Liu Zhenghua, Xin Peng, Wu Weiwei, Jin Mingyue, Du Yang, Jiang Yuanjun, Liu Tao, Zhang Hao
Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P.R. China.
Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P.R. China.
Commun Biol. 2025 May 23;8(1):788. doi: 10.1038/s42003-025-08174-w.
Metastatic bladder cancer is characterized by its aggressive behavior and complex molecular mechanisms that remain largely undefined. This study explores the therapeutic potential of targeting peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) using liposomal nanoparticles to deliver PGC-1α siRNA to bladder cancer cells. We employed comprehensive transcriptomic, proteomic, and metabolomic analyses to investigate the impact of PGC-1α silencing. Our in vitro results demonstrate that targeting PGC-1α significantly impairs mitochondrial function and disrupts energy metabolism, affecting critical pathways such as glycolysis and the citric acid cycle, as well as altering mRNA nuclear export. In vivo experiments in animal models show that nanoparticles loaded with si-PGC-1α effectively reduce lung metastasis, indicating a significant impact on metastatic progression. These findings highlight PGC-1α as a key regulator of metabolic reprogramming in metastatic bladder cancer and suggest that its inhibition could serve as a promising therapeutic strategy. By elucidating the role of PGC-1α in cancer metabolism, this study provides new insights into the molecular underpinnings of bladder cancer metastasis and offers potential avenues for developing targeted therapies aimed at the metabolic vulnerabilities of this malignancy.
转移性膀胱癌具有侵袭性的行为和复杂的分子机制，而这些机制在很大程度上仍不明确。本研究探讨了使用脂质体纳米颗粒将过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）小干扰RNA（siRNA）递送至膀胱癌细胞，以靶向PGC-1α的治疗潜力。我们采用了全面的转录组学、蛋白质组学和代谢组学分析来研究PGC-1α沉默的影响。我们的体外研究结果表明，靶向PGC-1α会显著损害线粒体功能并扰乱能量代谢，影响糖酵解和柠檬酸循环等关键途径，还会改变mRNA的核输出。在动物模型中的体内实验表明，装载si-PGC-1α的纳米颗粒能有效减少肺转移，表明对转移进展有显著影响。这些发现突出了PGC-1α作为转移性膀胱癌代谢重编程的关键调节因子，并表明抑制它可能是一种有前景的治疗策略。通过阐明PGC-1α在癌症代谢中的作用，本研究为膀胱癌转移的分子基础提供了新的见解，并为开发针对这种恶性肿瘤代谢脆弱性的靶向治疗提供了潜在途径。
