metabolic surge and redirects transcriptional output toward effective differentiation. The Tahoe-100 M analysis reveals that cancers harboring oncogenic RAS mutations exhibit heightened metabolic responsiveness to ATRA, a vulnerability confirmed in RAS-mutant lung and colon carcinoma cell lines. In these models, ATRA and PP242 synergistically promotes cell maturation and reduces viability. CONCLUSIONS: These findings uncover a conserved metabolic barrier that limits ATRA-induced differentiation beyond APL. mTOR acts as a critical node governing the balance between pro-differentiation and pro-metabolic signals. Co-targeting mTOR overcomes this barrier, particularly in RAS-mutant malignancies, providing a genotype-informed rationale for extending differentiation therapy to broader cancer contexts. © 2026. The Author(s).

BACKGROUND: Neuroblastoma (NB) is the most common malignant extracranial solid tumor in children, with poor prognosis, inadequate therapeutic responses, and high recurrence rates. Zinc fingers and homeoboxes protein 2 (ZHX2) functions in various cancers, but its role in NB remains unclear. Retinoic acid (RA) has been used as a pro-differentiation agent in NB, but its limited response rate necessitates novel combinations. This study aims to explore key transcription factors (TFs) in improving RA efficacy and NB prognosis. METHODS: ZHX2 was identified as the key TF related to RA efficacy via RNA-seq analysis of RA-treated NB cell lines. Based on TARGET and GEO databases, we analyzed the correlation of ZHX2 with NB prognosis, survival, and clinical characteristics. Effects of ZHX2 knockdown/overexpression on NB cell proliferation, migration, colony formation, and apoptosis were assessed, with confirmation in subcutaneous xenografts. Bioinformatic analysis identified ZHX2's downstream targets, verified by PCR, WB, CHIP-qPCR, and histopathology. ZHX2's impact on RA efficacy was evaluated via cell proliferation, apoptosis, cell cycle, differentiation markers, spheroid formation, and in vivo tumor growth. RESULTS: ZHX2 presented as the key TF that potentially influences the sensitivity of NB to RA. Its expression was lower in NB patients with poor prognostic factors. ZHX2 overexpression inhibited NB malignancy (reduced proliferation, migration, tumor growth; increased apoptosis). Notably, ZHX2 enhanced RA efficacy by transcriptionally repressing CRABP1 to modulate retinoid metabolism, augmenting RA-induced neuronal differentiation and reducing tumor growth in mice. CONCLUSION: Transcription factor ZHX2 acts as a tumor suppressor in NB, which enhances RA's therapeutic effects via CRABP1-mediated retinoid metabolism regulation.

BACKGROUND: Acute myeloid leukemia (AML) with rare aberrations like AML1-MTG16 fusion encounters precision oncology challenges, exacerbated by the "Long-Tail" dilemma. Preclinical data show all-trans retinoic acid (ATRA) restores myeloid differentiation in MTG16-deficient AML models, but its clinical translation remains unexplored. CASE PRESENTATION: We treated a 73-year-old unfit AML patient with early molecular progression (AML1-MTG16 burden elevated to 0.2%) using ATRA plus azacitidine/venetoclax. Sustained measurable residual disease-negative remission (21 months) and undetectable fusion transcripts were achieved with only grade 2 neutropenia. CONCLUSIONS: This case may preliminarily suggest ATRA's potential in AML1-MTG16⁺ AML, offering translational clues for ultra-rare leukemia subtypes, pending further validation.

Vitamin A derivatives imprint adaptive immune cells for small-intestinal homing, yet the microbiota's role remains unclear. In this issue, Srinivasan et al. demonstrate that the microbiota help load vitamin A derivatives onto CD11c+ myeloid cells, thereby enabling their migration to mesenteric lymph nodes, where T cells are conditioned for small-intestinal homing.

Musculoskeletal trauma is exceedingly common and experiences a high incidence of complications, including bone non-union. Previous studies have implicated a dysregulated systemic immune response after injury as an important factor contributing to complications. We have previously identified a negative correlation between circulating myeloid-derived suppressor cells (MDSCs) and bone regeneration in a rat model of composite bone and muscle trauma. MDSCs are an immature, heterogeneous cell population of myeloid lineage that expands after injury and possesses potent immunosuppressive functions including the inhibition of T cells and expansion of regulatory T cells (Tregs), which could contribute to poor outcomes. As such, they may represent a novel therapeutic target in bone trauma. All-trans retinoic acid (ATRA) is a vitamin A derivative that has previously been shown to reduce MDSCs in cancer models by promoting their differentiation into mature myeloid cell populations. However, ATRA's effects on MDSCs have not been explored in the context of trauma. Here, we investigated the effects of ATRA on peripheral blood immune cells both in vitro and in vivo using a rodent model of bone and muscle trauma. Treatment with ATRA depleted MDSCs in blood derived from traumatized rats in vitro. Further, in vivo studies revealed that a specific subset of MDSCs were depleted by systemic ATRA administration. Tregs were also depleted and correlated negatively with endpoint bone healing, although healing overall was not altered by ATRA treatment. Additionally, higher doses of ATRA had the unanticipated effect of increasing rather than decreasing circulating MDSC levels. Further studies will be necessary to develop and optimize immunomodulatory interventions targeting systemic immune dysregulation after trauma and to determine whether such interventions possess the potential to improve functional bone regenerative outcomes.

