The role and mechanisms of vitamin A in suppressing hepatic stellate cell activation

Hepatic fibrosis (HF) is a key pathological process in chronic liver disease progression, driven by hepatic stellate cell (HSC) activation. Quiescent HSCs store vitamin A and maintain extracellular matrix homeostasis. Upon liver injury, HSCs transform into proliferative myofibroblasts, causing collagen deposition and tissue remodeling. This study investigates vitamin A’s role in HSC activation regulation through clinical and animal models linking vitamin A deficiency to HF severity, and mechanistic insights into how all-trans retinoic acid (ATRA) reverses HSC activation via ferroptosis and endoplasmic reticulum stress (ERS). Serum vitamin A levels were compared between 37 healthy controls and 43 chronic liver disease patients. 48 Balb/c mice fed standard or vitamin A-deficient diets for 4 weeks, followed by CCl4-induced HF. Liver function, histopathology (HE/Masson staining), and lipid metabolomics were analyzed. Mice received ATRA either concurrently with CCl4 (early) or post-fibrosis (late). HSC-T6/LX-2 cells were pretreated to induce quiescence, then activated with ferric ammonium citrate (FAC) and ATRA/ERS inhibitors. Mitochondrial function, lipid droplets, and ferroptosis markers were assessed. Clinical data showed significantly lower vitamin A in patients versus controls ( p < 0.0001).Vitamin A-deficient mice exhibited worse liver injury ( p < 0.05), collagen deposition, and iron accumulation under CCl4. Early ATRA intervention reduced fibrosis and ERS, while late intervention had marginal effects. ATRA suppressed mitochondrial hyperactivity and ERS in HSCs, promoting quiescence via ferroptosis induction. Both clinical and animal experiments consistently demonstrate that vitamin A deficiency is not merely a concomitant phenomenon of liver injury, but rather a key pathogenic factor that drives the vicious cycle of fibrosis by disrupting lipid/iron metabolic homeostasis and exacerbating oxidative stress. During the early fibrotic stage, while iron accumulates in the liver, ERS exerts cytoprotective effects, preventing ferroptosis occurrence. ATRA can inhibit ERS to activate the ferroptosis pathway, thereby reprogramming HSCs toward a quiescent phenotype. This process involves restoration of mitochondrial membrane potential and normal mitochondrial morphology, ultimately reducing fibrogenic substance production.