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.

Intestinal dendritic cells (DCs) play a central role in maintaining gut tolerance through priming of peripheral regulatory T cells (pTreg cells). DC tolerogenicity has been linked to catabolic metabolism, but the role of AMP-activated kinase (AMPK), a key regulator of catabolic metabolism, in regulating intestinal tolerance remains unclear. We found high AMPK activation in intestinal DCs, and loss of AMPKα1 in CD11c-expressing cells (CD11c[ΔAMPKα1]) led to reduced frequencies of intestinal RALDH[+] CD103[+] cDC2s. This was associated with reduced pTreg cell induction and consequently increased type 2 immunity in models of intestinal helminth infection. Correspondingly, CD103[+] cDC2s from helminth-infected CD11c[ΔAMPKα1] mice failed to prime Treg cells ex vivo. Similarly, Treg cell induction by AMPK-deficient human retinoic acid (RA)-induced tolerogenic CD103[+] DCs was compromised. Mechanistically, AMPK underpinned RA-driven tolerogenicity by promoting RALDH activity and TGF-β secretion in a FoxO3-dependent manner, independent from metabolic reprogramming. Our findings identify AMPK as a key regulator of intestinal DC-mediated tolerance and as a therapeutic target to counter intestinal inflammatory disease.

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.

Müller glia are instrumental macroglia of the vertebrate retina, once thought to be a homogeneous population. Now Müller glia are generally accepted as transcriptionally heterogeneous, and new evidence suggests functional diversity may exist in the way these cells respond to retinal injury. It remains unclear, however, whether this functional heterogeneity is limited to a transient phenotype that stems from injury or a fundamental feature of the healthy retina. Here, we investigate Müller glia heterogeneity in the uninjured zebrafish retina across development and adulthood using a comprehensive single-cell transcriptomic atlas of the 5 days post-fertilization (dpf) eye, validated in vivo and integrated with 9 dpf and adult datasets. We reveal three constitutive subpopulations of Müller glia that persist from early larval stages into adulthood: (1) a proliferative and immature population in both the peripheral and central retina; (2) a novel cohort of neuron-associated Müller glia that express coherent transcriptional programs specific to distinct neuronal subtypes, including retinal ganglion, amacrine, and horizontal cells; and (3) spatially distinct Müller glia subsets that appear to define a dorso-ventral axis of retinoic acid metabolism, bisected by a novel cyp26c1-expressing equatorial domain. Finally, cross-species analysis reveals that while neuron-associated programs are evolutionarily conserved in mammals, the spatial patterning of morphogens in adult retinae may be specific to the teleost lineage. Collectively, these findings provide robust evidence for intrinsic functional heterogeneity in the uninjured vertebrate retina, reframing Müller glia from a general support population to a specialized cellular network that actively maintains retinal geography and function.

Fecal microbiota transplantation (FMT) shows inconsistent clinical efficacy in treating obesity, and the specific microbial determinants dictating its success remain poorly characterized. Our previous clinical FMT trial identified Phocaeicola vulgatus as a key microbe contributing to the therapeutic efficacy of obesity treatment. Here, to investigate its role in obesity, we established an independent clinical cohort comprising obese and lean individuals, revealing that the P. vulgatus-centered network and ornithine synthesis are impaired in the obese group. We then confirmed causality by utilizing a humanized rat model carrying microbiota from a P. vulgatus-deficient obese patient, demonstrating that P. vulgatus supplementation significantly mitigates HFD-induced obesity, including reductions in body weight and serum total cholesterol levels, as well as the alleviation of hepatic steatosis. To further explore the functional mechanisms of P. vulgatus, integrated metagenomic and metabolomic analyses revealed a potential functional association between P. vulgatus and Phascolarctobacterium faecium that is associated with enhanced intestinal arginine biosynthesis and systemic availability. Furthermore, hepatic transcriptomics linked these elevated circulating arginine levels to the upregulation of retinoic acid (RA) signaling. Taken together, our findings outline a potential microbial-host network wherein P. vulgatus mitigates obesity via the arginine-RA axis, providing a valuable scientific basis for exploring this strain as a probiotic candidate for metabolic health.

Disseminated superficial actinic porokeratosis (DSAP) is a rare, UV-associated keratinization disorder that causes significant cosmetic impairment. In recent years, a new pathogenesis-based therapeutic approach using topical formulations containing statins and cholesterol has been introduced. We report on a 56-year-old woman who had DSAP on both forearms and lower legs for 6 years. Clinically, she presented with multiple, extensor-surfaced, pale erythematous, flat plaques with collarette-like scaling. Previous treatments with topical tretinoin and photodynamic therapy had not resulted in any significant improvement. After 4 months of treatment with a 2% simvastatin/2% cholesterol cream (SC cream) applied twice daily, the lesions had nearly completely resolved. The findings improved on the Investigator Global Assessment (IGA) scale from 3/5 to 1/5. Over a 15-month follow-up period, the improvement remained stable with continued therapy. The patient did not experience any side effects. The favorable clinical course prompted a retrospective evaluation of all DSAP patients treated with SC cream at our institution. A total of 14 patients were surveyed using questionnaires regarding efficacy, tolerability, and satisfaction. The mean duration of treatment was 9 months; 12 patients were treated for at least 6 months, and 5 patients for at least 12 months. With the exception of 1 patient, all reported clinical improvement. The average subjective improvement was over 50% after 6 months and approximately 70% after 12 months. No loss of efficacy was observed. One patient developed mild, self-limiting contact dermatitis without discontinuing therapy. Laboratory tests in 6 patients revealed no clinically relevant abnormalities. Our observations support the sustained efficacy and good tolerability of the SC cream during prolonged use. At the same time, potential contact dermatitis should be considered as a relevant adverse drug reaction. These observations are consistent with the recently published results of the Mainz working group led by Prof. Staubach-Renz, which are also discussed in our article.