BACKGROUND: Acute myeloid leukemia (AML) is predominantly a disease of older patients with a poor long-term survival. Approval of the combination of venetoclax (VEN) with azacitidine (AZA) or decitabine (DAC) in the European Union in 2021 for the treatment of patients with newly diagnosed AML who are ineligible for induction chemotherapy has become the treatment backbone for older, medically non-fit AML patients. Based on in vitro priming of AML cells to all-trans retinoic acid (ATRA) by DAC, we had previously conducted a randomized phase II trial (DECIDER, AMLSG 14 - 09) in 200 elderly, non-fit AML patients on the effect of ATRA as add-on to DAC. Median overall survival (OS) was 8.2 months with ATRA versus 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P = 0.006). Notably, ATRA did not add toxicity, the combination was active also in patients with adverse genetics, and prolonged time to treatment resistance. Investigating a triple combination of DAC, VEN and ATRA was a logical next step. This randomized double-blind phase III trial compares the efficacy of ATRA versus placebo as add-on to the backbone treatment (DAC and VEN) with respect to OS, objective best response, quality of life and safety. The accompanying translational research will contribute to identify molecular markers for drug efficacy and better tailoring epigenetic therapy. METHODS: DECIDER-2 (AMLSG 32 - 21) is a prospective, randomized, double-blind, placebo-controlled, parallel group, multicenter trial. The primary study objective is to compare the efficacy of ATRA versus placebo as add-on to the backbone treatment (DAC and VEN) in terms of OS. The target population is adult AML patients unfit for standard induction chemotherapy. Patients are randomized (1:1) to receive backbone treatment in combination with either ATRA or placebo. Four interim safety analyses were planned with the involvement of the Data Monitoring Committee. DISCUSSION: This trial investigates whether the in vitro cooperativity of DAC, VEN, and ATRA prolongs OS in unfit AML patients compared to placebo, offering a novel, low-toxicity triplet combination with a promising risk-benefit ratio. CLINICAL TRIAL N

The human neuroblastoma cell line SH-SY5Y is widely used in vitro as a model due to its ability to acquire neuron-like properties. Conventional differentiation protocols often rely on retinoic acid (RA), which can lead to limited stability of neuronal-like phenotypes over time. In this study, we evaluated a differentiation approach combining RA with a laminin-rich extracellular matrix (LrECM). This approach accelerated differentiation, with neuron-like morphology and neurite outgrowth observed as early as 4 days and sustained features for up to 10 days. Immunofluorescence analysis indicated increased NeuN expression, and Western blot confirmed the sustained presence of β3-tubulin during differentiation. Furthermore, a trend toward enhanced acetylcholinesterase (AChE) activity suggested partial cholinergic features. Altogether, these findings indicate that incorporating LrECM supports the stability of RA-induced neuron-like characteristics in SH-SY5Y cells and may provide a useful alternative for studies of neuronal-phenotype differentiation. © 2026 The Author(s). genesis published by Wiley Periodicals LLC.

Folic acid (FA) supplementation during pregnancy is the commonly accepted treatment to prevent neural tube defects. The mechanism by which FA prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including alcohol-induced malformations in Fetal Alcohol Syndrome models. We show that FA acts through a metabolic link to retinoic acid (RA) signaling. Using a pax3-knockdown Xenopus model of FA-rescuable NTDs, we show that RA or its precursors equally rescue these defects. Similarly, FA rescues alcohol-induced NTDs in a model previously shown to be rescued by retinoids. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydrogenase (ALDH1L1, FTHFD), encoded by the aldh1l1 gene, as essential for this rescue. Mechanistically, FA upregulates aldh1l1 expression, thereby increasing RA biosynthesis. Knockdown of ALDH1L1 activity using CRISPR/Cas9 abolishes the FA protective effect. To support these observations, we show that the human ALDH1L1 enzyme converts retinaldehyde to RA, and its overexpression restores neural tube closure in aldh1l1-knockdown embryos when retinaldehyde is provided. At the cellular level, reduced RA signaling results in overproliferation of neural plate precursors and a pathological expansion of the neural tube. ALDH1L1 enables FA to restore normal neural plate proliferation, thereby preventing NTDs. These findings establish ALDH1L1 as an unexpected enzymatic link between FA (vitamin B9) and RA signaling, revealing how FA supplementation safeguards neural development and suggesting opportunities to refine strategies for NTD prevention.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains a major cause of cancer-related mortality. Despite advances in targeted therapies, tumor heterogeneity and acquired resistance frequently undermine clinical outcomes. This study aimed to identify novel oncogenic drivers and underlying mechanisms in LUAD. METHODS: We examined cellular retinoic acid-binding protein 2 (CRABP2) expression in human LUAD specimens and evaluated its functional role through in vitro assays (cell proliferation, migration, invasion, and apoptosis) and in vivo xenograft tumor growth. Mechanistic exploration involved RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and immunoblotting for the nuclear factor kappa B (NF-κB) signaling components, along with rescue experiments to dissect the pathway dependency. RESULTS: CRABP2 was identified as a candidate oncogene in LUAD. Functional assays confirmed that CRABP2 promoted proliferation, migration, and invasion, suppressed apoptosis, and accelerated xenograft tumor growth. Mechanistically, CRABP2 potentiated retinoic acid (RA) signaling and activated the NF-κB pathway, as evidenced by enhanced inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) phosphorylation, subsequent NF-κB inhibitor alpha (IκBα) phosphorylation, and nuclear translocation of total and phosphorylated p65. Rescue experiments revealed that CRABP2‑induced NF-κB activation is RA-dependent and that this activation mediates the oncogenic effects of CRABP2. CONCLUSIONS: Our findings establish a CRABP2/RA/NF‑κB axis that drives LUAD progression, highlighting this pathway as a potential therapeutic target for intervention in LUAD. Copyright: © 2026 The Author(s). Published by IMR Press.

