Background: The malignant progression of lung adenocarcinoma (LUAD) is not only a hallmark of this prevalent cancer but is also closely linked to epigenetic regulation, particularly N6-methyladenosine (m6A) methylation. Disruption of the m6A regulatory machinery results in the uncontrolled upregulation of multiple oncogenic drivers, thereby fueling tumor development. Our study investigated the mechanism by which G Protein Subunit Gamma 4 (GNG4), a gene upregulated via m6A modification, promoted LUAD by enhancing its mRNA stability and subsequently inhibiting the cGAS-STING pathway. This provides novel mechanistic insight for clinical LUAD research.

Methods: Based on transcriptomic and m6A sequencing data from The Cancer Genome Atlas Program (TCGA) database, the candidate gene GNG4, associated with m6A regulation, was identified. Correlations of GNG4 expression with two m6A regulators—the writer Vir Like M6A Methyltransferase Associated (VIRMA) and reader Insulin Like Growth Factor 2 MRNA Binding Protein 3 (IGF2BP3)—were statistically evaluated. Prediction of the biological functions pertaining to GNG4 was performed using Single-gene Gene Set Enrichment Analysis (Single-gene GSEA). Cellular experiments, including gene knockdown/overexpression, Western blot, flow cytometry, m6A-related assays, and cellular senescence detection, as well as animal models were employed to investigate the regulatory effects of m6A-modified GNG4 on the cGAS–STING pathway and its impact on cell cycle progression and cellular senescence.

Results: TCGA data combined with functional experiments demonstrated that GNG4 was highly expressed in LUAD (p < 0.05). Knockdown of GNG4 activated the cGAS-STING pathway, upregulated p21, induced G1/S cell cycle arrest (p < 0.05) and cellular senescence (p < 0.05), thereby inhibiting LUAD cell proliferation (p < 0.05) and tumor growth (p < 0.05). Mechanistically, increased GNG4 mRNA expression was associated with elevated m6A modification in LUAD. GNG4 expression was positively correlated with the m6A writer VIRMA and the m6A reader IGF2BP3. Knockdown of VIRMA or IGF2BP3 significantly reduced both m6A modification and mRNA expression of GNG4 (p < 0.05), thereby alleviating its suppressive effect on the cGAS-STING pathway, promoting cellular senescence (p < 0.05), and inhibiting proliferation in LUAD cells (p < 0.05).

Conclusion: The upregulation of m6A modification of GNG4 in LUAD enhances its mRNA stability, which in turn suppresses the cGAS–STING signaling pathway, ultimately inhibiting cellular senescence and promoting LUAD cell proliferation, thereby driving disease progression.