2. Academic Validation
  3. Capsaicin Inhibits Ferroptosis through Facilitating SYVN1-Mediated Ubiquitination and Degradation of ACSL4

Capsaicin Inhibits Ferroptosis through Facilitating SYVN1-Mediated Ubiquitination and Degradation of ACSL4

  • J Agric Food Chem. 2025 Jul 23;73(29):18437-18447. doi: 10.1021/acs.jafc.5c04577.
Xiaolong Yang 1,  Zixuan Zhang 1,  Fan Wang 2,  Xiaoqing Dong 3,  Sijia Huang 3,  Xueke Ren 3,  Xiangjie Yao 4,  Hans-Uwe Dahms 5,  Yaoping Li 2,  Jian Yang 2 3 6
Affiliations

Affiliations

  • 1 Department of Cell Biology and Genetics, College of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi 030001, People's Republic of China.
  • 2 Department of Colorectal Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, People's Republic of China.
  • 3 Disease prevention and control Doctoral Studio, Lvliang Center for Disease Prevention and Control, Lvliang, Shanxi 033000, People's Republic of China.
  • 4 Division of Conservation and Application of Biological Resources, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, People's Republic of China.
  • 5 Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 6 Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, People's Republic of China.
PMID: 40658633 DOI: 10.1021/acs.jafc.5c04577
Abstract

As the primary active component of chili peppers, capsaicin (CAP) remains controversial regarding its potential carcinogenic effects. This study aimed to elucidate the role of capsaicin in tumor progression and its underlying molecular mechanisms. Cellular proliferation was assessed using MTT assay and soft-agar colony formation assay. Mitochondrial morphology was observed via transmission electron microscopy (TEM), while untargeted metabolomics and proteomics were combined to identify key targets. Molecular docking, cellular thermal shift assay (CETSA), and ACSL4 point mutant plasmid validation were employed to investigate mechanistic interactions. Results demonstrated that capsaicin inhibits Ferroptosis by promoting ubiquitination of long-chain acyl-CoA synthetase 4 (ACSL4). Molecular docking and coimmunoprecipitation-mass spectrometry (Co-IP/MS) revealed that capsaicin and the E3 ubiquitin Ligase SYVN1 synergistically target ACSL4. Key site mutation experiments confirmed that capsaicin directly binds to the Asp362 residue of ACSL4, enhancing its interaction with SYVN1. This promotes SYVN1-mediated polyubiquitination of ACSL4 at Lys367, ultimately suppressing Ferroptosis and accelerating tumor progression. This study is the first to elucidate capsaicin's novel mechanism of antagonizing Ferroptosis by regulating ACSL4 degradation via the ubiquitin-proteasome system. These findings provide a theoretical foundation for dietary interventions for colorectal Cancer (CRC) patients.

Keywords

ACSL4; SYVN1; capsaicin; colorectal cancer; ferroptosis.

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