Hypoxia-induced autophagy attenuates ferredoxin 1-mediated cuproptosis in colorectal cancer cells

Introduction Cuproptosis has emerged as a potential therapeutic target for colorectal cancer (CRC). This study investigated the role of ferredoxin 1 (FDX1) in regulating cuproptosis under hypoxic conditions and explored the impact of autophagy on this process in CRC. Methods CRC patient samples and cell lines were used in this study. Cells were exposed to hypoxia and treated with Es-Cu (a copper supplement) and rapamycin, an autophagy inducer. FDX1 expression in clinical tissues was assessed in clinical tissues using qPCR and Western blot. The CCK8 assay, EdU staining, and Transwell assay were employed to evaluate the malignant behavior of tumor cells. Copper content and DLAT oligomerization were measured. A nude mouse xenograft model was used to explore the role of FDX1 under hypoxic conditions. Results Compared with adjacent normal tissues, elevated FDX1 expression was observed in CRC tissues. In vitro , hypoxia or Es-Cu treatment upregulated FDX1 expression in CRC cell lines, resulting in reduced cell proliferation and increased cellular damage. FDX1 overexpression under hypoxic conditions suppressed migration, invasion, and proliferation while promoting cellular damage and DLAT oligomerization. Rapamycin-induced autophagy reversed the inhibitory effects of FDX1 overexpression on CRC cells. In vivo , rapamycin treatment attenuated the tumor-suppressive effects of FDX1 overexpression in nude mouse xenograft models. Discussion This study demonstrated that hypoxia-induced autophagy inhibits FDX1-mediated cuproptosis, leading to resistance to copper-induced cell death in CRC cells. Targeting the autophagy pathway may provide a novel therapeutic strategy to overcome resistance to cuproptosis and improving CRC treatment outcomes.