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Background <p>Glucose deprivation is a prevalent stressor within the tumor microenvironment. Nonetheless, the fundamental mechanism through which non-small cell lung cancer (NSCLC) cells orchestrate survival and progression through specific metabolic hubs under such conditions remains poorly understood.</p> Methods <p>This study utilized integrated multiomics analyses, encompassing transcriptomics and metabolomics, to identify pivotal targets. Functional validation was performed via in vitro assays, including CCK-8, colony formation, Transwell, and EdU assays, as well as in vivo models, such as subcutaneous xenografts and tail-vein lung metastasis models. The function and mechanism of the MAPK/ATF3/ASNS signaling axis were comprehensively investigated using gene knockdown/overexpression techniques, Western blotting, immunohistochemistry, and metabolomic analysis.</p> Results <p>Combined transcriptomic and metabolomic analyses revealed that glucose deprivation markedly upregulates ASNS expression in NSCLC cells, correlating with unfavorable patient outcomes. Functionally, both in vitro and in vivo experiments confirmed that ASNS significantly promotes the malignant behaviors of NSCLC cells under glucose-deprived conditions. Metabolomic analysis revealed that ASNS supports tumor cell survival during energetic stress by maintaining a dynamic balance of multiple amino acids. Mechanistically, glucose deprivation activates the MAPK signaling pathway, leading to the upregulation of the transcription factor ATF3, which binds directly to the ASNS promoter and transcriptionally activates its expression, thereby promoting malignant progression in NSCLC. Finally, the combined targeting of glucose metabolism using 2-DG, along with ASNS inhibition, demonstrated additive antitumor efficacy in vivo.</p> Conclusion <p>The results of this study revealed that, under glucose deprivation stress, the MAPK/ATF3/ASNS axis functions as a critical signaling–metabolic hub, promoting NSCLC progression by driving amino acid metabolic reprogramming. Targeting this axis offers a novel strategy for intervening in tumor metabolic adaptation and developing innovative combination therapies.</p>

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The MAPK/ATF3/ASNS axis drives amino acid metabolic reprogramming to promote NSCLC survival under glucose deprivation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Fuzhi Yang,
  • Hao Qin,
  • Xuelin Zhang,
  • Yun Zhao,
  • Shuai Jiang,
  • Xiaoyu Chen,
  • Zheng Li,
  • Jing Wang,
  • Dongfang Tang,
  • Wen Gao,
  • Xunxia Zhu,
  • Xiaoyong Shen

摘要

Background

Glucose deprivation is a prevalent stressor within the tumor microenvironment. Nonetheless, the fundamental mechanism through which non-small cell lung cancer (NSCLC) cells orchestrate survival and progression through specific metabolic hubs under such conditions remains poorly understood.

Methods

This study utilized integrated multiomics analyses, encompassing transcriptomics and metabolomics, to identify pivotal targets. Functional validation was performed via in vitro assays, including CCK-8, colony formation, Transwell, and EdU assays, as well as in vivo models, such as subcutaneous xenografts and tail-vein lung metastasis models. The function and mechanism of the MAPK/ATF3/ASNS signaling axis were comprehensively investigated using gene knockdown/overexpression techniques, Western blotting, immunohistochemistry, and metabolomic analysis.

Results

Combined transcriptomic and metabolomic analyses revealed that glucose deprivation markedly upregulates ASNS expression in NSCLC cells, correlating with unfavorable patient outcomes. Functionally, both in vitro and in vivo experiments confirmed that ASNS significantly promotes the malignant behaviors of NSCLC cells under glucose-deprived conditions. Metabolomic analysis revealed that ASNS supports tumor cell survival during energetic stress by maintaining a dynamic balance of multiple amino acids. Mechanistically, glucose deprivation activates the MAPK signaling pathway, leading to the upregulation of the transcription factor ATF3, which binds directly to the ASNS promoter and transcriptionally activates its expression, thereby promoting malignant progression in NSCLC. Finally, the combined targeting of glucose metabolism using 2-DG, along with ASNS inhibition, demonstrated additive antitumor efficacy in vivo.

Conclusion

The results of this study revealed that, under glucose deprivation stress, the MAPK/ATF3/ASNS axis functions as a critical signaling–metabolic hub, promoting NSCLC progression by driving amino acid metabolic reprogramming. Targeting this axis offers a novel strategy for intervening in tumor metabolic adaptation and developing innovative combination therapies.