Abstract

Colorectal cancer (CRC) exhibits altered lipid metabolism associated with therapy resistance. FOXA2, a lipid metabolism activator, mediates fatty acid β-oxidation in CRC, but its role in irinotecan (CPT-11) resistance remains unclear. Through bioinformatics analysis, clinical sample assessment, and cell line validation, we confirmed the expression of FOXA2 in CRC. The impact of FOXA2 on the viability and CPT-11 sensitivity of CRC cells was tested via CCK-8 assay. DNA damage was evaluated using the comet assay and monitoring of γ-H2AX foci. Assay kits determined the concentrations of triglycerides, cholesterol, and phospholipids, as well as the rate of fatty acid β-oxidation. Protein expression related to lipid metabolism (ACLY, SCD1) was identified by WB. Bioinformatic tools were used to analyze the potential transcriptional control of Aldolase B (ALDOB) by FOXA2 and to scrutinize ALDOB expression in CRC. The molecular interaction was substantiated by dual-luciferase and CHIP assays. IHC was performed on an xenograft tumor model in mice to measure FOXA2, ALDOB, and Ki67 expression. Oil Red O staining was applied to detect triglyceride presence, and TUNEL was used to gauge apoptosis. The results showed that FOXA2 overexpression correlated with CPT-11 resistance in CRC. FOXA2 transcriptionally activated ALDOB, enhancing fatty acid β-oxidation and suppressing drug sensitivity. FOXA2 inhibition sensitized CRC cells to CPT-11 in vitro /vivo, while ALDOB overexpression restored resistance. These findings indicate that FOXA2 promotes CPT-11 resistance by upregulating ALDOB-mediated fatty acid β-oxidation. Targeting the FOXA2/ALDOB axis may overcome chemoresistance in CRC.