PURPOSE: To investigate the expression profile of IL-6 in patients with acute promyelocytic leukemia (APL) and its role in modulating the ability of hPMSCs to regulate the differentiation of NB4 cells. METHODS: Peripheral blood samples were obtained from newly diagnosed APL patients and healthy controls. IL-6 levels were measured using flow cytometry-based (FCM) multiplex immunoassays. A co-culture system of hPMSCs and NB4 cells was established. The effects of hPMSCs on ATRA-induced differentiation, proliferation, and phagocytic activity of NB4 cells were evaluated by Wright-Giemsa staining, FCM, CCK-8 assays, and phagocytosis assays. Western blot analysis was performed to investigate the signaling mechanisms by which IL-6 regulates CD73 expression in hPMSCs. To determine whether the regulatory effects of hPMSCs are mediated by CD73, interventions using a CD73 inhibitor and CD73-knockdown hPMSCs were conducted. RESULTS: IL-6 levels were significantly elevated in the peripheral blood of APL patients and showed a positive correlation with both risk stratification and the severity of retinoic acid syndrome (RAS). hPMSCs enhanced ATRA-induced differentiation of NB4 cells while suppressing their proliferation and phagocytic function. Moreover, inhibition or knockdown of CD73 markedly attenuated the pro-differentiation effect of hPMSCs on NB4 cells. NB4 cells exhibited high surface expression of adenosine receptors. IL-6 was found to upregulate CD73 expression in hPMSCs through activation of the PI3K/AKT signaling pathway. CONCLUSIONS: IL-6 enhances the pro-differentiation capacity of hPMSCs toward NB4 cells by upregulating CD73 expression, offering a potential new strategy for the clinical treatment of APL. © 2026 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.

BACKGROUND: Vitamins A and C (VitA+C) are pivotal biomolecules, with synergistic effects, especially in conjoint presence, on cellular pluripotency and regenerative capabilities. This randomized trial aimed to evaluate (VitA+C)-augmented injectable platelet-rich fibrin (i-PRF) versus i-PRF alone with a modified minimally invasive surgical technique (M-MIST) in periodontal intraosseous defects in patients with stage III periodontitis. METHODS: This parallel group, two-arm, triple-blinded, randomized controlled trial included patients with stage III grade B periodontitis (n = 28) randomly allocated to the test (VitA+C/i-PRF+M-MIST; n = 14) or the control (i-PRF+M-MIST; n = 14) group. The changes in radiographic linear defect depth (RLDD) (primary outcome), radiographic bone fill (RBF), and radiographic bone density (RBD) were recorded at baseline, 6, and 9 months. Clinical attachment level (CAL), probing depth (PD), gingival margin level (GML), plaque index (PI), and gingival index (GI; secondary outcomes) were recorded at baseline, 3 6, and 9 months. The in vitro release kinetics of VitA and VitC from the i-PRF were characterized over 7 days using high-performance liquid chromatography (HLPC). RESULTS: VitA+C/i-PRF+M-MIST demonstrated a significantly higher RLDD-reduction at 6 months and a higher RBF percentage at 6 and 9 months compared with i-PRF+M-MIST (p < 0.05), with no intergroup differences regarding RBD. Both groups independently demonstrated significant improvements in CAL, PD, GML, RLDD, and BDA over time (p < 0.05). Significantly higher CAL-gain and PD-reduction were evident in the VitA+C/i-PRF+M-MIST group at 9 months (p < 0.05). CONCLUSIONS: I-PRF with M-MIST significantly enhance periodontal clinical and radiographic parameters over time. Conjoint vitamin A/C augmentation of i-PRF at the described concentration results in significantly greater improvement in radiographic and clinical parameters of intraosseous defects compared with i-PRF alone. CLINICAL TRIAL REGISTRATION: This study was registered in the US National Institutes of Health Clinical Trials Registry (NCT05499598; https://www. CLINICALTRIALS: gov/). Plain Language Summary: Platelet‐rich

Cancer development arises from dynamic interactions between inherited susceptibility and modifiable environmental exposures, among which diet plays a central role. Carotenoids, lipophilic plant-derived pigments including lycopene, α-carotene, and β-carotene, and retinoids, the vitamin A derivatives that regulate gene transcription via retinoic acid receptors (RARs) and retinoid X receptors (RXRs), have been extensively investigated for their chemopreventive and therapeutic potential. This review aims to provide an integrated, mechanism-based synthesis of the roles of lycopene, α- and β-carotene, and retinoids in cancer chemoprevention and to clarify the conditions under which they are most likely to be effective. Beyond summarizing established antioxidant and nuclear-receptor mechanisms, we highlight as a novel emphasis the epigenetic actions of these compounds, including effects on DNA methylation, histone modification, and microRNA regulation, and we integrate these with the well-recognized divergence between dietary and high-dose supplement outcomes. Experimental evidence demonstrates that carotenoids modulate oxidative stress, inflammation, proliferation, apoptosis, angiogenesis, and metastasis through pathways such as Nrf2/ARE, NF-κB, STAT3, Akt/mTOR, MAPK, and Wnt/β-catenin. Lycopene, in particular, exhibits strong antioxidant capacity and multi-target signaling effects, while provitamin A carotenoids additionally influence retinoid-mediated transcriptional programs. Retinoids exert broader differentiation-inducing and antiproliferative effects through direct nuclear receptor signaling and represent one of the few successful differentiation therapies in oncology, most notably in acute promyelocytic leukemia. Epidemiologic studies generally associate higher dietary carotenoid intake with reduced risk of several malignancies, including prostate, breast, lung, colorectal, and gastric cancers. However, randomized trials of isolated high-dose supplementation, particularly β-carotene in smokers, have demonstrated null or harmful effects, highlighting a critical divergence between whole-food dietary patterns and pharmacologic supplementation. In conclusion, carot

