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<p>Tumor-initiating cells (TICs) are central to cancer progression and metastasis; however, they remain challenging to target therapeutically. Here, using a breast-specific CYP4Z1-transgenic MMTV-PyMT mouse model, we show that CYP4Z1 notably accelerates tumor initiation, enlarges tumor size, promotes metastasis, and expands TIC populations. Multi-omics analyses reveal that CYP4Z1<sup>+</sup> epithelial cells exhibit enhanced stemness and reduced differentiation compared with CYP4Z1<sup>−</sup> counterparts. Notably, ISG15-mediated ISGylation of CYP4Z1 at lysine residues K259, K279, and K502 stabilizes the protein, augments its enzymatic function, promotes endoplasmic reticulum localization, and prevents ubiquitination, thereby amplifying TIC-like properties. This modification further upregulates triglyceride synthesis and promotes lipid droplet formation. Finally, we develop BM-51, a specific CYP4Z1 inhibitor that attenuates TIC-like traits and enhances chemotherapy efficacy. Our findings highlight the therapeutic potential of targeting CYP4Z1 and its ISGylation to disrupt TIC-driven breast cancer progression.</p><p></p>

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ISGylation-mediated stabilization of CYP4Z1 fuels breast cancer initiation and progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Yin Yuan,
  • Yu Lu,
  • Xuedan Han,
  • Yidong Zhang,
  • Qianqian Guo,
  • Hong Yao,
  • Qiyi Yu,
  • Manzhen Zhou,
  • Xinting Huang,
  • Hongqi Wang,
  • Miaomiao Niu,
  • Jun Yin,
  • Haibo Rong,
  • Lei Huang,
  • Xiaoman Li,
  • Shengtao Xu,
  • Lufeng Zheng

摘要

Tumor-initiating cells (TICs) are central to cancer progression and metastasis; however, they remain challenging to target therapeutically. Here, using a breast-specific CYP4Z1-transgenic MMTV-PyMT mouse model, we show that CYP4Z1 notably accelerates tumor initiation, enlarges tumor size, promotes metastasis, and expands TIC populations. Multi-omics analyses reveal that CYP4Z1+ epithelial cells exhibit enhanced stemness and reduced differentiation compared with CYP4Z1− counterparts. Notably, ISG15-mediated ISGylation of CYP4Z1 at lysine residues K259, K279, and K502 stabilizes the protein, augments its enzymatic function, promotes endoplasmic reticulum localization, and prevents ubiquitination, thereby amplifying TIC-like properties. This modification further upregulates triglyceride synthesis and promotes lipid droplet formation. Finally, we develop BM-51, a specific CYP4Z1 inhibitor that attenuates TIC-like traits and enhances chemotherapy efficacy. Our findings highlight the therapeutic potential of targeting CYP4Z1 and its ISGylation to disrupt TIC-driven breast cancer progression.