Knocking Down Ferredoxin 1 Inhibits the Progression of Colorectal Cancer and Regulates Cuproptosis via Mediating the Hippo Signaling Pathway

ABSTRACT Cuproptosis is a form of programmed cell death dependent on mitochondrial respiration and is crucial in cancer treatment. The study attempted to screen cuproptosis‐associated genes in colorectal cancer (CRC) and reveal regulatory pathways. Weighted gene co‐expression network analysis (WGCNA) was applied to screen the co‐expression modules based on gene expression in CRC patients. The cuproptosis‐associated genes were screened at the intersection of co‐expression modules and cuproptosis gene data set. RNA sequencing was performed to assess the transcriptome changes, followed by functional enrichment analyses to reveal the potential pathways. Ferredoxin 1 (FDX1) was knocked down in in vivo and in vitro experiments to investigate the effects of FDX1 knockdown on CRC progression and cuproptosis. FDX1 was found as a cuproptosis‐associated gene and was highly expressed in CRC tumor and CRC cells. Knockdown of FDX1 regulated cuproptosis in CRC cells, and inhibited CRC cell growth, migration and invasion. We screened 1956 upregulated DEGs and 2201 downregulated DEGs in si‐FDX1 cells, which were mainly enriched in mitogen‐activated protein kinase (MAPK) signaling pathway, tumor necrosis factor (TNF) signaling pathway and Hippo signaling pathway. Knockdown of FDX1 inhibited CRC progression by increasing the levels of dihydrolipoamide S‐succinyltransferase (DLST), lipoic acid synthetase (LIAS) and phosphorylation Yes‐associated protein (pYAP)/YAP, and downregulated transcriptional coactivator with a PDZ‐binding domain (TAZ). The inhibitor of Hippo pathway GA‐017 blocked this process. Knocking down FDX1 regulated cuproptosis and inhibited CRC progression by mediating the Hippo signaling pathway, which shed new insights into the development of biomarkers for CRC treatment.