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AKR1D1 suppresses liver cancer progression by promoting bile acid metabolism-mediated NK cell cytotoxicity

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机构: [1]Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China [2]National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China [3]Department of Colorectal Surgery, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, China [4]School of Medicine, South China University of Technology, Guangzhou, China [5]School of Medicine and Institute for Immunology, Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China [6]Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, the First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China [7]State Key Laboratory of Liver Research, Department of Pathology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China [8]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China
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Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of Bacteroidetes ovatus (B. ovatus), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by B. ovatus might be a promising strategy to activate NK cell cytotoxicity to treat HCC.Copyright © 2025 Elsevier Inc. All rights reserved.

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大类 | 1 区 生物学
小类 | 1 区 细胞生物学 1 区 内分泌学与代谢
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第一作者机构: [1]Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China [2]National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
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通讯机构: [1]Medical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China [2]National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China [6]Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, the First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China [8]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China
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