Pachymic Acid Alleviates Metabolic Dysfunction-Associated Steatotic Liver Disease by Inhibiting Ferroptosis through PPARα

Guilin Ren¹Yiyou Lin¹Jiannan Qiu¹Congcong Zhang¹Lin CHEN¹Linwensi Zhu²Xiaohui Fan³Xiaobing Dou^1*Qingsheng Liu^4,5*

• ¹Zhejiang Chinese Medical University, Hangzhou, China
• ²First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
• ³Zhejiang University, Hangzhou, Zhejiang Province, China
• ⁴Hangzhou Third Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
• ⁵Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang Province, China

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive lipid deposition in hepatocytes without a history of significant alcohol consumption. Pachymic acid (Pac), a bioactive triterpenoid from Poria cocos, has shown promise in treating MASLD due to its antioxidant and antiinflammatory capabilities. This study aimed to elucidate the molecular impact and mechanisms of Pac in MASLD. Methods: Male C57BL/6J mice were subjected to a high-fat diet (HFD) for 8 weeks, followed by a 4 weeks treatment with the Pac. Comprehensive assessments including physiological, biochemical, and histomorphological evaluations were performed posttreatment. Transcriptomic analysis of liver samples from normal control (NC), HFD, and HFD+high-dose Pac (Pac-H) groups was conducted, with validation through Western blot, and immunofluorescence. Results: HFD induced biochemical abnormalities and liver injury, which were significantly reversed by Pac, as evidenced by decreased plasma levels of AST (Aspartate aminotransferase), ALT (Alanine aminotransferase), TG (Triglyceride), and TC (Total cholesterol), and reduced hepatic TG and TC levels. Pac also mitigated lipid accumulation, peroxidation, and ferroptosis. Pac modulated the expression of PPARα (Peroxisome proliferator-activated receptor α), MAPKs (Mitogen-activated protein kinases), and ferroptosis pathways, thereby ameliorating MASLD. Discussion: The study demonstrated that Pac inhibited the MAPKs signaling pathway and reduced hepatic ferroptosis, alleviated steatosis through PPARα regulation, offering a potential therapeutic strategy for MASLD.