Isorhapontigenin alleviates acetaminophen-induced liver injury by promoting fatty acid oxidation

  • Biochim Biophys Acta Mol Basis Dis. 2025 Feb;1871(2):167575. doi: 10.1016/j.bbadis.2024.167575.
Huiyan Zha  1 ,  Shuying Lv  1 ,  Yuming Hu  2 ,  Yaochen Xie  1 ,  Lingkun Wang  1 ,  Chen Yang  1 ,  Guilin Li  1 ,  Shuchen Gong  2 ,  Li Ping  1 ,  Difeng Zhu  1 ,  Jiajia Wang  1 ,  Qinjie Weng  3 ,  Qiaojun He  4 ,  Jincheng Wang  5
Affiliations
  • 1. Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China.
  • 2. Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 3. Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Taizhou Institute of Zhejiang University, Taizhou, 318000, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; ZJU-Xinchang Joint Innovation Center (TianMu Laboratory), Gaochuang Hi-Tech Park, Xinchang, Zhejiang 312500, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 4. Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; ZJU-Xinchang Joint Innovation Center (TianMu Laboratory), Gaochuang Hi-Tech Park, Xinchang, Zhejiang 312500, China; Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: [email protected].
  • 5. Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Taizhou Institute of Zhejiang University, Taizhou, 318000, China; Beijing Life Science Academy, Beijing, 102200, China. Electronic address: [email protected].
PMID: 39577212 DOI: 10.1016/j.bbadis.2024.167575
Abstract

Acetaminophen (APAP) is a widely used analgesic and antipyretic medicine. It is frequently employed to alleviate pain and mitigate fever-related symptoms, but it can cause liver injury or even liver failure when overdosed. Isorhapontigenin, a compound derived from Chinese herbs and grapes, has been demonstrated to exhibit antioxidant and anti-inflammatory effects. This study focused on evaluating the effect of isorhapontigenin in alleviating APAP-induced liver injury. In the study, a single intraperitoneal administration of APAP was employed to induce liver injury, and isorhapontigenin was given orally 3 days before or 1 h after APAP administration. The results revealed that isorhapontigenin significantly mitigated liver injury by effectively inhibiting APAP-induced Apoptosis, oxidative stress, and inflammation. Furthermore, transcriptomic RNA Sequencing of liver tissues indicated that isorhapontigenin probably protected against APAP-induced liver injury by promoting fatty acid oxidation. Pharmacological experiments also demonstrated that isorhapontigenin treatment led to a significant reduction in triglyceride accumulation, increased ATP levels and direct fatty acid oxidation activity, as well as enhanced expression of proteins associated with fatty acid oxidation, including PPAR-α, PGC-1α, and CPT-1A. Moreover, the protective effects of isorhapontigenin against APAP-induced liver injury were abolished by a CPT-1A inhibitor, etomoxir. Notably, we found that combining isorhapontigenin with NAC (N-acetyl-L-cysteine) resulted in a more significant alleviation of APAP-induced liver injury compared to NAC alone. In conclusion, our study indicates that isorhapontigenin is a potential therapeutic strategy that works by regulating fatty acid oxidation to alleviate APAP-induced liver injury.

Keywords
Acetaminophen; Fatty acid oxidation; Isorhapontigenin; Liver injury.
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