Li Dongqing, Su Hang, Deng Xiaolin, Huang Yuan, Wang Zihuan, Zhang Jinge, Chen Chen, Zheng Zaosong, Wang Qiong, Zhao Shanchao, Chen Zhe-Sheng, Chen Haiyong, Hou Lina, Tan Wanlong, Li Fei
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Department of Urology, Ganzhou People's Hospital, Ganzhou, P.R. China.
Int J Biol Sci. 2025 Jan 27;21(4):1530-1544. doi: 10.7150/ijbs.107632. eCollection 2025.
Globally, bladder cancer is the tenth most common cancer. Mitophagy, a critical process regulating mitochondrial quantity and quality, has attracted increasing attention for its pivotal function in cancer. Nonetheless, its roles and underlying mechanisms in bladder cancer are yet to be elucidated. Therefore, in this study, 16 mitophagy-related genes were screened to construct a robust prognostic model with exceptional predictive accuracy for the outcomes of patients with bladder cancer. Of these genes, DARS2 was identified as a key regulator that significantly affected cancer progression. The findings established that DARS2 promoted the G1-to-S phase transition by upregulating CDK4 expression, thereby suppressing cellular senescence and driving cell proliferation. In addition, DARS2 augmented PINK1 expression, leading to increased PINK1-mediated mitophagy. Both and experiments confirmed that DARS2 inhibited cellular senescence and facilitated tumor progression by enhancing PINK1-mediated mitophagy. The observations from this study have provided novel insights into the multifaceted roles of DARS2-mediated mitophagy in bladder cancer. Targeting DARS2 and its regulation of mitophagy is a promising therapeutic strategy to improve the outcomes for patients with bladder cancer.
在全球范围内，膀胱癌是第十大常见癌症。线粒体自噬是一种调节线粒体数量和质量的关键过程，因其在癌症中的关键作用而受到越来越多的关注。尽管如此，其在膀胱癌中的作用和潜在机制仍有待阐明。因此，在本研究中，筛选了16个与线粒体自噬相关的基因，以构建一个对膀胱癌患者预后具有极高预测准确性的强大预后模型。在这些基因中，DARS2被确定为一个显著影响癌症进展的关键调节因子。研究结果表明，DARS2通过上调CDK4表达促进G1期到S期的转变，从而抑制细胞衰老并驱动细胞增殖。此外，DARS2增强了PINK1的表达，导致PINK1介导的线粒体自噬增加。体内和体外实验均证实，DARS2通过增强PINK1介导的线粒体自噬抑制细胞衰老并促进肿瘤进展。本研究的观察结果为DARS2介导的线粒体自噬在膀胱癌中的多方面作用提供了新的见解。靶向DARS2及其对线粒体自噬的调节是改善膀胱癌患者预后的一种有前景的治疗策略。
