GJB2 drives LUAD progression in part via cAMP-mediated M2 macrophage polarization through the PKA-CREB pathway.

BACKGROUND: M2 macrophage polarization is a key driver of lung adenocarcinoma (LUAD) progression, yet its underlying regulatory mechanisms remain unclear. The expression pattern and biological function of the gap junction protein GJB2 in LUAD have not been elucidated to date. METHODS: TCGA database analysis was used to determine GJB2 expression in LUAD and its correlation with prognosis. GJB2 knockdown (KD) and overexpression (OE) models were established in A549/NCI-H1975 cells. EdU, Transwell, and flow cytometry assays evaluated LUAD cell proliferation, migration, invasion, and apoptosis. A LUAD-THP-1 macrophage co-culture system, cAMP agonist/inhibitor treatment, and PKA-CREB pathway analysis were applied to explore mechanisms. Nude mouse xenograft models validated findings in vivo. RESULTS: GJB2 was significantly upregulated in LUAD tissues and correlated with reduced overall survival. GJB2-KD inhibited LUAD cell malignant behaviors and promoted apoptosis, while GJB2-OE exerted opposite effects. GJB2 mediated gap junction-dependent cAMP transfer to macrophages, activating the PKA-CREB axis to induce M2 polarization; cAMP agonists reversed GJB2-KD effects. In vivo, GJB2-KD suppressed tumor growth, reduced serum cAMP and M2 cytokines, and inhibited PKA/CREB phosphorylation. CONCLUSIONS: The GJB2-cAMP-PKA-CREB axis drives LUAD progression by inducing M2 macrophage polarization. GJB2 may serve as a novel prognostic biomarker and potential therapeutic target for LUAD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03537-1.