Nie Lulin, He Kaiwu, Wu Wei, Zhang Huan, Gao Chuanyue, Xiong Bocheng, Li Shangming, Xie Yongmei, Xie Haihui, Yang Xifei
Department of Anesthesiology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, China.
Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Diabetes Obes Metab. 2025 Sep;27(9):4950-4967. doi: 10.1111/dom.16542. Epub 2025 Jun 17.
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.
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.
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.
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.
全球肥胖患病率的上升加速了代谢功能障碍相关脂肪性肝病（MASLD）的发病率，其中非酒精性脂肪性肝炎（NASH）代表其进展性和危及生命的表型。尽管临床需求迫切，但目前尚无针对NASH的药物疗法获批。AdipoRon是一种口服活性脂联素受体激动剂，对葡萄糖/脂质稳态具有双重调节作用，并具有抗炎和抗氧化特性。然而，其在代谢应激驱动的NASH中的治疗潜力仍未得到充分探索。本研究阐明了AdipoRon减轻代谢应激诱导的NASH的疗效和分子机制。
我们采用了结合体外和体内模型的多模式方法：用棕榈酸（PA）刺激的α小鼠肝脏12（AML12）肝细胞以及喂食西式饮食（WD）或蛋氨酸-胆碱缺乏（MCD）饮食的小鼠。利用蛋白质组学分析结合生物信息学分析来剖析AdipoRon的作用机制。通过内质网（ER）应激调节（如辛可宁）进行的药理学验证进一步阐明了途径特异性。
在体外，AdipoRon减轻了PA诱导的肝细胞脂质积累和炎性细胞因子释放。在体内，给予AdipoRon可显著降低饮食诱导的NASH小鼠的肝损伤、脂肪变性、小叶炎症和胶原沉积。从机制上讲，蛋白质组学分析确定ER应激抑制是一条核心途径，挽救实验证实辛可宁（一种ER应激激活剂）消除了AdipoRon的肝脏保护作用。
我们的研究结果表明AdipoRon是一种有效的ER应激抑制剂，可有效对抗代谢应激诱导的NASH发病机制。这些结果突出了其作为NASH靶向治疗的转化前景，满足了关键的未满足临床需求。
