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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03558-w.