ALKBH5-mediated NPC2 mRNA m6A demethylation promotes resistance to oxaliplatin in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer globally and a leading cause of cancer-related death. Oxaliplatin, a key platinum-based chemotherapy, significantly improves outcomes in CRC patients. Nevertheless, oxaliplatin resistance often emerges, leading to worse prognosis. Exploring new biomarkers and mechanisms of resistance is crucial for overcoming oxaliplatin resistance and enhancing therapeutic efficacy. Through bioinformatics analysis, high NPC2 expression was found to be associated with oxaliplatin resistance and poor prognosis in CRC patients. Moreover, NPC2 was highly expressed in CRC tissues, especially in metastatic CRC tissues. Additionally, the expression of N6-methyladenosine (m⁶A) demethylase ALKBH5 was elevated in oxaliplatin-resistant colorectal cancer cells. Mechanically, ALKBH5 promotes m⁶A demethylation of NPC2 mRNA in a YTHDF2-dependent process, thereby enhancing the stability of NPC2 mRNA and making colorectal cancer cells oxaliplatin-resistant. Our results show that by inhibiting NPC2 or ALKBH5, we can re-sensitize resistant CRC cells to oxaliplatin in vitro and in vivo. In summary, ALKBH5-mediated m⁶A demethylation promotes the stability of NPC2 mRNA and plays a key role in promoting oxaliplatin resistance in colorectal cancer. Targeting the ALKBH5/NPC2 axis have important therapeutic potential for patients with oxaliplatin-resistant colorectal cancer.