What question did this study set out to answer?

This study aims to investigate the efficacy of ferroptosis induction in overcoming oxaliplatin resistance in pancreatic cancer.

June 1, 2026Open Access

Ferroptosis-based therapeutic strategy targeting iron metabolism and SLC7A11 overcomes oxaliplatin resistance in patient-derived pancreatic cancer organoids

Puntos clave

This study aims to investigate the efficacy of ferroptosis induction in overcoming oxaliplatin resistance in pancreatic cancer.
Established 42 patient-derived pancreatic cancer organoids (PDPCOs) for profiling.
Performed comprehensive molecular profiling including whole-exome sequencing and RNA sequencing.
Conducted drug response assays to evaluate cell viability, lipid peroxidation, and mitochondrial function.
Ferroptosis inducer artesunate (ART) showed enhanced anticancer effects in combination with oxaliplatin (OXA).
Combination therapy increased lipid peroxidation and iron accumulation, effectively inhibiting tumor growth in xenograft models.
Knockdown of SLC7A11 sensitized cells to therapy, indicating its role in resistance.

Resumen

Abstract Background Oxaliplatin resistance remains a significant challenge in pancreatic cancer (PC) treatment. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has emerged as a promising therapeutic target for overcoming chemotherapy resistance. This study investigated whether ferroptosis induction could overcome oxaliplatin resistance in PC. Methods We established 42 patient-derived pancreatic cancer organoids (PDPCOs) and performed comprehensive molecular profiling including whole-exome sequencing, RNA sequencing and drug response assays. Cell viability, lipid peroxidation, iron levels, mitochondrial function, and drug synergy were evaluated. Survival analysis and differential gene expression analyses were conducted according to the biomarker candidate. Results Transcriptomic analysis revealed distinct ferroptosis-related alterations in OXA-resistant PDPCOs, including a negative enrichment of ferroptosis suppressor genes. The ferroptosis inducer artesunate (ART) synergistically enhanced anticancer effects of OXA in cell lines and PDPCOs. Mechanistic studies demonstrated that combination therapy induced ferroptotic cell death by promoting lipid peroxidation, intracellular iron accumulation, and mitochondrial dysfunction. Combination therapy remarkably inhibited tumor growth in PDPCO-derived xenograft models. ART/OXA treatment upregulated expressions of iron transport proteins transferrin receptor (TFRC) and divalent metal transporter 1 (DMT1), contributing to ferroptosis induction. Overexpression of solute carrier family 7 member 11 (SLC7A11) conferred dual resistance to OXA and ART by suppressing ferroptosis, whereas its knockdown or pharmacological inhibition with erastin sensitized resistant cells to combination therapy. Notably, triple combination of ART, OXA, and erastin effectively overcame resistance in dual-resistant PDPCOs. Conclusions Ferroptosis-based therapeutic strategies can overcome oxaliplatin resistance in PC, supporting further investigation of SLC7A11 as a candidate biomarker for ferroptosis-based therapeutic responsiveness.

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