MSRB3 promotes gastric cancer progression and immunotherapy resistance by stabilizing GPX4 to inhibit ferroptosis

Methionine sulfoxide reductase B3 (MSRB3) possesses potent antioxidant activity and is highly expressed in various cancers, often correlating with poor prognosis. However, its biological effect and clinical importance in gastric cancer (GC) remain elusive. In this study, we first validated the expression and prognostic value of MSRB3 in GC through bioinformatics analyzes and clinical specimens. Subsequently, a series of functional experiments in vitro and in vivo were executed to explore the effect of MSRB3 in regulating GC cell proliferation, invasion, migration, ferroptosis, and the tumor immune microenvironment, as well as the underlying mechanisms. Finally, a subcutaneous xenograft model was established to assess the influence of MSRB3 on tumor growth and the efficacy of anti-PD-1 therapy. MSRB3 was markedly elevated in GC, and linked to poor patient prognosis. Functionally, MSRB3 facilitated the growth, migration, and invasion of GC cells. Indeed, MSRB3 stabilized GPX4 protein by inhibiting its ubiquitin-proteasomal-degradation, thereby suppressing lipid peroxidation and ferroptosis, which sustained GC cell survival and malignant progression. In vivo experiments confirmed that MSRB3 promoted tumor growth by inhibiting ferroptosis. Moreover, loss of MSRB3 increased intratumoral CD8⁺ T-cell accumulation and significantly enhanced the therapeutic response to PD-1 blockade. This synergy was reversed via the ferroptosis inhibitor Ferrostatin-1. MSRB3 functions as a suppressor of ferroptosis in GC by preserving GPX4 protein stability. MSRB3 drives tumor progression and confers immunotherapy resistance by stabilizing GPX4 to inhibit ferroptosis. Therefore, targeting MSRB3 may represent a potential strategy to improve immunotherapeutic efficacy in GC.