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<p>The roles of glutamic-oxaloacetic transaminase 2 (GOT2) in malate-aspartate shuttle (MAS), fatty acid binding/trafficking, and peroxisome proliferator-activated receptor (PPAR) delta axis have been documented. However, its function in ferroptosis remains unexplored. Here, we report that GOT2 promotes ferroptosis by disturbing mitochondrial redox homeostasis through inhibiting the synthesis of radical scavenger coenzyme Q10 (CoQ<sub>10</sub>). Mechanism, by fueling MAS, GOT2 increases net influx of NADH into mitochondria and enhances aerobic respiration, increasing cellular ATP generation. The high ATP/ADP ratio inactivates adenosine 5′-monophosphate-activated protein kinase (AMPK) and PPARα, downregulating the transcription of core enzymes in CoQ<sub>10</sub> synthesis pathway (FDPS, PDSS1/2, COQ3/5/6). In lung adenocarcinoma (LUAD), high expression of GOT2 restrains tumor progression by activating ferroptosis and igniting antitumor immunity. Whereas, the activation of GOT2-mediated ferroptosis exacerbates lesion in atherosclerosis disease. Our study reveals that GOT2-AMPK-PPARα-CoQ<sub>10</sub> axis is a novel pro-ferroptosis pathway, and modulating GOT2-mediated ferroptosis suggests an intriguing method to treat LUAD and atherosclerosis.</p><p></p>

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GOT2-mediated suppression of CoQ10 biosynthesis drives ferroptosis with divergent effects in lung adenocarcinoma and atherosclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Han Zhang,
  • Xinsheng Gu,
  • Yidan Sun,
  • Pengcheng Chen,
  • Qiangsheng Hu,
  • Hao Li

摘要

The roles of glutamic-oxaloacetic transaminase 2 (GOT2) in malate-aspartate shuttle (MAS), fatty acid binding/trafficking, and peroxisome proliferator-activated receptor (PPAR) delta axis have been documented. However, its function in ferroptosis remains unexplored. Here, we report that GOT2 promotes ferroptosis by disturbing mitochondrial redox homeostasis through inhibiting the synthesis of radical scavenger coenzyme Q10 (CoQ10). Mechanism, by fueling MAS, GOT2 increases net influx of NADH into mitochondria and enhances aerobic respiration, increasing cellular ATP generation. The high ATP/ADP ratio inactivates adenosine 5′-monophosphate-activated protein kinase (AMPK) and PPARα, downregulating the transcription of core enzymes in CoQ10 synthesis pathway (FDPS, PDSS1/2, COQ3/5/6). In lung adenocarcinoma (LUAD), high expression of GOT2 restrains tumor progression by activating ferroptosis and igniting antitumor immunity. Whereas, the activation of GOT2-mediated ferroptosis exacerbates lesion in atherosclerosis disease. Our study reveals that GOT2-AMPK-PPARα-CoQ10 axis is a novel pro-ferroptosis pathway, and modulating GOT2-mediated ferroptosis suggests an intriguing method to treat LUAD and atherosclerosis.