Key result
Dapagliflozin protects cardiac tissue in HF models by inhibiting STAT1 signaling and reducing myocardial inflammation.
Why the study?
Heart failure causes high morbidity and mortality, and while dapagliflozin has proven clinical benefits, its molecular mechanisms remain unclear.
Does dapagliflozin mitigate myocardial inflammation and metabolic stress in heart failure through STAT1 inhibition?
Does dapagliflozin mitigate myocardial inflammation and metabolic stress in heart failure through STAT1 inhibition?
Dapagliflozin exerts cardioprotective effects in heart failure by inhibiting STAT1 signaling, which bridges metabolic disturbances and immune dysregulation.
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Should not yet alter clinical HF care; extends understanding of STAT1 signaling in SGLT2i-mediated cardioprotection.
Background Heart failure (HF) is a global health challenge with high morbidity and mortality. While dapagliflozin (DAPA), a sodium–glucose cotransporter 2 inhibitor, has proven clinical benefits in HF, its molecular mechanisms remain unclear. Methods We integrated bulk and single-cell transcriptomic analyses with experimental validation to investigate the role of STAT1 in HF and its modulation by DAPA. Bulk RNA sequencing data from the GSE57345 dataset were analyzed for differential expression, enrichment, and weighted gene co-expression network analysis (WGCNA) to identify hub regulators. Single-cell RNA sequencing data (GSE145154) included normal controls (n = 4), dilated cardiomyopathy (DCM, n = 8), ischemic cardiomyopathy infarct regions (ICM_MI, n = 6), and non-infarct regions (ICM_NMI, n = 6), and were processed with Seurat and Harmony for integration, clustering, myeloid subcluster profiling, and AUCell pathway scoring. For in vivo validation, a rat model of myocardial infarction–induced HF was established and divided into control, HF, and HF+DAPA groups (6 mg/kg/day for 4 weeks). Histological examination, Western blotting, ELISA, flow cytometry, and serum bile acid assays were conducted. For in vitro assays, STAT1-overexpressing H9C2 cardiomyocytes were generated by lentiviral transduction. Cell viability (CCK‑8), STAT1 expression (qPCR and Western blot), and apoptosis (Annexin V/PI flow cytometry) were assessed with or without DAPA treatment. Results Transcriptomic analyses revealed widespread activation of bile acid, amino acid, and lipoic acid metabolic pathways in HF, coupled with immune remodeling dominated by increased M1 and reduced M2 macrophages. STAT1 emerged as a central hub gene linking metabolic stress and immune imbalance. Single-cell analysis confirmed aberrant STAT1 expression particularly in M1 and proliferating myeloid clusters. In vivo, DAPA suppressed myocardial STAT1 expression, alleviated inflammation, normalized macrophage polarization, and reduced cytokine and bile acid abnormalities. In vitro, DAPA rescued STAT1-overexpressing cardiomyocytes by restoring viability and reducing apoptosis. Conclusions STAT1 acts as a pivotal mediator bridging metabolic disturbances and immune dysregulation in HF. DAPA alleviates HF by inhibiting STAT1 signaling, thereby restoring immunometabolic balance and protecting cardiac tissue. These findings provide mechanistic insight into the cardioprotective effects of DAPA and position STAT1 as a promising biomarker and potential therapeutic candidate for HF management.
He et al. (2026) studied this question. Dapagliflozin inhibited STAT1 signaling, reducing myocardial inflammation and metabolic stress, improving macrophage balance, and protecting cardiac tissue in heart failure models.
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