BACKGROUND: All-trans retinoic acid (ATRA) is an essential agent in the treatment of acute promyelocytic leukemia (APL). However, careful monitoring is required due to its potential side effects, particularly intracranial hypertension (IH). CASE PRESENTATION: Here, we report a 15-year-old girl who presented with headache, blurred vision, vomiting, and was found to have left homonymous hemianopsia and an acute cerebral infarct. Etiological investigations revealed acute promyelocytic leukemia and treatment with ATRA was initiated. However, this treatment was complicated by repetitive episodes of IH, which improved with discontinuation of ATRA but recurred whenever reinitiation was attempted. Despite this side effect, the patient was able to complete the planned ATRA course under medical treatment of IH, guided by retinal nerve fiber layer (RNFL) thickness measured using optical coherence tomography (OCT). CONCLUSIONS: Changes in papilledema were detected on OCT earlier than on clinical examination. This case illustrates the reversibility of IH secondary to ATRA therapy, the feasibility of completing ATRA treatment despite the side effect of IH, the importance of medical treatment for IH in combination with appropriate dose adjustments, and the accuracy and convenience of RNFL thickness as a biomarker for treatment efficiency. Managing IH in the context of a chronic systemic disorder requires a collaborative approach, close follow-up, and individualized management.

Cancer stem-like cells contribute to innate tumour immunoresistance and an immunosuppressive tumour microenvironment, leading to poor responses to immune checkpoint inhibitors. Chemotherapeutic agents can elicit tumour immunogenicity by inducing immunogenic cell death to reinforce the therapeutic efficacies of immune checkpoint inhibitors, but suffer from inefficient immunogenic cell death activation in highly resistant cancer stem-like cells. Here we report an immunostimulatory lyotropic liquid-crystal-based lipogel for localized co-delivery of all-trans retinoic acid, a differentiation-inducing drug, and doxorubicin, an immunogenic-cell-death-inducing chemotherapeutic agent with distinct release kinetics. The lipogel is tailored to release the combinatorial drugs in a differential and sustained manner, which fulfils the requirement for enhanced drug synergism in promoting the immunogenic cell death of cancer stem-like cells. Local implantation of the immunostimulatory lipogel elicits an antitumour immune response that is further augmented by an immune checkpoint inhibitor to suppress tumour growth and metastasis, as well as to prevent post-surgical recurrence in murine models of high-stemness tumours. © 2026. The Author(s), under exclusive licence to Springer Nature Limited.

BackgroundChildren undergoing chemotherapy often experience gastrointestinal (GI) symptoms, negatively impacting health-related quality of life (HRQOL). Although macro- and micronutrients have been associated with GI symptoms and HRQOL following cancer diagnosis, more evidence is needed in pediatric oncology populations. This study examines how dietary intake is associated with GI symptoms and HRQOL in children with solid tumors undergoing chemotherapy.MethodThis secondary analysis used the Block Kids Food Screener to assess intake of macro- and micronutrients; the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events to measure GI symptoms; and the PedsQL 4.0 to evaluate HRQOL. Logistic and adjusted linear regression models were used to examine how dietary intake was associated with GI symptoms and HRQOL.ResultsThis study included 57 children with a mean age of 13.8 years (SD = 3.5). The majority were male (64.9%) and non-Hispanic White (43.9%). Increased vitamin C was associated with reduced nausea, while increased carbohydrates and beta-carotene were correlated with reduced diarrhea and increased vitamin E with reduced constipation. Increased total fat increased the odds of diarrhea. Higher protein and selenium and lower carbohydrates and vitamin C were associated with better physical HRQOL. A positive association between vitamin A and social HRQOL was noted.ConclusionHigher intakes of carbohydrates, beta-carotene, vitamin C, and vitamin E and lower intake of fat were associated with fewer GI symptoms, while greater consumption of protein, selenium, and vitamin A and lower carbohydrates were linked to improved HRQOL. Findings provide preliminary evidence for development of nutritional plans for pediatric patients undergoing chemotherapy.

OBJECTIVE: To evaluate the diagnostic performance of fecal elastase (FE) in exocrine pancreatic insufficiency (EPI) and examine the risk factors for EPI in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). STUDY DESIGN: We analyzed prospectively collected demographic, clinical, and EPI data of children with ARP or CP (n = 1007) enrolled in the INSPPIRE-2 (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) consortium. FE performance was assessed against individual markers of fat malabsorption and a composite reference standard in which the presence of any 1 of the following was considered consistent with fat malabsorption in lieu of a gold-standard pancreas function test: (1) clinical diagnosis of EPI, (2) vitamin A or E deficiency, or (3) body mass index z-score ≤-2. Cox regression models were used to identify predictors of EPI. RESULTS: EPI was diagnosed in 195/1007 (19.4%) children with ARP/CP, with FE being the most commonly used diagnostic tool. FE demonstrated low sensitivity (55.8% and 65.1%), moderate specificity (82.8% and 75.5%), and a high negative predictive value (92% and 93%), at cut-offs of 100 μg/g and 200 μg/g stool, respectively, in detecting at least 1 marker of fat malabsorption. The 7-year cumulative incidence of EPI after the first pancreatitis episode was 24%. Genetic risk factors were associated with earlier progression to EPI (hazard ratio 1.56; 95% confidence interval 1.02-2.39). CONCLUSIONS: EPI affects nearly 20% of children with ARP/CP. FE is a valuable diagnostic tool in ruling out EPI. Children with genetic risk factors need closer surveillance due to an increased risk for developing EPI.

