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<p>Ferroptosis is a form of iron-dependent cell death of interest for the development of novel anti-cancer therapies. Ferroptosis research uses a process of elimination based on assumed ferroptosis-specific inducers and inhibitors; these molecules however have off-target effects and cannot provide a comprehensive picture of overlapping pathways. We investigated whether pyroptosis—a form of inflammatory cell death—is initiated in cancer cells following treatment with the ferroptosis inducer RSL3. We treated 6 cancer cell lines with RSL3 alone or in combination with inhibitors of ferroptosis (Ferrostatin-1), caspases (zVADfmk), necroptosis (Necrostatin-1), BID (BI-6C9), or STING (H-151). Biomarkers of pyroptosis and ferroptosis were assessed using our novel quantitative multiplex immunoassay. Increased secretion of pyroptosis-associated cytokines (IL-1α, IL-1β, IL-18), and gasdermin D and E (GSDMD/E) cleavage with parallel loss of respective full-length proteins—both hallmarks of pyroptosis—were recorded in 5/6 cell lines following RSL3 treatment. RSL3 cytotoxicity was blocked by Ferostatin-1; BID and STING inhibitors also prevented GSDMD/E cleavage. We conclude that the ferroptosis-inducer RSL3 triggers pyroptosis in cancer cells; further work is required to elucidate the role of mitochondria in this process. Measurement of pathway-specific protein biomarkers is therefore necessary to identify the exact mechanism of action of novel cytotoxic agents.</p>

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Potent ferroptosis agent RSL3 induces cleavage of Pyroptosis-Specific gasdermins in Cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月12日

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  • William G. Herrick,
  • Huong-Lan Tran,
  • Francesca R. Tomaino,
  • Brittany Beall,
  • Jeevan Govindharajulu,
  • Dominic Esposito,
  • Laura Kuhlmann,
  • Ralph E. Parchment,
  • James H. Doroshow,
  • Apurva K. Srivastava

摘要

Ferroptosis is a form of iron-dependent cell death of interest for the development of novel anti-cancer therapies. Ferroptosis research uses a process of elimination based on assumed ferroptosis-specific inducers and inhibitors; these molecules however have off-target effects and cannot provide a comprehensive picture of overlapping pathways. We investigated whether pyroptosis—a form of inflammatory cell death—is initiated in cancer cells following treatment with the ferroptosis inducer RSL3. We treated 6 cancer cell lines with RSL3 alone or in combination with inhibitors of ferroptosis (Ferrostatin-1), caspases (zVADfmk), necroptosis (Necrostatin-1), BID (BI-6C9), or STING (H-151). Biomarkers of pyroptosis and ferroptosis were assessed using our novel quantitative multiplex immunoassay. Increased secretion of pyroptosis-associated cytokines (IL-1α, IL-1β, IL-18), and gasdermin D and E (GSDMD/E) cleavage with parallel loss of respective full-length proteins—both hallmarks of pyroptosis—were recorded in 5/6 cell lines following RSL3 treatment. RSL3 cytotoxicity was blocked by Ferostatin-1; BID and STING inhibitors also prevented GSDMD/E cleavage. We conclude that the ferroptosis-inducer RSL3 triggers pyroptosis in cancer cells; further work is required to elucidate the role of mitochondria in this process. Measurement of pathway-specific protein biomarkers is therefore necessary to identify the exact mechanism of action of novel cytotoxic agents.