2. Academic Validation
  3. Salinomycin inhibits SREBP1 to sensitize ferroptosis and ameliorate sorafenib resistance in clear cell renal cell carcinoma

Salinomycin inhibits SREBP1 to sensitize ferroptosis and ameliorate sorafenib resistance in clear cell renal cell carcinoma

  • Biochim Biophys Acta Mol Cell Res. 2025 Aug;1872(6):119989. doi: 10.1016/j.bbamcr.2025.119989.
Yu Su 1,  Xuan Liu 1,  Dekun Wang 1,  Gang Li 2,  Xue Mi 1,  Yuying Zhang 1,  Shijing Yue 1,  Zhujun Zhang 1,  Tianyu Shen 3,  Xiaoyue Tan 4
Affiliations

Affiliations

  • 1 The School of Medicine, Nankai University; 94 Wei Jin Road, Tianjin, China.
  • 2 Department of Urology, Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, 23 Pingjiang Road, Tianjin, China.
  • 3 The School of Medicine, Nankai University; 94 Wei Jin Road, Tianjin, China. Electronic address: shentianyu@nankai.edu.cn.
  • 4 The School of Medicine, Nankai University; 94 Wei Jin Road, Tianjin, China. Electronic address: xiaoyuetan@nankai.edu.cn.
PMID: 40360020 DOI: 10.1016/j.bbamcr.2025.119989
Abstract

Backgrounds Resistance to sorafenib, a frontline therapy for advanced ccRCC, is associated with decreased sensitivity to Ferroptosis. Our research focuses on elucidating the mechanisms underlying ccRCC's resistance to sorafenib-induced Ferroptosis and identifying potential new agents that could overcome this resistance.

Methods: The silencing of SREBP1 was employed to evaluate the role of this key transcription factor in lipid synthesis and its contribution to Ferroptosis resistance in sorafenib-treated ccRCC cells. The ATF4-mediated induction of SREBP1 following salinomycin treatment was assessed by western blot, RT-PCR, immunohistochemistry, chromatin immunoprecipitation, and dual-luciferase reporter assays. In cultured ccRCC cells, the combined effects of salinomycin and sorafenib on Ferroptosis induction were evaluated by assessing cell viability, glutathione levels, malondialdehyde levels, BODIPY fluorescence, and intracellular Fe2+ concentration. In an orthotopic ccRCC mouse model, the synergistic effects of salinomycin and sorafenib on both Ferroptosis and tumor progression were examined.

Results: Overexpression of SREBP1 was observed in ccRCC tumor tissue, and induced by sorafenib treatment. Silencing SREBP1 reduced the resistance of ccRCC cells to Ferroptosis induced by sorafenib. Salinomycin decreased ATF4 level, which in turn inhibited SREBP1 transcription. Treatment with salinomycin enhanced the sensitivity of ccRCC cells to sorafenib-induced Ferroptosis. In the orthotopic xenograft mouse model of ccRCC, the combination of salinomycin and sorafenib showed a synergistic effect in inducing Ferroptosis inhibiting tumor growth.

Conclusions: Salinomycin treatment mitigates resistance to sorafenib-induced Ferroptosis by inhibiting SREBP1. The combination of salinomycin and sorafenib synergistically enhances Ferroptosis and suppresses ccRCC growth.

Keywords

Clear cell renal cell carcinoma; Ferroptosis resistance; Salinomycin; Sorafenib; Sterol regulatory element binding protein 1.

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