Finerenone attenuates experimental autoimmune myocarditis and modulates cardiac macrophage and Th17-cell responses

Introduction Autoimmune myocarditis is characterized by immune-mediated myocardial injury and remodeling. However, whether the selective nonsteroidal mineralocorticoid receptor antagonist finerenone modulates the cardiac cellular microenvironment in autoimmune myocarditis remains unclear. This study aimed to investigate the effects of finerenone on experimental autoimmune myocarditis (EAM) and its regulation of the cardiac cellular microenvironment. Methods An EAM model was established in BALB/c mice by α -myosin heavy chain immunization, followed by finerenone treatment. Echocardiography, histopathology, immunohistochemistry, and RT-qPCR were used to evaluate cardiac injury, inflammation, fibrosis, and function. Single-cell RNA sequencing, T-cell receptor clonotype analysis, transcription factor regulatory network analysis, and cell-cell communication analysis were performed to characterize finerenone-induced changes in cardiac immune and stromal cell populations. Flow cytometry and macrophage-CD4 + T-cell co-culture experiments were performed to further validate the immune-related findings. Results Finerenone alleviated myocardial injury, inflammatory infiltration, and collagen deposition and improved left ventricular systolic function in EAM mice, including under a delayed-treatment regimen. Single-cell transcriptomic analysis revealed that finerenone remodeled the cardiac cellular microenvironment, reduced remodeling-associated Spp1 + macrophages and inflammation-associated Cxcl10 + macrophages, and suppressed IRF7-, STAT1-, STAT2-, and RFX5-associated transcriptional programs. Finerenone also reduced Th17-related inflammatory and cytotoxic programs and T-cell clonal expansion. Cell-cell communication analysis predicted reduced macrophage-Th17-cell communication, particularly MHC-II-associated signaling. Furthermore, macrophage-CD4 + T-cell co-cultures from finerenone-treated EAM mice exhibited reduced CD4 + T-cell proliferation and IL-17A + CD4 + T-cell proportions compared with those from untreated EAM mice. Profibrotic fibroblast programs and neutrophil inflammatory signaling were also suppressed. Discussion Targeting mineralocorticoid receptor-related immune networks may represent a potential therapeutic strategy for autoimmune myocarditis.