Retinoid biology from embryonic patterning to adult tissue homeostasis: metabolism, RAR signaling, disease mechanisms, and clinical translation.

Vitamin A gives rise to functionally distinct retinoids that regulate vision, embryonic patterning, and adult tissue homeostasis. The principal endogenous transcriptional ligand, all-trans-retinoic acid (ATRA), activates RARα, RARβ, and RARγ within RAR-RXR heterodimers; this mechanism is distinct from direct RXR activation by synthetic rexinoids. Tissue retinoic acid homeostasis is maintained through tightly coordinated regulation of vitamin A absorption, storage, transport, intracellular metabolism, and degradation. We integrate these pathways across embryonic development and adult physiology, with emphasis on the eye, adipose tissue-liver immunometabolic axis, pancreas, lung, heart, and skin. Recent single-cell, spatial, metabolomic, and multi-omic studies show that retinoid responses depend on cell state, tissue architecture, dose, and timing. We further compare retinoid and rexinoid therapies across chromophore replacement, acute promyelocytic leukemia, dermatologic and musculoskeletal disorders, and RXR-directed indications, focusing on receptor selectivity, efficacy, pharmacokinetics, resistance, and toxicity. Integrating quantitative retinoid metabolomics with spatial omics, causal perturbation, and validated computational models should enable more precise and safer therapeutic modulation of retinoid signaling.