This study aimed to determine if habitual intake of key dietary antioxidants, both individually and collectively, is associated with all-cause and cause-specific mortality among U.S. adults, given that oxidative stress heightens cardiovascular and cancer mortality risk. This prospective cohort study analysed 34,955 participants from the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Intakes of vitamins A, C, E, zinc, selenium, and carotenoids were assessed, and a composite dietary antioxidant index (CDAI) was calculated. The principal results, from 347,580 person-years of follow-up where 4,456 deaths occurred (1,368 CVD; 1,038 cancer), showed significant associations. Compared with the lowest intake quintile, the highest quintile of vitamin E was associated with lower all-cause mortality (HR: 0.69, 95% CI: 0.58-0.83) and CVD mortality (HR: 0.67, 0.48-0.92). High carotenoid intake was inversely associated with all-cause mortality (HR: 0.77, 0.67-0.88). Participants in the highest CDAI quintile experienced an 18% lower risk of all-cause mortality (HR: 0.82, 0.70-0.97) and a 39% lower risk of cancer mortality (HR: 0.61, 0.45-0.84). Dose-response relationships for vitamins A, C, selenium, and zinc were U-or L-shaped, and WQS analyses assigned the greatest weights to vitamin A or C. In conclusion, while individual antioxidants like vitamin E show strong protective associations, the evidence collectively suggests that greater overall antioxidant exposure from a varied diet is linked to materially lower risks of death. This reinforces that focusing on diets rich in diverse antioxidant sources is superior to single-nutrient strategies. © The Author(s) 2026.

Tretinoin (all-trans-retinoic acid, ATRA) is an established therapy for acute promyelocytic leukemia (APL) and neuroblastoma (NB); however, its broader oncological application is limited by poor bioavailability and rapid resistance development. In this study, we developed lipidic ester derivatives of ATRA as a potential prodrug approach aimed at modulating its physicochemical and biological properties. Three ATRA derivatives were evaluated in vitro in six human cancer cell lines: leukemia (MV4-11), gastric (AGS), colon (HT-29), lung (A549), and breast cancer cells (MCF-7, MDA-MB-468). Cytotoxicity toward normal human breast epithelial cells (MCF-10A) was also assessed. Among the synthesized derivatives, cetyl all-trans-retinoate (ATRA-CA) exhibited the strongest anticancer activity, showing up to threefold greater potency than ATRA, with inhibitory concentrations ranging from 1.34 to 23.1 µM and minimal toxicity toward normal cells. Moreover, ATRA-CA enhanced the efficacy of conventional chemotherapeutics. In A549 cells, treatment with 5 and 10 µM ATRA-CA reduced the cisplatin IC50 from 25.7 ± 3.2 µM to 9.1 ± 3.0 and 5.9 ± 1.5 µM, corresponding to synergistic (CI = 0.63) and additive (CI = 0.88) effects, respectively. Similar effects were observed in MCF-7 cells and in combination with doxorubicin and paclitaxel.

Cytotoxic CD8⁺ T lymphocytes eliminate pathogen-infected and malignant cells through migration to affected tissues, cytokine production, and cytotoxic activity. A mounting body of evidence indicates that CD8 T cell differentiation into functionally different subsets, such as effector, memory, tissue-resident memory, and exhausted T cells, is controlled by a group of nuclear receptors (NRs). NRs sense signals from various physiological and environmental cues, such as nutritional, endocrine, stress/circadian, and metabolic signals, and translate them into gene-regulatory decisions. NRs act through direct and indirect DNA binding, corepressor-coactivator exchange, and transrepression of effector-associated transcription factors, thereby reshaping chromatin accessibility and metabolic programs during CD8 T cell differentiation. This review highlights major CD8 T cell-regulating pathways involving vitamin A-sensing RAR-α, sterol-responsive LXR-β and ROR-α, orphan NR4A proteins; vitamin D receptor (VDR), glucocorticoid receptor (GR), and androgen receptor (AR). Understanding the shared and separable functions of NRs and their ligands provides insights into therapeutic strategies, such as pharmacologic modulation, checkpoint blockade, and chimeric antigen receptor T cell therapies, to promote durable antitumor and antiviral CD8 T cell activities. © The Author(s) 2026. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

CLINICAL CHARACTERISTICS: Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include progressive obstructive pulmonary disease with bronchiectasis, recurrent sinusitis and bronchitis, exocrine pancreatic deficiency and malnutrition, pancreatitis, gastrointestinal manifestations (meconium ileus, rectal prolapse, distal intestinal obstructive syndrome), liver disease, diabetes, osteopenia/osteoporosis, male infertility due to hypoplasia or aplasia of the vas deferens, and reduced fertility or infertility in some women. By 2025, 95% of individuals with CF were eligible for targeted therapies, which has significantly altered the long-term course of the disease with a reduced overall disease burden. The impact is most evident in fewer hospitalizations, reduced clinic visits, and a decreased need for lung transplantation, all of which are associated with improved survival. While the CF disease phenotype has overall become less severe and more heterogenous in the era of highly effective CF transmembrane conductance regulator (CFTR) modulator therapy, pulmonary disease is the major cause of morbidity and mortality in CF. DIAGNOSIS/TESTING: The diagnosis of CF is established in a proband with (1) elevated immunoreactive trypsinogen on newborn screening, signs and/or symptoms suggestive of CF, or family history of CF; AND (2) evidence of an abnormality in CFTR function: sweat chloride ≥60 mmol/L on sweat chloride testing, biallelic CFTR CF-causing pathogenic variants, or nasal transmembrane epithelial potential difference measurement consistent with CF. MANAGEMENT: Targeted therapies: CFTR modulator therapy is available for individuals with responsive CFTR variants. These should be prescribed and managed by a clinician with CF expertise, particularly when initiating therapy. Supportive care: Newborns – management by a CF specialist or CF care center; airway clearance instruction; encouraging feeding with breast milk; routine vaccinations; contact precautions with every clinical encounter; antibiotics for bacterial suppression and treatment; nutrition

Drug resistance in acute promyelocytic leukemia (APL) remains clinically challenging despite the success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapy. Existing explanations, including promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) mutations and alterations in individual death pathways, do not fully account for the heterogeneity of resistant phenotypes. This review proposes regulated cell death network (RCDN) remodeling as a testable framework for APL resistance. RCDN remodeling is defined as coordinated changes in network coupling, stress routing, and cellular death thresholds. We hypothesize that resistance emerges from coordinated adaptation across redox, survival signaling, and mitochondrial gating, rather than from defects in any single pathway. This predicts coupled shifts across multiple death modules and non-additive responses to combinatorial perturbations, distinguishing network-level remodeling from pathway-specific resistance. We further define experimental criteria for distinguishing network-level remodeling from pathway-specific resistance and discuss Tanshinone IIA (Tan IIA) as a preclinical multi-node perturbation probe.

