Qi Chen, Tao Chen, Lifeng Gan, Yiran Lu, Biao Qian
BACKGROUND: Bladder cancer (BC) is the second most prevalent malignancy of the urinary system, characterized by high recurrence rates and aggressive behavior. Although treatment modalities have advanced, patient prognosis remains poor, largely due to late-stage diagnosis, postoperative recurrence, and the development of therapy resistance. Mitophagy, a selective form of autophagy responsible for degrading dysfunctional mitochondria, is a critical mechanism for maintaining cellular homeostasis. Dysregulation of mitophagy leads to the accumulation of damaged mitochondria and is implicated in the pathogenesis of numerous diseases, including cancer. MAIN BODY: This review synthesizes current understanding of the molecular mechanisms by which mitophagy regulates the initiation and progression of BC. Concurrently, we critically evaluate its context-dependent functions in disease biology and therapeutic response. The role of mitophagy in BC is dual and highly context-dependent. It can function as either a tumor promoter or a tumor suppressor, with its net effect determined by multiple factors, including tumor stage, genetic background, tumor microenvironment composition, and the extent of autophagic activation. While targeting mitophagy represents a promising therapeutic strategy, its functional duality necessitates approaches that extend beyond simple inhibition or activation. Future therapeutic development must therefore focus on precise, individualized modulation tailored to specific tumor contexts. CONCLUSION: Mitophagy plays a multidimensional and pivotal role in BC pathogenesis and treatment response. A deeper understanding of its nuanced mechanisms not only advances the fundamental knowledge of BC pathology but also unveils innovative avenues for diagnosis and targeted therapy, offering a promising strategy to overcome current clinical challenges.