Multiple signaling pathways and transcription factors (TFs) establish organ domains in the developing gastrointestinal tract. How these are integrated into spatial-temporal networks to regulate organogenesis and how disruptions to those networks lead to congenital syndromes remain poorly understood. Using human pluripotent stem cell cultures and Xenopus embryos, we demonstrate that retinoic acid (RA) from the lateral plate mesoderm directly activates expression of the TF rfx6 in posterior foregut endoderm. Rfx6 subsequently promotes posterior foregut identity while suppressing Wnt-dependent hindgut and Bmp-dependent pharyngeal fates through direct and indirect mechanisms. Rfx6 can directly activate the expression of several key foregut TFs (onecut1 and pdx1) and Wnt antagonists (sfrp2/5) while indirectly restricting expression of Wnt and Bmp ligands. Rfx6 also directly suppresses transcription of the Wnt-dependent hindgut TF cdx2 and the Bmp-dependent pharyngeal TFs nkx2-5 and nkx2-6. Thus, Rfx6 acts at multiple levels to integrate RA, Wnt and Bmp activity into a network with lineage-promoting TFs to control gut tube patterning. These results provide insight into the molecular basis of Mitchell-Riley Syndrome congenital anomalies, which are caused by RFX6 mutations.

Retinoic acid (RA), a biologically active metabolite of vitamin A, regulates gene expression through retinoic acid receptor/retinoid X receptor (RAR/RXR)-dependent transcription and is important for various biological phenomena. To understand the role of forebrain RA signaling in synaptic plasticity and memory, we generated transgenic mice expressing a dominant-negative form of retinoic acid receptor α (dnRARα) in adult forebrain. We previously showed that dnRARα expression in the adult forebrain impairs α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission and long-term potentiation (LTP) in hippocampal CA1 neurons and hippocampus-dependent memory. To investigate the molecular basis of these impairments, we here examined expressions of synaptic plasticity-related molecules in the hippocampus of dnRARα mice. We found that protein levels of GluA1 and postsynaptic density protein 95 (PSD-95) were significantly reduced in the hippocampus of dnRARα mice in a dnRARα expression-dependent manner. To further examine protein expression changes in dnRARα mice, we performed proteome analysis and found that expression of actin-related protein 3 (ARP3), a molecule implicated in activity-dependent spine enlargement and maturation, was also reduced. Combined with our previous findings, these results suggest that forebrain RAR/RXR signaling is crucial for maintaining synaptic transmission, plasticity, and memory formation by upregulating GluA1, PSD-95, and ARP3.

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.

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-1[βBD]) through activation of the canonical WNT/β-catenin pathway. In a mouse glioma model, adoptively transferred ATRA-conditioned CD8[+] T cells exhibited increased TCF-1[βBD] 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-1[βBD] expression, suggesting that ATRA has therapeutic potential for overcoming resistance to ICB in glioma.

Large-scale production of cultivated meat will require robust myogenic differentiation of muscle stem cells (MuSCs) into muscle tissue using food-compatible cues. Retinoic acid (RA), a bioactive metabolite of dietary vitamin A, is an attractive candidate for this purpose. Here, we demonstrate that RA priming transitions fetal bovine MuSCs from a PAX7[+] proliferative state to an activated pre-differentiation program. The pro-myogenic effect observed in two-dimensional (2D) culture was recapitulated in three-dimensional (3D) scaffolds, where RA priming accelerated and enhanced myotube formation in a setting that is more relevant to tissue. This response required canonical retinoic acid receptor (RAR) signaling. RA-RAR signaling increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) and nuclear respiratory factor 1 (NRF1), which is consistent with enhanced mitochondrial biogenesis and improved mitochondrial function. These findings are supported by elevated mitochondrial membrane potential and higher levels of respiratory chain components, together with modest changes in mitochondrial dynamics. In parallel, RA reduced the expression of PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PRKN), and microtubule-associated protein 1 light chain 3 (LC3) and suppressed the transcriptional program associated with mitophagy. Taken together, these results suggest that the RA priming modulates mitochondrial function and quality-control pathways, reduces reliance on PINK1-PRKN-dependent mitophagy, and supports an activated, pro-myogenic primed state. This provides a food-compatible priming strategy with potential relevance for scalable cultivated beef production.

Basal cell carcinoma (BCC) is the most common skin malignancy, and surgical excision remains the first-line treatment for most lesions. However, therapeutic options for elderly patients who are unsuitable for or decline surgery are limited. Acitretin, a systemic retinoid, has shown potential antitumor effects, while topical tretinoin may enhance local therapeutic efficacy. We herein report an elderly patient with facial BCC presenting as an ulcerative lesion on the right forehead. Reflectance confocal microscopy revealed basaloid cells arranged in cord-like structures, and histopathological examination demonstrated nests of basaloid tumor cells with peripheral palisading and retraction clefts, confirming the diagnosis of nodular BCC. The patient was treated with oral acitretin in combination with topical 0.1% tretinoin cream. After 12 weeks of treatment, the ulcerative lesion showed near-complete healing with marked clinical improvement. During the treatment course, only mild adverse events, including skin dryness and cheilitis, were observed, and no significant laboratory abnormalities occurred. This case suggests that oral acitretin combined with topical 0.1% tretinoin cream may represent a feasible and well-tolerated nonsurgical option for selected elderly patients with facial BCC, and no recurrence was observed during the 4-month follow-up.