Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma

Paraoxonase-1 (PON1) is specifically expressed in the liver and has crucial effects on various liver diseases. The functions and underlying mechanisms of PON1 in hepatocellular carcinoma (HCC) remain unclear. Here, we demonstrate that PON1 serves as a metabolic regulator to counteract regulatory T (Treg) cell-mediated immunosuppression, thereby suppressing HCC progression. Mechanistically, PON1 promotes Von Hippel-Lindau protein (VHL)-mediated ubiquitination and degradation of hypoxia-inducible factor alpha (HIF-1α), leading to attenuated lactic acid production and limited Treg cell accumulation in the HCC microenvironment. In clinical settings, higher PON1 expression is correlated with a better prognosis in patients with HCC. Recombinant PON1 protein (rPON1) effectively impeded tumor growth. Furthermore, enhancing Pon1 expression with quercetin sensitized HCC to anti-programmed death-1(PD-1) therapy in murine HCC. Our findings elucidate a role of PON1 in orchestrating lactic acid production to relieve immunosuppression and suppress HCC, paving the way for targeting PON1 as a therapeutic strategy. Paraoxonase-1 (PON1) is a liver-specific glycoprotein that has been shown to be a tumor suppressor in hepatocellular carcinoma (HCC). Here, the authors show that PON1 reduces HCC tumor growth due to regulation of lactic acid production and regulatory T cell-mediated immunosuppression.