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<p>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 <i>Sqle</i> transgenic (tg) mice showed accelerated tumorigenesis, while <i>Sqle</i> 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 <i>Sqle</i>-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.</p><p></p>

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SQLE drives bladder cancer progression by boosting mitochondrial oxidative phosphorylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Yihong Dong,
  • Xinjian Jiang,
  • Xinxin Yang,
  • Jinfeng Zhang,
  • Qiang Fu,
  • Yunfei Zhou,
  • Xun Yang,
  • Yin Fu,
  • Yunjing Hou,
  • Mujiao Li,
  • Jun Yan,
  • Jianwen Xu,
  • Yujuan Yi,
  • Meijuan Liu,
  • Xiaorui Huo,
  • Jiang Han,
  • Yumeng Wang,
  • Chenxu Guo,
  • Qingxin Zhang,
  • Aodi Wu,
  • Xiaoqing Li,
  • Xiaohan Zhang,
  • Shuyuan Chang,
  • Ayaka Tomii,
  • Lin Jia,
  • Yu Xiao,
  • Xiaoyang Hu,
  • Hongxue Meng,
  • Dabin Liu,
  • Shuijie Li

摘要

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.