Distinct basal and stress-inducible xCT programs define therapeutic vulnerabilities in gastric cancer subtypes

xCT (SLC7A11), a key regulator of cellular redox homeostasis, has emerged as a potential therapeutic target in cancer; however, its regulatory heterogeneity and therapeutic implications in gastric cancer remain poorly understood. In this study, we investigated xCT expression patterns, regulatory states, and their therapeutic relevance across gastric cancer subtypes. Single-cell RNA sequencing analysis revealed higher xCT expression in diffuse-type gastric cancer than in intestinal-type gastric cancer, and elevated xCT expression was associated with poorer clinical outcomes. Consistent with these findings, diffuse-type gastric cancer cell lines exhibited markedly elevated basal xCT expression. In contrast, a subset of intestinal-type gastric cancer cell lines displayed stress-inducible xCT activation following oxidative stress or TGF-β stimulation. This inducible program was associated with increased basal NRF2 activity and coordinated induction of NRF2 target genes. Functionally, NRF2-high intestinal-type cancer cells acquired resistance to cisplatin following stress exposure, whereas NRF2-low intestinal-type cells remained relatively sensitive to cisplatin. In contrast, diffuse-type gastric cancer cells with high basal xCT expression exhibited enhanced sensitivity to combined xCT inhibition and cisplatin treatment. These findings identify distinct xCT regulatory states in gastric cancer, characterized by high basal xCT expression in diffuse-type tumors and NRF2-associated inducible xCT activation in a subset of intestinal-type tumors. Collectively, our results suggest that histologic subtype and NRF2 activity may provide a useful framework for therapeutic stratification and support subtype- and state-specific targeting of the xCT pathway in gastric cancer.