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<p>Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options and poor prognosis. Although the single-nucleotide polymorphism <i>rs3810151</i> (p.Val94Ala) in <i>ZNF526</i> has been identified as a breast cancer susceptibility locus, the functional role and mechanistic basis of ZNF526 in TNBC remain unknown. In this study, we observed that <i>ZNF526</i> is highly expressed in TNBC, and its elevated expression correlates with worse clinical outcomes. Functional assays revealed that <i>ZNF526</i> overexpression promotes TNBC cell growth, whereas its knockdown suppresses tumor growth. Mechanistically, we discovered that ZNF526 activates SHMT1 expression, which subsequently enhances flux through the serine-glycine-one-carbon (SGOC) metabolic pathway. This metabolic activation increases glutathione (GSH) production, reduces reactive oxygen species (ROS) levels, and strengthens cellular antioxidant defenses, thereby facilitating TNBC progression. Our findings reveal ZNF526 as a novel regulator of redox balance in TNBC through SHMT1-mediated metabolic control, positioning it as a potential therapeutic target for TNBC.</p>

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ZNF526 drives tumor growth by enhancing SHMT1-dependent serine metabolism and antioxidant capability in TNBC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月20日

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  • Wenxing Qin,
  • Lujing Shao,
  • Qi Li,
  • Dan Zhang,
  • Xinyan Jia,
  • Chunyan Dong

摘要

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options and poor prognosis. Although the single-nucleotide polymorphism rs3810151 (p.Val94Ala) in ZNF526 has been identified as a breast cancer susceptibility locus, the functional role and mechanistic basis of ZNF526 in TNBC remain unknown. In this study, we observed that ZNF526 is highly expressed in TNBC, and its elevated expression correlates with worse clinical outcomes. Functional assays revealed that ZNF526 overexpression promotes TNBC cell growth, whereas its knockdown suppresses tumor growth. Mechanistically, we discovered that ZNF526 activates SHMT1 expression, which subsequently enhances flux through the serine-glycine-one-carbon (SGOC) metabolic pathway. This metabolic activation increases glutathione (GSH) production, reduces reactive oxygen species (ROS) levels, and strengthens cellular antioxidant defenses, thereby facilitating TNBC progression. Our findings reveal ZNF526 as a novel regulator of redox balance in TNBC through SHMT1-mediated metabolic control, positioning it as a potential therapeutic target for TNBC.