2. Academic Validation
  3. FATP5 deficiency alleviates MASH via remodeling hepatic lipid composition to suppress ferroptosis

FATP5 deficiency alleviates MASH via remodeling hepatic lipid composition to suppress ferroptosis

  • Free Radic Biol Med. 2025 Aug 19:240:170-182. doi: 10.1016/j.freeradbiomed.2025.08.035.
Yiran Liu 1,  Mingyu Zhang 1,  Chen Zhu 1,  Yu Zhang 1,  Yujie Huang 1,  Suhong Xia 2,  Jiazhi Liao 3
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China; Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
  • 2 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China; Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China. Electronic address: suhxia159@163.com.
  • 3 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China; Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China; Department of Gastroenterology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China. Electronic address: liaojiazhi@tjh.tjmu.edu.cn.
PMID: 40840619 DOI: 10.1016/j.freeradbiomed.2025.08.035
Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) represents an advanced stage of fatty liver disease characterized by hepatocyte ballooning, cell death, inflammation and fibrosis. Fatty acid transport protein 5 (FATP5), a hepatocyte-specific transmembrane protein, mediates both long-chain fatty acids (LCFAs) uptake and bile acids (BAs)-coenzyme A (CoA) conjugation. While FATP5 upregulation has been documented in MASH patients, its functional role in disease progression through hepatic lipid metabolic regulation remains unclear. In this study, we identified FATP5 elevation both in vitro and in vivo MASH models. Treatment with the Ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly attenuated MASH histopathology and steatotic HepG2 cell death. Furthermore, FATP5 deficiency protected against methionine-choline-deficient diet (MCD)-induced MASH in the mouse model and prevented steatotic HepG2 cell deaths through reducing Ferroptosis. Notably, we discovered an inverse correlation between FATP5 and stearoyl-CoA desaturase 1 (SCD1) expression. As the rate-limiting enzyme for monounsaturated fatty acid (MUFA) biosynthesis, SCD1 overexpression exhibited Ferroptosis resistance in erastin-treated HepG2 cells. Untargeted lipidomics revealed that FATP5 knockdown preferentially reduced pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing lipids. Mechanistically, reduction of PUFA-lipids alleviated suppression of Sterol regulatory element binding protein 1 (SREBP1), subsequently upregulating its transcriptional target SCD1. Finally, we found that adeno-associated virus-mediated SCD1 overexpression in vivo effectively attenuated inflammation and liver injury in MASH by inhibiting hepatic Ferroptosis. In conclusion, our findings suggest that FATP5 knockdown alleviates MASH via remodeling hepatic lipid composition to activate the SREBP1/SCD1 axis, thereby inhibiting Ferroptosis. The findings also indicate that FATP5 may serve as a potential therapeutic target of MASH.

Keywords

FATP5; Ferroptosis; Lipid metabolism; MASH; SCD1.

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