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Background <p>Mitochondrial dysfunction has been implicated in various cancers, including non-small cell lung cancer (NSCLC). This study aimed to elucidate the role of mitochondrial dysfunction in NSCLC prognosis and the molecular mechanisms involved, particularly focusing on the Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in mitochondrial metabolism.</p> Methods <p>We analyzed the expression of SHMT2 in NSCLC tissue and its prognostic correlation by using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus Series (GSE81809) databases. Further, the CRISPR-Cas9 system was employed to establish SHMT2-knockout lung adenocarcinoma (LUAD) cell lines, assessing its impact on cell proliferation and apoptosis through various in vitro assays and in vivo nude mouse xenograft models. Mitochondrial homeostasis was evaluated by assessing the ROS levels, mitochondrial morphology, and membrane potential. Meanwhile, the SHMT2 inhibitor SHIN1 and the ROS scavenger N-Acetylcysteine (NAC) were employed to validate the underlying mechanism.</p> Results <p>The results revealed that SHMT2 was significantly overexpressed in LUAD tissues and was associated with poor patient prognosis. SHMT2-knockout as well as SHIN1-treatment significantly inhibited the proliferation of LUAD cells and induced ROS-dependent mitochondrial apoptosis. Mechanistically, SHMT2 deficiency could increase the recruitment of BAX to mitochondria, reducing ΔΨm, and release of Cytochrome C (Cyto C) from mitochondria, thereby activating the caspase cascade and initiating intrinsic mitochondrial apoptosis. NAC treatment can reverse the apoptosis and mitochondrial dysfunction induced by SHMT2 knockout. In vivo experiments further confirmed that SHMT2 knockout significantly inhibited tumor growth, whereas ROS scavenging attenuated its antitumor effects.</p> Conclusions <p>Our findings suggest that SHMT2 is vital for regulating LUAD apoptosis by maintaining mitochondrial ROS homeostasis, and its deficiency triggers apoptosis through the ROS-BAX-Cyto C-Caspase signaling. Targeting SHMT2 could thus offer new clinical insights and be a promising strategy for LUAD treatment.</p>

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SHMT2 inhibition triggers mitochondrial apoptosis to suppress lung adenocarcinoma progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Yili Chen,
  • Xinyu Zhang,
  • Xiaodong Pang,
  • Yang Yang,
  • Di Lu,
  • Jian Zhao,
  • Jianjie Zhu,
  • Wenwen Du,
  • Chen Gu,
  • Jianjun Li,
  • Lei Gu,
  • Jian-an Huang,
  • Zeyi Liu,
  • Yuanyuan Zeng

摘要

Background

Mitochondrial dysfunction has been implicated in various cancers, including non-small cell lung cancer (NSCLC). This study aimed to elucidate the role of mitochondrial dysfunction in NSCLC prognosis and the molecular mechanisms involved, particularly focusing on the Serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in mitochondrial metabolism.

Methods

We analyzed the expression of SHMT2 in NSCLC tissue and its prognostic correlation by using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus Series (GSE81809) databases. Further, the CRISPR-Cas9 system was employed to establish SHMT2-knockout lung adenocarcinoma (LUAD) cell lines, assessing its impact on cell proliferation and apoptosis through various in vitro assays and in vivo nude mouse xenograft models. Mitochondrial homeostasis was evaluated by assessing the ROS levels, mitochondrial morphology, and membrane potential. Meanwhile, the SHMT2 inhibitor SHIN1 and the ROS scavenger N-Acetylcysteine (NAC) were employed to validate the underlying mechanism.

Results

The results revealed that SHMT2 was significantly overexpressed in LUAD tissues and was associated with poor patient prognosis. SHMT2-knockout as well as SHIN1-treatment significantly inhibited the proliferation of LUAD cells and induced ROS-dependent mitochondrial apoptosis. Mechanistically, SHMT2 deficiency could increase the recruitment of BAX to mitochondria, reducing ΔΨm, and release of Cytochrome C (Cyto C) from mitochondria, thereby activating the caspase cascade and initiating intrinsic mitochondrial apoptosis. NAC treatment can reverse the apoptosis and mitochondrial dysfunction induced by SHMT2 knockout. In vivo experiments further confirmed that SHMT2 knockout significantly inhibited tumor growth, whereas ROS scavenging attenuated its antitumor effects.

Conclusions

Our findings suggest that SHMT2 is vital for regulating LUAD apoptosis by maintaining mitochondrial ROS homeostasis, and its deficiency triggers apoptosis through the ROS-BAX-Cyto C-Caspase signaling. Targeting SHMT2 could thus offer new clinical insights and be a promising strategy for LUAD treatment.