WTAP weakens oxaliplatin chemosensitivity of colorectal cancer by preventing PANoptosis

As the most abundant post-transcriptional modification in eukaryotes, N 6 -methyladenosine (m 6 A) plays a crucial role in cancer cell proliferation, invasion and chemoresistance. However, its specific effects on chemosensitivity to oxaliplatin-based regimens and the impact of these drugs on m 6 A methylation levels in colorectal cancer (CRC) remain largely unexplored. In this study, we demonstrated that the m 6 A methyltransferase Wilms tumor 1-associating protein (WTAP) weakens oxaliplatin chemosensitivity in HCT116 and DLD1 cells. Mechanistically, oxaliplatin treatment upregulated WTAP expression, preventing multiple forms of cell death simultaneously, a process known as PANoptosis, by decreasing intracellular oxidative stress through maintaining the expression of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element, in an m 6 A-dependent manner. In addition, high WTAP expression in CRC patients is associated with a poor prognosis and reduced benefit from standard chemotherapy by clinical data analysis of The Cancer Genome Atlas (TCGA) database and patient cohort study. These findings suggest that targeting WTAP-NRF2-PANoptosis axis could enhance the antitumor efficacy of oxaliplatin-based chemotherapy in CRC treatment. • Oxaliplatin treatment increases the m 6 A level in CRC cells. • WTAP depletion triggers PANoptosis with increased ROS to enhance the chemosensitivity. • WTAP stabilizes NRF2 mRNA in an m 6 A-dependent manner. • High WTAP expression in CRC patients is associated with poor prognosis and reduced benefit from standard chemotherapy.