肝细胞癌（HCC）是全世界最常见的癌症之一。 PregnaneX受体（PXR）是一种外源性敏感核受体，在肝脏内源性和外源性物质的代谢中发挥着关键作用。在这里，我们研究 PXR 是否在 HCC 的发病机制中发挥作用。我们发现，经过二乙基亚硝胺 (DEN) 处理的 PXR 敲除 (KO) 小鼠体内出现了肝脏肿瘤。在 DEN 处理的 PXR KO 小鼠中，前列腺素 F2α (PGF2α) 和醛酮还原酶家族 1 成员 C18 (Akr1c18)（一种催化 PGH2 还原为 PGF2α 的前列腺素合酶）的肝脏水平显着升高。 DEN 处理的 PXR KO 小鼠中，甲胎蛋白 (AFP)、细胞周期蛋白 D1 (Ccnd1)、成纤维细胞生长因子 21 (FGF21) 和炎症细胞因子白细胞介素 6 (IL-6) 的肝脏 mRNA 水平显着增加。在 DEN 处理的 PXR KO 小鼠中，Akr1c 家族的其他成员、肝脏代谢酶（包括 Cyp1a2、Cyp2b10 和 Cyp3a11）以及胆汁酸合成酶 Cyp7a1 mRNA 水平显着降低。我们的研究结果表明，PXR 缺陷通过诱导 Akr1c18 表达和 PGF2α 水平促进 DEN 诱导的小鼠肝癌，并且 Akr1c18 合成的 PGF2α 水平增加增强肝细胞增殖并诱导炎症细胞因子产生，从而加速 DEN 治疗后肝脏肿瘤的发展，这表明 PXR 缺乏缺乏可能会创造一个更容易发生 DEN 诱导的肝脏肿瘤的微环境，而靶向 PXR 和 Akr1c18 来减少 PGF2α 生物合成可能是 HCC 的一种潜在且新颖的治疗策略。版权所有 © 2024。由 Elsevier Inc. 出版。

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F2α (PGF2α) and aldo-keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH2 to PGF2α, were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF2α levels and the increased PGF2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF2α biosynthesis may be a potential and novel therapeutic strategy for HCC.Copyright © 2024. Published by Elsevier Inc.