Photodynamic therapy (PDT) is a minimally invasive anticancer modality based on the interaction of a photosensitizer, light of an appropriate wavelength, and molecular oxygen, resulting in reactive oxygen species (ROS)-mediated tumor injury. This review discusses PDT as a mechanism-dependent therapeutic platform and evaluates how photosensitizers, vitamin A, vitamin D, nanotechnology, and combination strategies may influence its efficacy. The article synthesizes mechanistic and translational evidence concerning photosensitizer activation, ROS generation, tumor cell death, vascular shutdown, immunogenic cell death, and clinically relevant PDT applications. Particular attention is given to the divergent roles of vitamin A and vitamin D. Mechanistic and limited experimental evidence indicates that the effects of vitamin A-related compounds on PDT are heterogeneous and context-dependent. Selected compounds may attenuate PDT through antioxidant or cytoprotective mechanisms, whereas enhancement has also been reported for specific retinoid-photosensitizer combinations; however, clinical evidence remains limited. In contrast, vitamin D may enhance ALA/MAL-PDT by increasing intracellular protoporphyrin IX accumulation through modulation of the heme biosynthetic pathway, especially in non-melanoma skin cancer contexts. Nanocarriers, targeted photosensitizers, oxygen-modulating platforms, chemotherapy, and immunotherapy may further improve PDT when selected according to mechanistic compatibility. Overall, PDT combination design should be guided by whether adjunctive agents support or undermine photosensitizer accumulation, oxygen availability, ROS-mediated cytotoxicity, and immune activation.

Acute promyelocytic leukemia (APL) predominantly affects younger patients with significantly prolonged survival. Therefore, controlling the incidence of secondary hematological malignancies represents a crucial therapeutic goal. Secondary, acute T-lymphoblastic leukemia (T-ALL) following APL is rare and confers a poor prognosis, with only 2 cases reported to date. Herein, we present a case of a young female with APL who attained complete remission (CR) after receiving dual induction therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), followed by standard consolidation and maintenance treatment cycles. After discontinuing chemotherapy for 26 months, the patient conceived naturally and was later diagnosed with T-ALL in the first trimester of pregnancy. She attained a second CR after receiving the VDCLP chemotherapy regimen (vincristine+daunorubicin+cyclophosphamide+L-asparaginase+prednisone). She subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and remained in sustained CR at the 18-month follow-up time point. For patients with T-ALL secondary to APL after treatment remission, early diagnosis combined with the VDCLP regimen and allo-HSCT demonstrated certain therapeutic efficacy. © 2026 by the Association of Clinical Scientists, Inc.

BACKGROUND: Emerging evidence suggests that vitamin intake may be associated with colorectal cancer (CRC) risk, yet prospective studies on CRC incidence and mortality remain limited. We therefore investigated the associations between vitamin intake and CRC incidence and mortality in a large cohort of US adults. METHODS: We included 101,692 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Vitamin intake (including dietary and supplement sources) was assessed using the Dietary History Questionnaire based on the USDA 1994-1996 survey and the University of Minnesota Nutrition Data System for Research. Prospective associations with CRC incidence and mortality were estimated using Cox proportional hazards regression models. Restricted cubic spline regression was applied to evaluate potential nonlinear relationships. Subgroup analyses were conducted to explore potential effect modifiers of CRC incidence and mortality. RESULTS: During 896,655 person-years of follow-up (mean 8.82 years), 1,085 participants were diagnosed with CRC, and 529 CRC deaths occurred during 1,533,506 person-years of follow-up (mean 15.08 years). In fully adjusted models, higher intakes of vitamin A (HR = 0.75, 95% CI: 0.60-0.93; P-trend = 0.005), vitamin B6 (HR = 0.74, 95% CI: 0.61-0.90; P-trend = 0.015), vitamin D (HR = 0.77, 95% CI: 0.64-0.93; P-trend = 0.022), and vitamin E (HR = 0.81, 95% CI: 0.68-0.97; P-trend = 0.008) were significantly associated with a lower incidence of CRC. In addition, higher intakes of vitamins A, B6, and C were significantly associated with reduced CRC mortality. No significant associations were observed for vitamin B12 with CRC incidence and mortality. Sensitivity and subgroup analyses supported the robustness of these findings. CONCLUSION: In conclusion, higher intake of vitamins A, B6, C, D, and E is associated with an decreased risk of CRC incidence and mortality. Appropriate vitamin intake may represent a modifiable factor for the primary prevention of CRC.

Retinoic acid, the active metabolite of vitamin A, is a pleiotropic signaling molecule that integrates developmental, homeostatic, and pathological processes across multiple organ systems. During embryogenesis, RA gradients regulate tissue patterning and lineage commitment, while in adult tissues, RA contributes to epithelial integrity, stem-cell regulation, immune homeostasis, and metabolic balance. Disruption of retinoic acid synthesis, degradation, receptor signaling, or pathway crosstalk underlies a broad spectrum of diseases, including congenital malformations, autoimmune and inflammatory conditions, neurodegenerative disorders, cardiovascular disease, pulmonary and ophthalmic pathologies, and cancer. In the tumor, RA signaling exhibits remarkable plasticity, acting as either a differentiation inducer or a stemness-maintaining factor, depending on genetic, metabolic, and microenvironmental cues. Therapeutically, retinoid-based interventions have revolutionized the treatment of acute promyelocytic leukemia. Still, their broader application has been constrained by resistance mechanisms, pharmacokinetic limitations, tissue-specific effects, and the dual nature of retinoic acid signaling across different disease states. Advances in organoid systems, single-cell and spatial transcriptomics, and multimodal epigenomics are revealing highly localized and cell-type specific retinoid responses, supporting a systems-level model of RA signaling. This framework defines "retinoid endotypes" as tissue- and stage-specific states shaped by retinoid metabolic niches, chromatin state, and microenvironmental organization, with potential to guide patient stratification and precision retinoid therapy. © 2026. The Author(s).

