SIRT5 Sustains Stemness and Promotes Metastasis and Angiogenesis in Cervical Cancer via Activation of the TGF-β Signaling Pathway

Background: SIRT5, a mitochondrial NAD+‑dependent deacetylase, plays diverse roles in cancer. This study explored its expression, clinical relevance, and functions in cervical cancer. Methods: We systematically analyzed SIRT5 expression in cervical cancer tissues, assessed its correlation with patient survival, and investigated its functional roles through overexpression and knockdown experiments in vitro and in vivo. Results: SIRT5 was significantly overexpressed in cervical cancer tissues and correlated with poor patient survival. Functionally, SIRT5 overexpression enhanced cell migration, invasion, and stemness phenotypes (tube and sphere formation), while its knockdown reversed these effects. Mechanistically, SIRT5 upregulated stemness markers SOX2 and Nanog and activated Smad2/3 phosphorylation. Inhibition of the TGF-β signaling pathway reversed these SIRT5-induced effects. In vivo, SIRT5-overexpressing xenografts showed increased p-Smad2, Nanog, and CD31 expression, promoting metastasis and angiogenesis, but tumor growth remained unchanged. Conclusions: These findings suggest that SIRT5 facilitates cervical cancer metastasis and angiogenesis via TGF-β signaling, identifying it as a potential therapeutic target.