SLC25A39 facilitates Sorafenib resistance in hepatocellular carcinoma by inhibiting mitochondrial oxidative stress-induced ferroptosis.

[UNLABELLED] Mitochondria are intracellular double-membrane-bound organelles that play a crucial role in maintaining redox homeostasis, disruptions of which are closely linked to oncogenesis. Recent investigations have identified SLC25A39 as a mitochondrial membrane transporter essential for the importation of glutathione (GSH) into mitochondria. However, the roles of SLC25A39 in human malignancies remain inadequately understood. Here, we observed a marked upregulation of SLC25A39, which correlates with poor prognostic outcomes in hepatocellular carcinoma (HCC). The silencing of SLC25A39 resulted in a reduction of HCC cell viability and proliferation through inducing ferroptosis via increasing mitochondrial ROS accumulation. In contrast, the overexpression of SLC25A39 enhanced survival and proliferation of HCC cells by promoting ferroptosis evasion through reducing mitochondrial ROS accumulation. Importantly, we discovered that the expression of SLC25A39 was notably increased in Sorafenib-resistant HCC cells, and silencing of SLC25A39 could sensitize HCC cells to ferroptotic cell death and augment the therapeutic efficacy of Sorafenib against HCC. Overall, our investigation provides comprehensive evidence that SLC25A39 is a critical regulator of ferroptosis evasion and proposes its potential as a therapeutic target to improve the effectiveness of Sorafenib in the treatment of HCC.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12935-025-04151-9.