NRF2-SOX4 complex regulates PSPH in hepatocellular carcinoma and modulates M2 macrophage differentiation

Hepatocellular carcinoma (HCC) progression is tightly linked to metabolic reprogramming and immune evasion. However, the transcriptional networks driving these processes remain misunderstood. Here, we identified a novel regulatory axis wherein the transcription factor SOX4 formed a stress-responsive complex with NRF2, as confirmed by co-immunoprecipitation and proximity ligation assay. This process was orchestrated via p62-mediated disruption of the KEAP1-SOX4 complex. The SOX4-NRF2 complex directly activated Phosphoserine Phosphatase (PSPH) transcription-as revealed by luciferase reporter and chromatin immunoprecipitation-enhancing serine biosynthesis and downstream metabolites critical for oxidative phosphorylation (OXPHOS) and redox balance. Inhibition of SOX4 or NRF2 impaired PSPH expression, exacerbated oxidative damage-marked by elevated 4-hydroxynonenal-and increased sensitivity to sorafenib treatment in HCC cells. Furthermore, PSPH-driven metabolites, particularly serine, fostered M2-like macrophage polarization, thereby potentially contributing to the promotion of an immunosuppressive tumor microenvironment. Analysis of HCC specimens from TCGA and clinical cohorts confirmed that high SOX4/NRF2/PSPH expression was correlated with increasing M2 macrophage infiltration and poor patient prognosis. Our findings revealed a previously unrecognized SOX4-NRF2-PSPH regulatory loop that coupled cancer metabolism with immune modulation. Targeting this axis may offer a promising therapeutic avenue to simultaneously disrupt metabolic support and immune evasion in HCC.