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서울대학교 의과대학, 서울대학교병원
J. Exp. Clin. Cancer Res., May 30 2026, | https://doi.org/10.1186/s13046-026-03745-z
Ferroptosis-based therapeutic strategy targeting iron metabolism and SLC7A11 overcomes oxaliplatin resistance in patient-derived pancreatic cancer organoids
Jin Ho Choi1,*, Kyung Min Lee2,*, Minsik Oh3, Janghyun Noh3, Yooyeon Kim2, Eunhye Hwang2, In Rae Cho1, Woo Hyun Paik1, Ji Kon Ryu1, Ja-lok Ku4, Sang Hyub Lee1
1Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
2Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
3Department of Data Technology, Myongji University, Seoul, Republic of Korea
4Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
*These authors contributed equally to this work as co-first authors.
Correspondence : Sang Hyub Lee, MD, Ph.D.
1Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
2Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
3Department of Data Technology, Myongji University, Seoul, Republic of Korea
4Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
*These authors contributed equally to this work as co-first authors.
Correspondence : Sang Hyub Lee, MD, Ph.D.
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.
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.
논문정보
- Research article
- 2026년 05월 (BRIC 등록일 2026-06-02)
- 국내 연구진
- 의약학 > 종양의학
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