Yang Xiaolong, Zhang Zixuan, Wang Fan, Dong Xiaoqing, Huang Sijia, Ren Xueke, Yao Xiangjie, Dahms Hans-Uwe, Li Yaoping, Yang Jian
Department of Cell Biology and Genetics, College of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi 030001, People's Republic of China.
Department of Colorectal Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, People's Republic of China.
J Agric Food Chem. 2025 Jul 23;73(29):18437-18447. doi: 10.1021/acs.jafc.5c04577. Epub 2025 Jul 14.
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.
作为辣椒的主要活性成分，辣椒素（CAP）的潜在致癌作用仍存在争议。本研究旨在阐明辣椒素在肿瘤进展中的作用及其潜在的分子机制。使用MTT法和软琼脂集落形成试验评估细胞增殖。通过透射电子显微镜（TEM）观察线粒体形态，同时结合非靶向代谢组学和蛋白质组学来确定关键靶点。采用分子对接、细胞热位移分析（CETSA）和ACSL4点突变质粒验证来研究机制相互作用。结果表明，辣椒素通过促进长链酰基辅酶A合成酶4（ACSL4）的泛素化来抑制铁死亡。分子对接和免疫共沉淀质谱（Co-IP/MS）显示，辣椒素和E3泛素连接酶SYVN1协同靶向ACSL4。关键位点突变实验证实，辣椒素直接与ACSL4的Asp362残基结合，增强其与SYVN1的相互作用。这促进了SYVN1介导的ACSL4在Lys367处的多聚泛素化，最终抑制铁死亡并加速肿瘤进展。本研究首次阐明了辣椒素通过泛素-蛋白酶体系统调节ACSL4降解来拮抗铁死亡的新机制。这些发现为结直肠癌（CRC）患者的饮食干预提供了理论基础。
