IRF4 transcriptionally activates CD36 to regulate glycolysis and suppress oxaliplatin resistance in colorectal cancer

Oxaliplatin (OXA) resistance in colorectal cancer (CRC) remains a major therapeutic challenge, prompting investigation into the role of the interferon regulatory factor 4 (IRF4)/leukocyte differentiation antigen 36 (CD36) regulatory axis and its impact on glycolysis. Bioinformatic analysis identified CD36 as a key gene, with IRF4 predicted as its upstream regulator. OXA-resistant CRC cell lines were established. Gene expression was analyzed by reverse transcription quantitative polymerase chain reaction and Western blot. The IRF4-CD36 interaction was validated via chromatin immunoprecipitation and dual-luciferase assays. Glycolysis was assessed by measuring glucose consumption, lactate production, and ATP levels. Drug sensitivity was evaluated using cell counting kit-8 and apoptosis assays. Both IRF4 and CD36 were downregulated in OXA-resistant cells. IRF4 directly bound to the CD36 promoter to activate its transcription. Overexpression of CD36 or IRF4 inhibited glycolysis and restored OXA sensitivity. Knockdown of CD36 in IRF4-overexpressing cells reversed these effects, confirming CD36 as the functional mediator. The study demonstrates that the IRF4/CD36 axis attenuates OXA resistance in CRC by transcriptional repression of glycolysis. This axis presents a promising therapeutic target for overcoming chemoresistance.