BACKGROUND: Dietary carotenoids and vitamin A may contribute to gastric cancer (GC) prevention through anti-inflammatory and antioxidant mechanisms; however, epidemiological evidence remains limited. We investigated the associations of total and individual carotenoid and vitamin A intakes with GC and their relationships with inflammatory/oxidative stress biomarkers. METHODS: The case-control study included 177 adults (82 GC incidence cases/95 controls). A validated 168-item food frequency questionnaire assessed dietary intakes of individual carotenoids and preformed vitamin A. Metabolic biomarkers, lipid profile, inflammatory/oxidative stress markers [e.g., high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukins (6/1β/10/4), total antioxidant capacity (TAC), and malondialdehyde (MDA)] were measured. Multivariable logistic regression models estimated odds ratios (ORs) for GC risk; linear regression models examined associations between carotenoid intakes and biomarkers. RESULTS: Total carotenoid (mg/d; OR: 0.86, 95%CI: 0.81-0.98), β-carotene (mg/d; OR: 0.77, 95%CI: 0.65-0.90) and vitamin A (mg RAE/d; OR: 0.29, 95%CI: 0.09-0.95) intakes, as continuous variables, and also as binary variables (based on the median cut-offs), in all models (also adjusted for age, sex, smoking, education, marital status, physical activity, cancer history, H. pylori, NSAIDs intake, body mass index, total energy intake), were inversely associated with GC odds. In fully adjusted models, higher total carotenoid intake (mg/d) was associated with lower LDL-c (β: -1.60, 95%CI: -2.91, -0.25) and IL-6 (β: -7.92, 95%CI: -14.00, -2.00); lycopene (mg/d) with higher LDL-c (β: 2.030, 95%CI: 0.27, 4.31) and vitamin A intake (mg RAE/d) with lower TNF-α (β: -12.12, 95%CI: -24.71, -0.47) and higher TAC (β: 0.64, 95%CI: 0.001, 1.27). CONCLUSION: Higher intakes of total carotenoids and vitamin A were associated with lower odds of GC and more favorable profiles of inflammatory/oxidative stress biomarkers. These findings support an inverse association between carotenoid-rich dietary patterns and gastric carcinogenesis.

Persistently poor glioblastoma (GBM) survival necessitates better elucidation of tumor drug responses. After observing that low curcumin and all-trans retinoic acid (ATRA) doses stimulated cell proliferation and counteracted each other's high-dose antiproliferative effects in U87 GBM cells, drug influences on cell growth, migration, and death and the antiproliferative interaction proteome were further studied. Cell proliferation and migration were assessed by xCELLigence Real-Time Cell Analysis (RTCA). Cell death was defined using flow cytometry. Drug interactions were determined with CompuSyn software (version 1.0). Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), High-Performance Liquid Chromatography (HPLC), and SequestHT software (version 1.4) were utilized for peptide generation and identification. ATRA at high doses inhibited cell growth and migration more efficiently. Curcumin was more proliferative and antagonistic against anti-growth effects at low doses. Migration inhibition and apoptosis occurred synergistically at the highest drug doses. ATRA influenced the proteome more remarkably, reducing Transforming Growth Factor Beta Induced (TGFBI), Phosphoglycerate Dehydrogenase (PHGDH), tenascin, and Sequestosome 1 (SQSTM1). These effects were alleviated by curcumin, except for SQSTM1. Uveal Autoantigen With Coiled-Coil Domains And Ankyrin Repeats (UACA) and Sad1 And UNC84 Domain Containing 2 (SUN2) were increased by ATRA and curcumin, and to a lesser extent by the combination. Hexokinase 2 (HXK2) was increased by curcumin and the combination. Heme Oxygenase 1 (HMOX1) was depleted by the combination, but not by the single agents. SQSTM1 and HMOX1 reductions may mediate anticancer synergism, while the remaining changes may indicate ongoing hormetic pathways not reflected in cell counts.

Liver fibrosis and its terminal stage, cirrhosis, represent a major cause of morbidity and mortality related to hepatic pathologies. Activated hepatic stellate cells (aHSCs) are the principal drivers of fibrogenesis and therefore constitute key therapeutic targets. Lanifibranor, a pan-peroxisome proliferator-activated receptor agonist, has shown promising antifibrotic efficacy; however, its clinical application is limited by rapid systemic clearance and insufficient accumulation in fibrotic liver tissue. In this study, we report an aHSC-targeted nanoplatform for lanifibranor delivery based on vitamin A-functionalized two-dimensional iron sulfide nanosheets (FeS-VA@lanifibranor, FVL). Lanifibranor was electrostatically loaded onto vitamin A-modified FeS nanosheets, enabling selective uptake by aHSCs and enhancing hepatic accumulation of lanifibranor. FVL significantly downregulated the expression of key fibrogenic markers and markedly reduced collagen accumulation. Mechanistically, the therapeutic efficacy of FVL arises from a dual-action mechanism: inhibition of SMAD2/3 phosphorylation within the transforming growth factor-β (TGF-β) signaling pathway and induction of ferroptosis in aHSCs. In conclusion, this study provides an effective aHSC-specific nanotherapeutic strategy for liver fibrosis treatment and highlights the translational potential of FVL nanoplatforms for targeted antifibrotic therapy. © 2026 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.

