Finerenone mitigates type 1 diabetic cardiomyopathy via modulation of cardiac macrophage–fibroblast crosstalk

Background Diabetes mellitus has reached epidemic proportions worldwide. Diabetic cardiomyopathy (DbCM), a major diabetic complication, is a leading cause of increased morbidity and mortality among diabetic patients. The pathogenesis of DbCM is highly complex, with cardiac cellular crosstalk critically involved in its pathological progression. Finerenone (Fine) has been shown to exert beneficial effects in patients with heart failure, while, its role and precise molecular mechanisms in DbCM remain incompletely understood. Purpose This study was designed to investigate the cardiac intercellular crosstalk in DbCM and elucidate the specific mechanisms underlying the protective effects of Fine against DbCM. Methods A mouse model of type 1 DbCM was established via streptozotocin (STZ) intraperitoneal injection. Fine was orally administered to evaluate its cardioprotective effects. A macrophage depletion strategy was employed to explore the involvement of macrophages in the cardioprotection of Fine. RNA sequencing and Transwell co-culture assays using isolated macrophages and fibroblasts were performed to investigate the role of cardiac macrophage–fibroblast crosstalk in myocardial fibrosis and the intervention effect of Fine. Furthermore, gene-edited mice were used to verify the molecular mechanism underlying the cardioprotective effect of Fine. Results Fine significantly attenuated macrophage infiltration in DbCM, and macrophage depletion partially abolished the cardioprotective effect conferred by Fine (Figure 1). Fine markedly suppressed cardiac inflammatory activation and pro-fibrotic signalling pathways, as well as IL-33 expression in macrophages (Figure 2). In vitro experiments further demonstrated that Fine primarily disrupted the IL-33/ST2-dependent crosstalk between macrophages and fibroblasts, thereby inhibiting fibroblast activation and the expression of pro-fibrotic proteins. Notably, fibroblast-specific overexpression of ST2 reversed the therapeutic benefits of Fine against DbCM. Mechanistically, Fine downregulated macrophage IL-33 via modulation of Trem2, and macrophage-specific Trem2 knockout abrogated the inhibitory effect of Fine on IL-33, thus neutralising its cardioprotective action. Conclusions Fine alleviates DbCM via modulating the crosstalk between cardiac macrophages and fibroblasts. Targeting the macrophage Trem2/IL-33/ST2 signalling axis may represent a novel therapeutic strategy for DbCM.