Chemotherapy remains a cornerstone in the treatment of bladder cancer (BLCA)
however, the development of chemoresistance substantially limits its efficacy and significantly affects patient survival. Thus, elucidating the molecular mechanisms underlying BLCA chemoresistance is critical to improving patient outcomes. Our study identified MCM6 as an oncogene that facilitates BLCA proliferation and invasion and is linked to cisplatin resistance. Further analysis demonstrated that MCM6 is upregulated in BLCA tissues with poor chemotherapy response. Moreover, MCM6 knockdown enhanced cisplatin sensitivity in BLCA cells both in vitro and in vivo, indicating that MCM6 is a key driver of cisplatin resistance. Mechanistically, MCM6 contributes to cisplatin resistance by enhancing DNA damage repair (DDR). Knockdown of MCM6 reduced nuclear c-Myc levels and promoted its ubiquitin-mediated degradation, thereby increasing DNA damage. Conversely, c-Myc, as a transcription factor, binds to the MCM6 promoter and promotes its transcription, thereby regulating MCM6 expression. Our findings suggest that targeting MCM6-mediated DDR represents a promising strategy to overcome cisplatin resistance in BLCA.