CALD1/IGF2BP1 complex mediates cisplatin resistance in bladder cancer via enhancing RFC4 mRNA stability in an m6A-dependent manner.

Cisplatin-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer, but most patients develop drug resistance within a short period. M6A modification (N6-methyladenosine) has been extensively validated as a key hallmark of multiple cancers, and its dysregulation may contribute to cisplatin resistance. Overall design: Here, we established a cisplatin-resistant xenograft model of human bladder cancer through long-term intermittent chemotherapy and identified CALD1 as a critical determinant of cisplatin resistance. CALD1 was elevated in cisplatin-resistant bladder cancer cells, and loss of CALD1 conferred sensitivity to cisplatin. In patients, CALD1 was highly expressed in bladder cancer and associated with poor outcomes. Mechanistic investigations demonstrated that CALD1 interacts with the RRM1 domain of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which enhances the mRNA stability of the downstream gene RFC4 in an m6A-dependent manner, thereby increasing RFC4 expression. Elevated RFC4 protein levels subsequently enhanced tumor cell stemness and promoted cisplatin resistance. These findings suggest that targeting the CALD1/IGF2BP1–RFC4 axis may represent a novel strategy to reverse cisplatin chemoresistance.