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

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.