SENP1 promotes deacetylation of isocitrate dehydrogenase 2 to inhibit ferroptosis of breast cancer via enhancing SIRT3 stability

Breast cancer, one of the most prevalent malignant tumors in women worldwide, is characterized by a poor prognosis and high susceptibility to recurrence and metastasis. Ferroptosis, a lipid peroxide-dependent programed cell death pathway, holds significant potential for breast cancer treatment. Therefore, investigating the regulatory targets and associated mechanisms of ferroptosis is crucial. In this study, we conducted proteomic screening and identified isocitrate dehydrogenase 2 (IDH2) as an important player in breast cancer progression. Our findings were further supported by CCK-8 assays, transwell experiments, and scratch assays, which demonstrated that the elevated expression of IDH2 promotes breast cancer progression. Through both in vitro and in vivo experiments along with the erastin treatment, we discovered that increased expression of IDH2 confers resistance to ferroptosis in breast cancer cells. By employing Western blot analysis, Co-IP techniques, and immunofluorescence staining methods, we elucidated the upstream molecular mechanism involving SENP1-mediated SIRT3 de-SUMOylatase, which enhances IDH2 enzyme activity through deacetylation, thereby regulating cell ferroptosis. In conclusion, our study highlights the role of the SENP1-SIRT3 axis in modulating ferroptosis via IDH2 in breast cancer cells, providing valuable insights for developing targeted therapies aimed at enhancing ferroptosis for improved management of breast cancer.