2. Academic Validation
  3. Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination

Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination

  • Chin Med. 2025 Jun 16;20(1):89. doi: 10.1186/s13020-025-01109-x.
Yuping Qiu # 1,  Shupei Li # 2,  Mingzuo Jiang # 1,  Ang Huang # 3,  Ya Yang 1,  Xi Chen 1 2,  Hui Li 4,  Zhizhou Yang 5 6,  Juan Wei 7,  Ji Xuan 8 9 10
Affiliations

Affiliations

  • 1 Department of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing University, 305 Zhongshan East Road, Nanjing, 210002, China.
  • 2 Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3 Department of Gastroenterology and Hepatology, The First Medical Center of PLA General Hospital, Beijing, China.
  • 4 Department of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 100 Shizi Street, Nanjing, 210028, China. jessica20110215@163.com.
  • 5 Department of Outpatient and Emergency, Qinhuai Medical District, Affiliated Hospital of Medical School, Jinling Hospital, Nanjing University, 305 Zhongshan East Road, Nanjing, 210002, China. yzzzwj@126.com.
  • 6 Department of Emergency Medicine, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China. yzzzwj@126.com.
  • 7 Department of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing University, 305 Zhongshan East Road, Nanjing, 210002, China. weijuannj2024@163.com.
  • 8 Department of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing University, 305 Zhongshan East Road, Nanjing, 210002, China. xuanji@nju.edu.cn.
  • 9 Department of Gastroenterology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China. xuanji@nju.edu.cn.
  • 10 Department of Gastroenterology, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China. xuanji@nju.edu.cn.
  • # Contributed equally.
PMID: 40524220 DOI: 10.1186/s13020-025-01109-x
Abstract

Background: Lang Qing A Ta (Huagan Tongluo Fang, HGTLF) is a Tibetan medicine with significant anti-liver fibrosis effects and good efficacy in the treatment of liver diseases, including non-alcoholic fatty liver disease (NAFLD). Quercetagetin (QG) has been identified as an active ingredient of HGTLF that is absorbed into the blood. This study aims to investigate the role of QG in the anti-liver fibrosis effect of HGTLF in NAFLD.

Methods: CCl4 injection-induced liver fibrosis and high-fat, high-cholesterol diet-induced non-alcoholic steatohepatitis (NASH) mouse models were established. Transforming growth factor-β1 (TGF-β1)-induced hepatic stellate cells (HSCs) were used as in vitro models. The effect of QG on the stability and degradation pathway of glu-tathione peroxidase 4 (GPX4) protein was investigated.

Results: QG improved liver function and hyperlipidemia in CCl4-injected mice and NASH mice, and alleviated hepatic lipid deposition and hepatic fibrosis. TGF-β1 treatment promoted the expression of α-smooth muscle actin and fibrosis-related genes, while QG reversed this phenomenon and inhibited HSC activation. QG increased the intracellular labile iron pool and lipid Reactive Oxygen Species in HSCs. Treatment with the Ferroptosis inhibitor ferrostatin-1 reversed the inhibitory effect of QG on TGF-β1-induced HSC activation. QG reduced GPX4 protein stability and regulated GPX4 K167 ubiquitination via the membrane-associated ring-CH-type finger 8 (MARCHF8)-mediated ubiquitin-proteasome pathway. Interference with MARCHF8 attenuated the effect of QG and promoted HSC activation induced by TGF-β1.

Conclusion: QG, the active ingredient of HGTLF, can induce Ferroptosis of HSCs by targeting the degradation of GPX4 through ubiquitination and inhibit HSC activation, thereby alleviating liver fibrosis in NAFLD.

Keywords

Ferroptosis; GPX4 ubiquitination; Hepatic stellate cells; Non-alcoholic fatty liver disease; Quercetagetin.

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