KIFC1 engages RUNX2/TGF-β signaling to promote lung cancer bone metastasis via disrupting bone homeostasis.

Bone metastasis affects 30-40% of lung cancer patients, markedly reducing survival and quality of life, yet the underlying molecular mechanisms remain incompletely understood. Comparative transcriptomic profiling of primary lung tumors and paired bone metastases revealed pronounced KIFC1 enrichment in metastatic lesions, which correlated with poor bone metastasis-free survival. Functionally, KIFC1 enhanced lung cancer cell migration and adhesion toward osteoblast-like cells and upregulated the bone-homing factors CXCR4 and OPN. KIFC1 promoted osteoclast recruitment and differentiation while suppressing osteogenic differentiation, thereby disrupting bone homeostasis. Mechanistically, KIFC1 associated with RUNX2 through its C-terminal motor domain and promoted RUNX2 nuclear accumulation in a motor activity-, microtubule-, and importin-dependent manner. Nuclear RUNX2 directly activated TGFB1 transcription, resulting in preferential activation of the TGF-β/SMAD3 signaling pathway. Genetic silencing of RUNX2 or pharmacological inhibition of SMAD3 largely abrogated KIFC1-mediated pro-metastatic and pro-osteolytic effects. In vivo, KIFC1 knockdown reduced intraosseous tumor burden and alleviated trabecular bone loss, whereas KIFC1 overexpression exacerbated osteolytic lesions, which were mitigated by disrupting RUNX2/TGF-β/SMAD3 signaling. Collectively, our findings identify KIFC1-mediated RUNX2 nuclear transport as a previously unrecognized upstream regulatory mechanism that activates the TGF-β/SMAD3 axis during lung cancer bone metastasis, which provides a conceptual framework for the development of targeted therapeutic strategies.