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 Kdeep. 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.
**背景/目的：** 骨转移是肺腺癌（LUAD）常见且严重的并发症，影响患者预后和治疗效果。阐明LUAD骨转移（LUADBM）背后的分子机制对于开发新的治疗策略至关重要。长链非编码RNA（lncRNA）、微小RNA（miRNA）和mRNA在竞争性内源RNA（ceRNA）网络中的相互作用在癌症进展和转移中至关重要，但它们在LUADBM中的调控机制尚不清楚。 **方法：** 对临床样本进行微阵列分析，随后进行加权基因共表达网络分析（WGCNA）并构建ceRNA网络。使用克隆形成实验、Transwell迁移实验、划痕愈合实验评估细胞迁移能力，以及破骨细胞生成实验评估破骨细胞分化，以验证分子机制。利用CMap数据库和Kdeep预测潜在治疗药物及其结合亲和力。通过表面等离子体共振（SPR）和药物亲和力响应靶点稳定性（DARTS）实验确认小分子药物与其靶蛋白的相互作用。进一步使用患者来源类器官（PDO）培养、药物敏感性实验和体内药物治疗验证了机制见解和治疗效果。 **结果：** 我们的研究结果确定XLOC_006941/hsa-miR-543/NPRL3轴是LUADBM中的关键调控通路。我们还证明，GATA3驱动的Th2细胞浸润创造了一个促进转移的免疫抑制微环境。此外，我们证实抑制剂E7449能有效靶向NPRL3，并且其与IL4R阻断抗体dupilumab联用，在LUADBM中改善了治疗效果。 **结论：** 这些发现为LUADBM的分子机制提供了新的见解，并突出了潜在的治疗靶点，包括XLOC_006941/miR-543/NPRL3轴和GATA3驱动的Th2细胞浸润。E7449与dupilumab联合的双靶点疗法显示出改善LUADBM患者预后的潜力，值得进一步的临床评估。
肿瘤(癌症)患者之家