GATA3-Driven ceRNA Network in Lung Adenocarcinoma Bone Metastasis Progression and Therapeutic Implications

Background/Objectives: Bone metastasis is a common and severe complication of lung adenocarcinoma (LUAD), impacting prognosis and treatment outcomes. Understanding the molecular mechanisms behind LUAD bone metastasis (LUADBM) is essential for developing new therapeutic strategies. The interactions between long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in the competing endogenous RNA (ceRNA) network are crucial in cancer progression and metastasis, but the regulatory mechanisms in LUADBM remain unclear. Methods: Microarray analysis was performed on clinical samples, followed by weighted gene co-expression network analysis (WGCNA) and construction of a ceRNA network. Molecular mechanisms were validated using colony formation assays, transwell migration assays, wound healing assays to assess cell migration, and osteoclastogenesis assays to evaluate osteoclast differentiation. Potential therapeutic drugs and their binding affinities were predicted using the CMap database and K_deep. The interaction between the small-molecule drug and its target protein was confirmed by surface plasmon resonance (SPR) and drug affinity responsive target stability (DARTS) assays. Mechanistic insights and therapeutic efficacy were further validated using patient-derived organoid (PDO) cultures, drug sensitivity assays, and in vivo drug treatments. Results: Our results identified the XLOC_006941/hsa-miR-543/NPRL3 axis as a key regulatory pathway in LUADBM. We also demonstrated that GATA3-driven Th2 cell infiltration creates an immunosuppressive microenvironment that promotes metastasis. Additionally, we confirmed that the inhibitor E7449 effectively targets NPRL3, and its combination with the IL4R-blocking antibody dupilumab resulted in improved therapeutic outcomes in LUADBM. Conclusions: These findings offer new insights into the molecular mechanisms of LUADBM and highlight potential therapeutic targets, including the XLOC_006941/miR-543/NPRL3 axis and GATA3-driven Th2 cell infiltration. The dual-target therapy combining E7449 with dupilumab shows promise for improving patient outcomes in LUADBM, warranting further clinical evaluation.