SLC25A39 binds and modulates PRDX1 to suppress ROS-induced necroptosis in hepatocellular carcinoma.

[BACKGROUND] Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with poor prognosis driven by tumor heterogeneity and therapy resistance. Mitochondrial solute carriers (SLC25 family) are crucial for metabolic and redox regulation, yet their roles in HCC remain poorly understood.

[METHODS] Transcriptome analysis integrating TCGA and GTEx datasets identified dysregulated SLC25 genes, from which prognostic members were screened by Cox and LASSO regression. Clinical validation was performed using patient tissues. Functional assays were conducted in SLC25A39 knockdown and overexpression models in vitro and in xenografts. Redox homeostasis and necroptotic signaling were evaluated by ROS/GSH/MDA assays, pharmacological inhibition, RNA-seq, and immunoblotting. Interactions between SLC25A39 and PRDX1 were verified by mass spectrometry, co-immunoprecipitation, and immunofluorescence, with PRDX1 rescue experiments assessing functional relevance.

[RESULTS] SLC25A39 was markedly upregulated in HCC tissues and correlated with poor overall survival. Knockdown of SLC25A39 suppressed cell proliferation, migration, invasion, and tumor growth, while overexpression enhanced malignant behaviors. Mechanistically, SLC25A39 deficiency disrupted mitochondrial redox homeostasis, inducing ROS accumulation, GSH depletion, MDA elevation, and activation of RIPK1/RIPK3/p-MLKL-mediated necroptosis. PRDX1 was identified as a direct binding partner of SLC25A39. Importantly, PRDX1 overexpression alleviated oxidative stress, suppressed necroptotic signaling, and partially restored proliferative and invasive phenotypes of SLC25A39-deficient cells.

[CONCLUSION] This study identifies SLC25A39 as a novel oncogenic driver in HCC. By stabilizing PRDX1 and sustaining mitochondrial redox balance, SLC25A39 promotes tumor progression while preventing necroptotic cell death. Targeting the interplay between SLC25A39, PRDX1, and necroptotic signaling may provide new therapeutic opportunities for HCC.