SQLE drives bladder cancer progression by boosting mitochondrial oxidative phosphorylation

作者：Yihong Dong, Xinjian Jiang, Xinxin Yang, Jinfeng Zhang, Qiang Fu, Yunfei Zhou, Yang Xun, Yin Fu, Yunjing Hou, Mujiao Li, Jun Yan, Jianwen Xu, Yujuan Yi, Meijuan Liu, Xiaorui Huo, Han Jiang, Yumeng Wang, Chenxu Guo, Qingxin Zhang, Alan H.B. Wu, Xiaoqing Li, Xiaohan Zhang, Shuyuan Chang, Akiko Tomii, Lin Jia, Xiao Yu, Xiaoyang Hu, Hongxue Meng, Dabin Liu, Shuijie Li · 发表于：Oncogene · 年份：2025 · DOI：10.1038/s41388-025-03626-3 · 被引用次数：3 · 研究领域：Cancer, Lipids, and Metabolism、Cholesterol and Lipid Metabolism、Eicosanoids and Hypertension Pharmacology

Bladder cancer (BCa) remains a prevalent malignancy with limited therapeutic options. Although cholesterol elevation links to BCa progression, the specific role of cholesterol metabolism remains unclear. Here, we demonstrate that squalene epoxidase (SQLE), a key cholesterol biosynthesis enzyme, drives BCa oncogenesis. SQLE is upregulated in BCa patients and correlates with poor survival. Functionally, bladder-specific Sqle transgenic (tg) mice showed accelerated tumorigenesis, while Sqle knockout (ko) demonstrated opposite effects in vivo. Mechanistically, SQLE localizes to mitochondria and directly interacts with Lon peptidase 1 (LONP1) to stabilize mitochondrial transcription factor A (TFAM) by preventing its proteolysis, leading to elevated oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mtROS). Pharmacological clearance of mtROS via Mito-TEMPO suppressed tumor growth in Sqle-overexpressing models. Importantly, the FDA-approved SQLE inhibitor terbinafine significantly suppressed BCa progression in preclinical models. Our findings establish SQLE as a critical regulator of mitochondrial metabolism in BCa, supporting SQLE inhibitors as potential therapeutics. In bladder cancer, overexpression of SQLE impairs LONP1-mediated TFAM degradation through direct interaction with LONP1, thereby leading to increased mitochondrial OXPHOS and the accumulation of mtROS, which ultimately contributes to tumor growth. Treatment with the SQLE inhibitor terbinafin...