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<p>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 <i>Pon1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Zhou Lu,
  • Huanchen Shi,
  • Rongshan Gao,
  • Chengjie zhong,
  • Wei Zhang,
  • Jian Zhu,
  • Jianhang Huang,
  • Ronghua Liu,
  • Yun Xing,
  • Yiwei Chu,
  • Haixiang Sun,
  • Guoming Shi,
  • Aiwu Ke,
  • Jian Zhou,
  • Jiabin Cai,
  • Jia Fan,
  • Pingting Gao,
  • Cheng Huang

摘要

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.