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 mechanismss of PON1 in hepatocellular carcinoma (HCC) remain obscure.Here, we demonstrate that PON1 serves as a metabolic regulator to counteractct regulatory T (Treg) cell-mediated immunosuppression, thereby suppressing HCC progression. Mechanistically, PON1 promotesVon Hippel-Lindau protein (VHL)-mediated ubiquitination and degradation of hypoxia-inducible factor alpha(HIF-1a), which attenuates lactic acid generation and limits Treg cell accumulation in HCC.In clinicalsettings, higher PON1 expression is correlated with a better prognosis in patients with HCC. RecombinantPON1 protein (rPON1) exhibited remarkable potency in impeding tumor growth, meanwhile, enhancingPON1 expression by quercetin sensitized HCC to anti-programmed death-1(PD-1) therapy. Our findingselucidate a novel role of PON1 in orchestrating lactic acid production to relieve immunosuppression andsuppress HCC, paving the way for therapeutic interventions for HCC by targeting PON1.