2. Academic Validation
  3. Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis

Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis

  • J Exp Clin Cancer Res. 2023 Jan 6;42(1):6. doi: 10.1186/s13046-022-02567-z.
Yan Li 1,  Wenjuan Yang 2,  Yuanyuan Zheng 1,  Weiqi Dai 3,  Jie Ji 1,  Liwei Wu 1,  Ziqi Cheng 1,  Jie Zhang 1,  Jingjing Li 3,  Xuanfu Xu 3,  Jianye Wu 4,  Mingwei Yang 5,  Jiao Feng 6,  Chuanyong Guo 7
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
  • 2 Department of Emergency, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
  • 3 Department of Gastroenterology, Shidong Hospital, Shanghai, 200433, China.
  • 4 Department of Gastroenterology, Putuo People's Hospital, Tongji University, Shanghai, 200060, China.
  • 5 Department of Oncology Radiotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230031, China. yangmw_ayyfy@126.com.
  • 6 Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. fengjiao080801@163.com.
  • 7 Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. guochuanyong@hotmail.com.
PMID: 36604718 DOI: 10.1186/s13046-022-02567-z
Abstract

Background: Sorafenib resistance is a key impediment to successful treatment of patients with advanced hepatocellular carcinoma (HCC) and recent studies have reported reversal of drug resistance by targeting Ferroptosis. The present study aimed to explore the association of fatty acid synthase (FASN) with sorafenib resistance via regulation of Ferroptosis and provide a novel treatment strategy to overcome the sorafenib resistance of HCC patients.

Methods: Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of Ferroptosis status. Biological information analyses, immunofluorescence assays, western blot assays, and co-immunoprecipitation analyses were conducted to elucidate the functions of FASN in HCC. Both in vitro and in vivo studies were conducted to examine the antitumor effects of the combination of orlistat and sorafenib and CalcuSyn software was used to calculate the combination index.

Results: Solute carrier family 7 member 11 (SLC7A11) was found to play an important role in mediating sorafenib resistance. The up-regulation of FASN antagonize of SLC7A11-mediated Ferroptosis and thereby promoted sorafenib resistance. Mechanistically, FASN enhanced sorafenib-induced Ferroptosis resistance by binding to hypoxia-inducible factor 1-alpha (HIF1α), promoting HIF1α nuclear translocation, inhibiting ubiquitination and proteasomal degradation of HIF1α, and subsequently enhancing transcription of SLC7A11. Orlistat, an inhibitor of FASN, with sorafenib had significant synergistic antitumor effects and reversed sorafenib resistance both in vitro and in vivo.

Conclusion: Targeting the FASN/HIF1α/SLC7A11 pathway resensitized HCC cells to sorafenib. The combination of orlistat and sorafenib had superior synergistic antitumor effects in sorafenib-resistant HCC cells.

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