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Background <p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent demand for novel diagnostic and therapeutic targets. While mitochondrial carriers (MCs) play crucial roles in tumor metabolism, their specific contributions to HCC pathogenesis are poorly understood.</p> Methods <p>By leveraging multi-omics analyses, including single-cell sequencing and spatial transcriptomics, <i>SLC25A39</i> was identified as a key mitochondrial carrier in HCC. To assess its diagnostic potential, receiver operating characteristic (ROC) curves were constructed across multiple retrospective independent cohorts. Functional experiments of HCC cell lines with <i>SLC25A39</i> knockdown were conducted in vitro (cell proliferation, Transwell migration and invasion, and apoptosis assays) and in vivo (xenograft experiments). For deeper mechanistic insights, we employed proteomic profiling and mitochondrial functional assays. Additionally, the mitochondrial-targeted antioxidant (2-oxo-2-((2,2,6,6-tetramethyl-1-oxyl-piperidin-4-yl)amino)ethyl)triphenylphosphonium chloride (mitoTEMPO) was employed to reverse the observed phenotypes.</p> Results <p><i>SLC25A39</i> exhibited significant overexpression in HCC tissues, particularly in advanced-stage tumors, and demonstrated robust diagnostic accuracy (area under the curve (AUC) &gt; 0.900 across cohorts). Deficiency of SLC25A39 markedly reduced HCC cell proliferation, migration, and invasion capabilities, triggering caspase-9/3-dependent apoptosis. Consistent with in vitro findings, xenograft models revealed impaired tumor growth upon <i>SLC25A39</i> suppression. Mechanistically, SLC25A39 deficiency induced mitochondrial dysfunction, characterized by excessive mitochondrial reactive oxygen species (ROS), reduced membrane potential, diminished adenosine triphosphate (ATP) synthesis, aberrant mitochondrial permeability transition pore (mPTP) opening, and cytochrome <i>c</i> release. Notably, mitoTEMPO treatment reversed these effects, restoring mitochondrial redox homeostasis and rescuing malignant phenotypes.</p> Conclusions <p>Our study reveals SLC25A39 as a critical regulator of HCC progression via the mitochondrial ROS-cytochrome <i>c</i>-caspase signaling axis, highlighting its potential as a diagnostic biomarker and therapeutic target in HCC.</p> Graphical abstract <p></p>

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SLC25A39 identified as a key regulator of hepatocellular carcinoma progression through the mitochondrial ROS–cytochrome c–caspase signaling axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Manqiu Yuan,
  • Meng Du,
  • Jiachi Yu,
  • Jinyang Wang,
  • Tian Xia,
  • Qi Shen,
  • Chengbin Wang,
  • Ruibing Li

摘要

Background

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent demand for novel diagnostic and therapeutic targets. While mitochondrial carriers (MCs) play crucial roles in tumor metabolism, their specific contributions to HCC pathogenesis are poorly understood.

Methods

By leveraging multi-omics analyses, including single-cell sequencing and spatial transcriptomics, SLC25A39 was identified as a key mitochondrial carrier in HCC. To assess its diagnostic potential, receiver operating characteristic (ROC) curves were constructed across multiple retrospective independent cohorts. Functional experiments of HCC cell lines with SLC25A39 knockdown were conducted in vitro (cell proliferation, Transwell migration and invasion, and apoptosis assays) and in vivo (xenograft experiments). For deeper mechanistic insights, we employed proteomic profiling and mitochondrial functional assays. Additionally, the mitochondrial-targeted antioxidant (2-oxo-2-((2,2,6,6-tetramethyl-1-oxyl-piperidin-4-yl)amino)ethyl)triphenylphosphonium chloride (mitoTEMPO) was employed to reverse the observed phenotypes.

Results

SLC25A39 exhibited significant overexpression in HCC tissues, particularly in advanced-stage tumors, and demonstrated robust diagnostic accuracy (area under the curve (AUC) > 0.900 across cohorts). Deficiency of SLC25A39 markedly reduced HCC cell proliferation, migration, and invasion capabilities, triggering caspase-9/3-dependent apoptosis. Consistent with in vitro findings, xenograft models revealed impaired tumor growth upon SLC25A39 suppression. Mechanistically, SLC25A39 deficiency induced mitochondrial dysfunction, characterized by excessive mitochondrial reactive oxygen species (ROS), reduced membrane potential, diminished adenosine triphosphate (ATP) synthesis, aberrant mitochondrial permeability transition pore (mPTP) opening, and cytochrome c release. Notably, mitoTEMPO treatment reversed these effects, restoring mitochondrial redox homeostasis and rescuing malignant phenotypes.

Conclusions

Our study reveals SLC25A39 as a critical regulator of HCC progression via the mitochondrial ROS-cytochrome c-caspase signaling axis, highlighting its potential as a diagnostic biomarker and therapeutic target in HCC.

Graphical abstract