Selenium is an essential dietary micronutrient, exerting beneficial effects over a limited range of concentrations. Insufficient dietary intake of selenium increases the risk of type 2 diabetes, infertility, immune dysfunction, prostate cancer, cognitive decline, prostate cancer, colorectal cancer in females, skeletal muscle disorders, overall mortality and an endemic cardiomyopathy known as Keshan disease. Excessive intake of selenium is toxic, leading to a condition termed selenosis, that is associated with damage to the nails, dermatitis, alopecia, central nervous system dysfunction and death. Selenium exerts its biological effects through low-molecular weight molecules, through a small family of selenoproteins which contain the 21st amino acid selenocysteine, and via selenium-binding proteins, in which an atom of selenium is covalently bound to a cysteine residue. In addition to being regulated by body selenium status, the abundance and function of these biomolecules can be controlled by other dietary components (including copper, zinc, folic acid, resveratrol, vitamin A and α-linoleic acid) and other factors, such as exercise and caloric restriction. This review comprehensively surveys the effects of selenium-containing biomolecules on aging and aims to generate rationales underpinning the biphasic effects of this element on life-span, health-span and disease. This will provide a framework for understanding the effects of selenium on mechanisms of aging, as the starting point for development of interventions that will promote longevity and health-span.

Erratum in J Exp Med. 2026 Oct 5;223(10):e2025233309092026c. doi: 10.1084/jem.2025233309092026c. While acute promyelocytic leukemia (APL) is always driven by fusions involving one of the three retinoic acid receptors, why PML and RARA are the preferred fusion partners has remained largely unsettled. Here, we demonstrate that corepressor (NCoR) binding onto the RARA moiety of PML::RARA is required for hematopoietic progenitor immortalization. We establish that PML-mediated tethering of the UBC9 SUMO-conjugating enzyme onto PML::RARA enforces SUMO2 conjugation of multiple RARA partner proteins, notably the NCoR complex, boosting its repressive power. PML mutants that fail to recruit UBC9 yield PML::RARA fusions that promote neither NCoR sumoylation nor transformation. Conversely, direct UBC9/RARA fusion drives both efficient corepressor complex sumoylation and immortalization. Sumoylation inhibitors reactivate retinoic acid target genes in PML::RARA-expressing, but not in RARA-expressing, progenitors and trigger APL differentiation. Thus, fusion of PML to RARA entails an unexpected gain of function that boosts RARA-mediated transcriptional repression through sumoylation of PML::RARA-bound proteins, explaining the recurrent implication of PML and RARA in APL pathogenesis. © 2026 Wu et al.

RARγ is expressed during embryogenesis by stem/primitive progenitor cells, indicating a role in controlling their development. Supporting this view is that a physiological level of 10 nM of the RARγ agonist AGN205327 blocked stem/progenitor cell differentiation during zebrafish embryogenesis, mouse gastruloid development, and adult chondro- and osteogenesis. Similarly, transgene expression of RARγ or the use of the RARγ agonist CD437 enhanced the generation of induced pluripotent stem cells (iPSCs) from human and mouse somatic cells. RARγ regulates many events that control the behavior of stem/progenitor cells regarding whether they develop to give rise to mature cells. RARγ positively regulates the expressions of NOTCH ligands and their receptors, transforming growth factors (TGFs), and molecules pertaining to cell identity, extracellular matrix communication, and all-trans retinoic acid synthesis and catabolism. The genes that are repressed by RARγ include RARγ, PPARγ, and RXRα. RARγ integrates into Wnt/β-catenin and TGFβ signaling by acting as a co-factor to the gene co-activator β-catenin and transcription factor Smad3, respectively. Within the cytoplasm, RARγ regulates Akt/NF-κB signaling. As a model, we propose that ATRA ligand-activated RARγ acts as a gatekeeper to stem cell developmental progression during embryogenesis and that this role extends to stem/progenitor cell homeostasis within adult tissues.

Terminal exhaustion of CD8⁺ T cells limits the efficacy of immune checkpoint blockade (ICB), particularly in glioblastoma, which is characterized by an immunosuppressive tumor microenvironment. Therefore, a better understanding of the regulators of terminal exhaustion could overcome intrinsic resistance to ICB and improve the efficacy of immunotherapy. In this study, we report that all-trans retinoic acid (ATRA) suppresses CD8⁺ T-cell terminal exhaustion. The administration of ATRA during CD8⁺ T-cell activation in vitro conferred resistance to terminal exhaustion and preserved effector cytokine production and effector function. Mechanistically, ATRA selectively induced the expression of the long isoform of T-cell factor 1 (TCF-1βBD) through activation of the canonical WNT/β-catenin pathway. In a mouse glioma model, adoptively transferred ATRA-conditioned CD8⁺ T cells exhibited increased TCF-1βBD and β-catenin expression and resistance to exhaustion, which led to superior tumor-infiltrating CD8+ T-cell polyfunctionality and enhanced glioma suppression. Importantly, oral administration of ATRA also suppressed terminal exhaustion of tumor-infiltrating CD8+ T cells and synergized with anti-PD-1 therapy, overcoming resistance to immune checkpoint blockade (ICB) in two mouse models of glioma. Combined ATRA and anti-PD-1 treatment also displayed synergistic therapeutic potential by significantly reducing recurrence in a mouse model of glioma that had undergone surgical resection. Single-cell transcriptomic analysis of glioblastoma patients receiving anti-PD-1 therapy revealed that CD8⁺ T cells from responders were enriched in genes that respond to retinoic acid and WNT-associated genes, which correlated with improved survival. These findings establish ATRA as a modulator of CD8⁺ T-cell exhaustion through the induction of WNT/β-catenin-dependent TCF-1βBD expression, suggesting that ATRA has therapeutic potential for overcoming resistance to ICB in glioma. © 2026. The Author(s).