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

ABSTRACT: Paraoxonase-1 (PON1) is specifically expressed in the liver and has crucial effects on various liver diseases. The functions and mechanisms underlying of PON1 in hepatocellular carcinoma (HCC) remain obscure. Here, we show that PON1 acts as a metabolic regulator to mitigate regulatory T (Treg) cell-induced immunosuppression and HCC progression. Mechanistically, PON1 crippled lactic acid generation via recruiting Von Hippel-Lindau protein (VHL) to ubiquitinate Hypoxia-inducible factor alpha (HIF-1α), thereby reducing Treg cell frequency in HCC. In clinical settings, high PON1 expression correlated with better prognosis in HCC patients. Recombinant PON1 protein (rPON1) exhibited remarkable potency in impeding tumor growth, meanwhile, enhancing PON1 expression by Quercetin sensitized HCC to anti-programmed death-1(PD-1) therapy. Our findings elucidate a novel role of PON1 in orchestrating lactic acid production to relieve immunosuppression and suppress HCC, which paves the way for therapeutic intervention of HCC by targeting PON1.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Malignant Cell, Hepatoma Cell Line

DISEASE(S): Liver Cancer

SUBMITTER: Huanchen Shi  

LAB HEAD: Cheng Huang

PROVIDER: PXD060315 | Pride | 2025-12-22

REPOSITORIES: Pride