Structural characterization and functional role of SLC7A6 in GSSG transport and Ferroptosis regulation

The role of solute carrier family 7 member 6 (SLC7A6) in cancer remains largely unexplored. In this study, we performed a comprehensive bioinformatics analysis to assess the expression profile, diagnostic potential, and prognostic significance of SLC7A6, and further validated its functional role in hepatocellular carcinoma (LIHC), cholangiocarcinoma (CHOL), and pancreatic cancer (PAAD). Integrative analyses using TCGA, and GTEx revealed dysregulated SLC7A6 expression across multiple cancer types with significant prognostic implications. In LIHC, SLC7A6-associated genes were identified through the STRING database and subjected to GO and KEGG enrichment analyses. Immunohistochemistry confirmed elevated SLC7A6 protein expression in LIHC, CHOL, and PAAD tissues. Functional assays, including CCK-8, colony formation, wound healing, and Transwell migration/invasion, demonstrated that SLC7A6 promotes proliferation, migration, and invasion of tumor cells. Mechanistically, AlphaFold 3 predicted a potential interaction between SLC7A6 and oxidized glutathione (GSSG), which was supported by biochemical assays showing altered intracellular levels of nitric oxide (NO), GSSG, and glutathione (GSH) upon SLC7A6 knockdown. These findings suggest that SLC7A6 contributes to tumor progression by regulating ferroptosis through disruption of redox homeostasis. Collectively, our study highlights SLC7A6 as a promising biomarker for cancer diagnosis and prognosis and provides experimental evidence supporting its functional role in driving tumor progression via ferroptosis modulation in LIHC, CHOL, and PAAD.