AdipoRon attenuates steatosis, inflammation and fibrosis in murine diet‐induced NASH via inhibiting ER stress

Abstract Aim The rising global prevalence of obesity has accelerated the incidence of metabolic dysfunction‐associated steatotic liver disease (MASLD), with nonalcoholic steatohepatitis (NASH) representing its progressive and life‐threatening phenotype. Despite its clinical urgency, no pharmacotherapy is currently approved for NASH. AdipoRon, an orally active adiponectin receptor agonist, exhibits dual regulatory effects on glucose/lipid homeostasis alongside anti‐inflammatory and antioxidant properties. However, its therapeutic potential in metabolic stress‐driven NASH remains underexplored. This study elucidates the efficacy and molecular mechanisms of AdipoRon in mitigating metabolic stress‐induced NASH. Materials and Methods We employed a multi‐modal approach combining in vitro and in vivo models: palmitic acid (PA)‐challenged alpha mouse liver 12 (AML12) hepatocytes and mice fed a Western diet (WD) or a methionine‐choline‐deficient (MCD) diet. Proteomic profiling integrated with bioinformatics analysis was utilized to dissect AdipoRon's mechanism. Pharmacological validation via endoplasmic reticulum (ER) stress modulation (e.g., cinchonine) further clarified pathway specificity. Results In vitro, AdipoRon attenuated PA‐induced lipid accumulation and inflammatory cytokine release in hepatocytes. In vivo, AdipoRon administration markedly reduced hepatic injury, steatosis, lobular inflammation and collagen deposition in diet‐induced NASH mice. Mechanistically, proteomic analysis identified ER stress suppression as a central pathway, with rescue experiments confirming that cinchonine (an ER stress activator) abrogated AdipoRon's hepatoprotection. Conclusions Our findings establish AdipoRon as a potent inhibitor of ER stress, effectively counteracting metabolic stress‐induced NASH pathogenesis. These results highlight its translational promise as a targeted therapy for NASH, addressing critical unmet clinical needs.