近日，南方医科大学教授高平及其小组揭示了AKR1D1通过促进胆汁酸代谢介导的NK细胞毒性抑制肝癌进展。相关论文于2025年2月25日发表在《细胞—代谢》杂志上。

该研究组发现，醛酮还原酶1D1 （AKR1D1）的缺失通过肠道微生物组失调促进异石胆酸（iso-LCA）的积累，从而损害自然杀伤细胞（NK）的细胞毒功能，导致肝细胞癌（HCC）的加速发展。从机制上讲，AKR1D1缺乏导致卵形拟杆菌（B. ovatthem）的比例增加，卵形拟杆菌将鹅去氧胆酸（CDCA）分解为iso-LCA。

此外，积累的iso-LCA以磷酸化- creb1 （p-CREB1）依赖的方式损害肝NK细胞的抗肿瘤活性。保钾利尿剂螺内酯治疗通过靶向iso-LCA介导的肿瘤免疫逃逸，显著增强抗PD1抗体对HCC进展的抑制作用。综上所述，他们的结果揭示了AKR1D1与HCC之间以前未被认识到的联系，并表明靶向B. ovatthem产生的iso-LCA可能是激活NK细胞毒性治疗HCC的一种有希望的策略。

据介绍，胆汁酸代谢和抗肿瘤免疫在肝癌进展过程中都被破坏。然而，它们之间复杂的监管关系在很大程度上仍不清楚。

附：英文原文

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

Author: Haoran Wei, Caixia Suo, Xuemei Gu, Shengqi Shen, Kashuai Lin, Chuxu Zhu, Kai Yan, Zhenhua Bian, Liang Chen, Tong Zhang, Ronghui Yan, Zhiyi Yang, Yingxuan Yu, Zhikun Li, Rui Liu, Junming He, Qiwei He, Xiuying Zhong, Weidong Jia, Chun-Ming Wong, Zhongjun Dong, Jie Cao, Linchong Sun, Huafeng Zhang, Ping Gao

Issue&Volume: 2025-02-25

Abstract: 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.

DOI: 10.1016/j.cmet.2025.01.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00011-7