Work

The DBC1-HIF-1α-PPAR-γ axis regulates Treg cell differentiation to promote myocardial fibrosis in experimental diabetic cardiomyopathy through the paracrine secretion of Areg

Year: 2026

Type: article

Abstract: Background Regulatory T (Treg) cells play crucial roles in myocardial fibrosis, a key pathological feature of diabetic cardiomyopathy (DCM). Deleted in breast cancer 1 (DBC1) has emerged as an inhibitor of the immunosuppressive function of Treg cells in inflammatory states. Here, we studied the subpopulation differentiation and function of Treg cells in the myocardium of DCM and explored the role of DBC1 in Treg cell differentiation. Methods DBC1 fl/fl , DBC1 fl/fl -Fxop3 Cre , HIF-1α fl/fl -Fxop3 Cre , PPAR-γ fl/fl -Fxop3 Cre DCM mouse models were established to evaluate the effects of DBC, HIF-1α, and PPAR-γ on cardiac fibrosis and function. Adoptive transfer therapy was performed to assess the impact of ST2 hi Areg hi Treg cells. Flow cytometry was used to confirm the role of DBC1 in Treg cell differentiation. Co-culture systems were performed to analyze the effect of ST2 hi Areg hi Treg cells on fibroblast behaviors. Results ST2 + Treg subsets were increased in the hearts of DCM mice and exhibited increased Areg expression. DBC1 was upregulated in DCM mice and promoted myocardial fibrosis. ST2 hi Areg hi Treg subsets exhibited increased DBC1 expression and promoted myocardial fibrosis by producing Areg. ST2 hi Treg subsets promoted the viability, migration, and fibrosis of mouse CFs through Areg paracrine secretion in vitro . Furthermore, DBC1 enhanced the differentiation of myocardial Treg cells into the ST2 hi Areg hi subgroup in DCM through the HIF-1α-PPAR-γ axis. Conclusion Our current investigation shows that the DBC1-HIF-1α-PPAR-γ axis promotes the differentiation of myocardial Treg cells into the ST2 hi Areg hi pro-fibrotic subgroup, which drives maladaptive myocardial fibrosis and cardiac dysfunction via paracrine secretion of Areg in DCM mice.

Source: Frontiers in Endocrinology

DOI: 10.3389/fendo.2026.1780666