Zhang_2025_iScience_28_114199

Irinotecan (CPT-11) is a key chemotherapeutic agent for gastric cancer (GC), but its efficacy is limited by variable patient responses. The activation of CPT-11 to its active form, SN-38, depends on the enzyme carboxylesterase 2 (CES2), yet the regulation of CES2 in GC is poorly understood. Here, we identify Krppel-like factor 13 (KLF13) as a direct transcriptional activator of CES2. We show that KLF13 expression correlates with CES2 levels and treatment response in GC patients. Mechanistically, KLF13 binds to specific elements in the CES2 promoter to drive its expression. This function of KLF13 is critically dependent on its acetylation by the co-activator p300, as demonstrated by site-directed mutagenesis and p300 inhibition. Functionally, the KLF13-CES2 axis dictates cellular sensitivity to CPT-11. Our findings unveil a p300-KLF13-CES2 signaling pathway that governs irinotecan sensitivity, providing potential predictive biomarkers and therapeutic targets for GC.