PSAT1 integrates ferroptosis resistance and immune evasion to drive hepatocellular carcinoma progression

The serine/glycine biosynthesis pathway plays a critical role in tumor progression and has emerged as a promising therapeutic target in cancer. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in this pathway and has been implicated in the progression of multiple malignancies. However, the functional significance and underlying mechanisms of PSAT1 in hepatocellular carcinoma (HCC) remain largely undefined. In this study, we identify PSAT1 as a critical determinant of ferroptosis resistance in HCC. Elevated PSAT1 expression was positively associated with ferroptosis resistance and poor clinical outcomes in patients with HCC. Both in vitro and in vivo functional assays demonstrated that PSAT1 promotes HCC cell proliferation and suppresses ferroptosis through an HSPA5-mediated adaptive endoplasmic reticulum response. Mechanistically, PSAT1 interacts with and stabilizes BCLAF1, thereby enhancing HSPA5 messenger RNA stability and translation in HCC cells. In addition, PSAT1 remodels the tumor immune microenvironment by promoting M2 tumor-associated macrophage polarization and regulatory T cell infiltration. PSAT1 up-regulates NRF2 expression, which directly binds to the CCL5 promoter to enhance CCL5 production and secretion by tumor cells, thereby fostering an immunosuppressive microenvironment. Therapeutically, pharmacological inhibition of PSAT1 with aminooxyacetic acid markedly potentiated the antitumor efficacy of anti-PD-1 immunotherapy. Our study reveals a previously unrecognized role of PSAT1 in coordinating ferroptosis resistance and immune escape in HCC and highlights therapeutic targeting of PSAT1 as a promising strategy for HCC treatment.