SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T?cell activation

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作者：Wenhui Liu, Danming You, Jiayang Lin, Huren Zou, Lei Zhang, Shenjian Luo, Youwen Yuan, Zhiyi Wang, Jingwen Qi, Weiwei Wang, Xueru Ye, Xiaoyu Yang, Yajuan Deng, Fei Teng, Xiaojun Zheng, Yuhao Lin, Zhiwei Huang, Yan Huang, Zhi Yang, Xuan Zhou, Yanan Zhang, Ruxin Chen, Lingling Xu, Jin Li, Wei Yang, Huijie Zhang
期刊：Cell Metabolism
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During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8 + T?cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8 + T?cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8 + T?cells via elevating 3-hydroxybutyrate dehydrogenase 1 ( Bdh1 ) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 ( Irf4 ), which is crucial for CD8 + T?cell activation. Furthermore, the ablation of Bdh1 in T?cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8 + T?cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8 + T?cells and may be an effective strategy for treating MASH.