Abstract
Solute carrier family 25 member 39 (SLC25A39) is a pivotal mitochondrial glutathione transporter and an emerging oncoprotein in hepatocellular carcinoma (HCC). While its cell-intrinsic roles are increasingly recognized, its comprehensive functions in modulating the tumor immune microenvironment (TIME) and epigenetic landscape within HCC remain undefined. To address this, we employed an integrated multi-omics and experimental approach, including TCGA, ssGSEA, CCK-8, Transwell, etc. Our study confirmed SLC25A39 upregulation and its pro-tumorigenic role. Notably, we provide several key novel insights: First, we establish the first link between SLC25A39 promoter hypermethylation at specific CpG sites and poor patient prognosis, revealing an epigenetic regulatory layer in HCC. Second and most importantly, we pioneer the exploration of SLC25A39 in the HCC immune context, demonstrating its association with a distinct immunosuppressive TIME characterized by a Th2-skewed profile, reduced cytotoxic cell infiltration, and elevated immune checkpoint (CTLA-4, PD-1) expression. Furthermore, drug sensitivity analysis linked SLC25A39 to a broader spectrum of pharmacological agents beyond sorafenib. Collectively, our findings not only reinforce SLC25A39 as a therapeutic target but, for the first time, reposition it as a potential modulator at the intersection of tumor metabolism, epigenetics, and immunology in HCC, offering a rationale for its inhibition, particularly combined with immunotherapy.