自噬降解FTH1诱导铁死亡提高结直肠癌对奥沙利铂敏感性的实验研究OA

Background and purpose:Ferritin heavy chain 1(FTH1)is a key regulator of iron homeostasis,maintaining iron balance through ferritin autophagy.However,the relationship between FTH1 and autophagy in tumor resistance and their underlying mechanisms remain unclear.This study aimed to investigate the relationship between oxaliplatin resistance and FTH1,ferroptosis,and autophagy,exploring the feasibility of reversing drug resistance by modulating FTH1 and ferroptosis through autophagy.Methods:Bioinformatics analysis was applied to identify differentially expressed genes between oxaliplatin-sensitive and-resistant cells and their relationship with ferroptosis.Key factors were determined through functional enrichment,prognostic,and interaction network analyses.In vitro cytology experiments screened and cultured oxaliplatin-sensitive and-resistant cell lines.Effects of autophagy regulation,FTH1 on ferroptosis,and cellular oxaliplatin sensitivity and biological behavior were observed through lentiviral transfection,oxaliplatin treatment,autophagy modulation,and ferroptosis rescue.Archived paraffin-embedded specimens from colorectal cancer patients,with complete clinical and pathological data,were collected from the Department of Pathology at Binzhou Medical University Affiliated Hospital and Liaocheng People's Hospital between June 2018 and December 2024 for validation.This study was approved by the Research Ethics Committees of Binzhou Medical University Affiliated Hospital and Liaocheng People's Hospital(approval No.KYLL-304;2026074),and informed consent was obtained from all patients.Results:Bioinformatics analysis revealed that FTH1 is highly expressed in drug-resistant cells,associated with poor prognosis,and closely linked to autophagy.Cell experiments demonstrated that compared to sensitive HCT-116 cells,drug-resistant HT-29 cells express elevated levels of FTH1 and reduced autophagy.Following oxaliplatin treatment,sensitive cells exhibited enhanced autophagy,decreased FTH1 expression,and increased ferroptosis markers;while these changes were less pronounced in drug-resistant cells with inherently low basal autophagy levels.Activating autophagy in drug-resistant HT-29 cells degraded FTH1,induced ferroptosis,and significantly enhanced oxaliplatin sensitivity:an effect reversible by ferroptosis inhibitors.Lentiviral experiments demonstrated that FTH1 overexpression reduced drug responsiveness in sensitive cells,while FTH1 knockdown increased sensitivity in resistant cells.Rescue experiments confirmed that FTH1 overexpression counteracts the sensitization effect induced by autophagy activation.Clonogenic and transwell assays demonstrated that autophagy activation-mediated FTH1 degradation inhibits proliferation and invasion in drug-resistant cells.Validation using 129 clinical samples revealed that the drug-resistant group exhibited low expression of autophagy-related protein LC3 and high expression of FTH1,with FTH1 levels negatively correlated with tumor regression rate.Conclusion:Low basal autophagy levels and FTH1-regulated high iron homeostasis constitute key mechanisms underlying oxaliplatin resistance.A causal cascade exists in colorectal cancer cells:oxaliplatin-autophagy-FTH1-iron-ions-ferroptosis/resistance.Activating autophagy represents a novel strategy to reverse colorectal cancer resistance.