Vitamin D Receptor Agonist Calcipotriol Protects Against Alcohol-Induced Hepatotoxicity in Male Mice.

Vitamin D deficiency is highly prevalent in alcohol-associated liver disease and may contribute to metabolic and inflammatory dysregulation in alcoholic steatohepatitis (ASH). To examine the hepato-metabolic actions of vitamin D receptor (VDR) activation in ASH, we evaluated calcipotriol, a VDR agonist, in male C57BL/6N mice fed a 5% ethanol-containing Lieber-DeCarli diet. Calcipotriol (20 µg/kg) reduced intra-hepatic triglyceride accumulation and serum alanine aminotransferase activity, indicating attenuation of alcohol-induced liver injury. Integrated transcriptomic, metabolomic, and biochemical analyses showed that VDR agonism suppressed hepatic lipogenic programs, including de novo lipogenesis, and improved alcohol-induced metabolic derangements. Calcipotriol also reduced oxidative injury and endoplasmic reticulum stress, as evidenced by lower hepatic protein carbonyl content and reduced p-eIF2α, XBP1s, CHOP, ATF4, and BiP expression, together with diminished inflammasome-associated inflammatory signalling. Metabolomic profiling further showed partial restoration of hepatic metabolic homeostasis by calcipotriol, as evidenced by increased choline, uridine monophosphate, and taurine levels. These findings identify calcipotriol as an endocrine-metabolic modulator of ASH and support VDR activation as a mechanistically relevant therapeutic strategy for alcohol-induced liver injury.