Retinoic acid in health and disease.

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.