Targeting TAGLN2 to Suppress Bone Metastasis of Lung Adenocarcinoma: A Spatiotemporal Regulatory Mechanism Driven by Dual-Axis FAP/FAK and PI3K/AKT/MYCN/IL-11 Signaling

Lung adenocarcinoma (LUAD), a predominant subtype of non-small cell lung cancer (NSCLC), exhibits bone metastasis that significantly impacts patient prognosis and quality of life. Transgelin-2 (TAGLN2), an actin-binding/cross-linking protein, is implicated in tumorigenesis through abnormal expression; however, its specific role, molecular mechanisms in LUAD, and spatiotemporal regulatory functions within the metastatic cascade remain incompletely understood, particularly lacking in-depth investigation. This study revealed that TAGLN2 is significantly overexpressed in both LUAD tissues and LUAD bone metastatic foci, and its expression level negatively correlated with the overall survival rate of LUAD patients. Experiments demonstrated that during the pre-metastatic phase, TAGLN2 binds to fibroblast activation protein (FAP), activating the focal adhesion kinase (FAK) signaling pathway. This activation drives cellular pseudopodia formation and epithelial-mesenchymal transition (EMT), thereby enhancing tumor cell migration and invasive capabilities, thus laying the groundwork for hematogenous metastasis. During the bone colonization phase, TAGLN2 upregulates the expression of the transcription factor MYCN via activation of the PI3K/AKT signaling pathway; MYCN subsequently binds to the promoter region of IL-11, driving its transcription and secretion; IL-11 further induces osteoclast activation, exacerbating bone resorption and osteolytic lesions. This dual-phase mechanism elucidates the spatiotemporal regulatory role of TAGLN2 throughout LUAD bone metastasis: regulating cellular motility in the early phase and reshaping the bone microenvironment in the late phase. Furthermore, computer-aided drug design (CADD) identified a natural compound capable of binding TAGLN2 with high affinity, suggesting its potential as a novel therapeutic strategy targeting TAGLN2 to disrupt the entire metastatic cascade.