CD73 promotes the immunoregulatory functions of hepatic Tregs through enzymatic and nonenzymatic pathways in MASLD development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver disease characterized by chronic inflammation. Regulatory T cells (Tregs) highly express CD73 and play a critical role in modulating the immune response. However, the roles and mechanisms by which CD73 modulates Tregs in MASLD are still unknown. A choline-deficient high-fat diet (CDHFD) or methionine/choline-deficient diet (MCD) was used to establish a MASLD model. We found that CD73 expression was upregulated in Tregs via the FFA-mediated p38/GATA2 signaling pathway. Cd73 KO promoted MASLD progression, accompanied by decreased Treg viability and activity. Compared with Cd73 KO Tregs, adoptively transferred WT Tregs exhibited increased Treg activity and provided greater protection against hepatic inflammatory responses in MASLD. This immune protection is mediated by CD73 via both enzymatic and nonenzymatic pathways, degrading AMP into ADO to increase Treg function and block DR5-TRAIL-mediated cell death signaling. These findings suggest a potential immunotherapeutic approach for MASLD treatment and highlight its possible relevance for clinical application.