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<p>Lung adenocarcinoma (LUAD), the most common lung cancer subtype, has a poor prognosis and limited treatments, underscoring the need for new biomarkers and targets, particularly in mitochondrial metabolism. Our study identifies SLC25A39, a mitochondrial glutathione transporter, as a key oncogenic factor in LUAD. Bioinformatics and tissue analyses revealed significantly elevated SLC25A39 protein levels despite stable mRNA expression, correlating with poorer patient survival. Functionally, SLC25A39 overexpression promoted LUAD cell proliferation and migration, while its knockdown or deletion suppressed these malignant traits in vitro and in vivo. Mechanistically, SLC25A39 loss impaired mitochondrial oxidative phosphorylation, increased reactive oxygen species (ROS), and triggered apoptosis. Notably, we found that reduced expression of the m-AAA protease AFG3L2 in LUAD post-translationally stabilizes SLC25A39, leading to its accumulation. These findings demonstrate that AFG3L2 downregulation drives SLC25A39’s oncogenic activity, positioning SLC25A39 as a promising therapeutic target for LUAD.</p><p></p>

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SLC25A39 overexpression exacerbates lung adenocarcinoma progression and is negatively regulated by AFG3L2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月24日

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  • Wenxuan Hu,
  • Jian Yang,
  • Zhike Chen,
  • Yongsen Li,
  • Gaomeng Luo,
  • Kang Hu,
  • Zihao Lu,
  • Xin Lv,
  • Yonghao Cao,
  • Haoyang Yuan,
  • Cong Cao,
  • Jun Zhao,
  • Chun Xu

摘要

Lung adenocarcinoma (LUAD), the most common lung cancer subtype, has a poor prognosis and limited treatments, underscoring the need for new biomarkers and targets, particularly in mitochondrial metabolism. Our study identifies SLC25A39, a mitochondrial glutathione transporter, as a key oncogenic factor in LUAD. Bioinformatics and tissue analyses revealed significantly elevated SLC25A39 protein levels despite stable mRNA expression, correlating with poorer patient survival. Functionally, SLC25A39 overexpression promoted LUAD cell proliferation and migration, while its knockdown or deletion suppressed these malignant traits in vitro and in vivo. Mechanistically, SLC25A39 loss impaired mitochondrial oxidative phosphorylation, increased reactive oxygen species (ROS), and triggered apoptosis. Notably, we found that reduced expression of the m-AAA protease AFG3L2 in LUAD post-translationally stabilizes SLC25A39, leading to its accumulation. These findings demonstrate that AFG3L2 downregulation drives SLC25A39’s oncogenic activity, positioning SLC25A39 as a promising therapeutic target for LUAD.