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

  • Diabetes Obes Metab. 2025 Jun 17. doi: 10.1111/dom.16542.
Lulin Nie  1  2 ,  Kaiwu He  3 ,  Wei Wu  4 ,  Huan Zhang  2 ,  Chuanyue Gao  2 ,  Bocheng Xiong  2 ,  Shangming Li  2 ,  Yongmei Xie  5 ,  Haihui Xie  1 ,  Xifei Yang  2
Affiliations
  • 1. Department of Anesthesiology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, China.
  • 2. Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
  • 3. Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan, China.
  • 4. Department of Hematology, Shenzhen Hospital of Southern Medical University, Shenzhen, China.
  • 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
PMID: 40528684 DOI: 10.1111/dom.16542
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.

Keywords
AdipoRon; endoplasmic reticulum (ER) stress; lipid accumulation; non‐alcoholic steatohepatitis (NASH).
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