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

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.

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