XPR1 downregulation inhibits hepatocellular carcinoma progression by suppressing serine metabolism

Xenotropic and polytropic retrovirus receptor 1 (XPR1) is highly expressed in various tumors and is associated with poor clinical prognosis, making it a proposed therapeutic target for cancer. However, the mechanism of XPR1 in tumorigenesis, particularly in hepatocellular carcinoma (HCC), remains unclear. Emerging evidence suggests that the knockdown of XPR1 in HCC cells leads to redox imbalance and mitochondrial damage. In this study, we aimed to investigate the molecular mechanisms and novel biological functions of XPR1 in HCC. Our findings revealed that XPR1 knockdown downregulated PHGDH expression, resulting in reduced serine biosynthesis, compromised redox homeostasis, exacerbated DNA damage, and pronounced mitochondrial fragmentation. Importantly, we identified MNX1 as a transcription factor of PHGDH. Restoration of MNX1 or PHGDH expression in XPR1-knockdown HCC cells effectively restored redox homeostasis and rescued tumor progression-associated functions. Moreover, in HCC cells in which XPR1 was knocked down, the re-expression of PHGDH effectively restored the intracellular serine level and tumorigenic capacity in vivo. Taken together, the results of our study demonstrate that XPR1 knockdown in HCC disrupts MNX1-mediated regulation of PHGDH expression, impairing serine metabolism and inducing redox imbalance, ultimately suppressing HCC progression. These findings suggest that XPR1 may serve as a therapeutic target for HCC.