BMP5 suppresses malignant progression of clear cell renal cell carcinoma by promoting DNA damage accumulation and sustained DNA damage response signaling.

Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy of the urinary system that lacks effective biomarkers for early diagnosis and prognosis. Bone morphogenetic protein 5 (BMP5), a member of the bone morphogenetic protein family within the TGF-β superfamily, is known to participate in the regulation of cellular differentiation, proliferation, and apoptosis. Bioinformatics analyses indicated that BMP5 expression is significantly reduced in ccRCC and is associated with unfavorable patient outcomes. Gain- and loss-of-function experiments in ccRCC cell lines showed that BMP5 overexpression markedly inhibited cell proliferation, migration, and invasion, promoted G1-phase arrest and apoptosis, and suppressed tumor growth in a xenograft mouse model, whereas BMP5 silencing produced the opposite effects. Rescue experiments further confirmed the specificity of BMP5-mediated phenotypes. RNA sequencing, Western blotting, comet assays, and immunohistochemical analyses further demonstrated that BMP5 overexpression was accompanied by increased markers of DNA double-strand breaks and sustained activation of DNA damage response (DDR) signaling. Time-course γ-H2AX analysis further revealed sustained DNA damage signals following genotoxic stress, consistent with increased DNA damage burden and delayed resolution of DNA lesions. In addition, pathway perturbation experiments further supported the contribution of DDR signaling to BMP5-associated cell fate regulation. Collectively, these findings suggest that BMP5 is associated with increased DNA damage burden and sustained DDR activation, which likely contribute to tumor-suppressive effects in ccRCC, highlighting its potential prognostic relevance and the possible therapeutic significance of BMP5-associated DDR signaling.