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Background <p>With the widespread of low-dose computed tomography (LDCT), an increasing number of early-stage lung adenocarcinomas (LUAD) presenting as ground-glass opacity (GGO) nodules are being detected. However, the metabolic dysregulation involved in the progression from GGO to solid nodule remains poorly understood. In this study, we investigated the significance of GPD1L-mediated glycerophospholipid metabolism dysregulation during this transition and explored potential therapeutic targets.</p> Methods <p>We conducted analysis on multi-omics of lung adenocarcinoma, including bulk RNA-seq, whole-exome sequencing, metabolomics and single-cell RNA seq data. Extensive experiments were conducted to validate the role of GPD1L and the potential therapeutic target GPX4. Rescue assays were performed to further elucidate the mechanism.</p> Results <p>Multi-omics analysis revealed the essential role of GPD1L-mediated glycerophospholipid metabolism dysregulation between ground-glass opacity and solid nodule. Knockdown of GPD1L in lung adenocarcinoma cell lines promoted tumor progression and attenuated the degradation of HIF-1α, conferring resistance to hypoxia and apoptosis. Metabolomics, transcriptomics, and in vitro experiments further demonstrated that GPD1L downregulation impairs GPX4 expression by reducing AKT phosphorylation. In addition, GPD1L expression was associated with poor prognosis and may serve as a potential biomarker for immunotherapy.</p> Conclusion <p>GPD1L-mediated glycerophospholipid metabolism dysregulation promotes lung adenocarcinoma progress by stabilizing HIF- 1α. Meanwhile, GPX4 were downregulates via AKT/NRF2/GPX4 pathway, suggesting a potential therapeutic target.</p>

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Integrated multi-omics analysis reveals GPD1L-mediated dysregulation of glycerophospholipid metabolism facilitates the progression of lung adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月14日

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  • Yifu Sun,
  • Yueren Yan,
  • Yudi Zhou,
  • Yuting Chen,
  • Chunnan Liu,
  • Yufang Bao,
  • Yang Zhang,
  • Han Han,
  • Haiquan Chen

摘要

Background

With the widespread of low-dose computed tomography (LDCT), an increasing number of early-stage lung adenocarcinomas (LUAD) presenting as ground-glass opacity (GGO) nodules are being detected. However, the metabolic dysregulation involved in the progression from GGO to solid nodule remains poorly understood. In this study, we investigated the significance of GPD1L-mediated glycerophospholipid metabolism dysregulation during this transition and explored potential therapeutic targets.

Methods

We conducted analysis on multi-omics of lung adenocarcinoma, including bulk RNA-seq, whole-exome sequencing, metabolomics and single-cell RNA seq data. Extensive experiments were conducted to validate the role of GPD1L and the potential therapeutic target GPX4. Rescue assays were performed to further elucidate the mechanism.

Results

Multi-omics analysis revealed the essential role of GPD1L-mediated glycerophospholipid metabolism dysregulation between ground-glass opacity and solid nodule. Knockdown of GPD1L in lung adenocarcinoma cell lines promoted tumor progression and attenuated the degradation of HIF-1α, conferring resistance to hypoxia and apoptosis. Metabolomics, transcriptomics, and in vitro experiments further demonstrated that GPD1L downregulation impairs GPX4 expression by reducing AKT phosphorylation. In addition, GPD1L expression was associated with poor prognosis and may serve as a potential biomarker for immunotherapy.

Conclusion

GPD1L-mediated glycerophospholipid metabolism dysregulation promotes lung adenocarcinoma progress by stabilizing HIF- 1α. Meanwhile, GPX4 were downregulates via AKT/NRF2/GPX4 pathway, suggesting a potential therapeutic target.