Cell Signal. 2026 Aug 21:112836. doi: 10.1016/j.cellsig.2026.112836. Online ahead of print.
ABSTRACT
Myocardial fibrosis secondary to pulmonary hypertension-induced right heart failure remains a challenging clinical condition with few effective therapeutic options. Gut microbiota-derived metabolites have emerged as critical regulators of cardiovascular homeostasis; however, the role and underlying mechanisms by which butyrate ameliorates right ventricular myocardial fibrosis remain undefined. Here, we established a monocrotaline (MCT)-induced rat model of right heart failure and performed in vitro macrophage-cardiac fibroblast co-culture assays. We demonstrated that butyrate-producing bacteria were significantly depleted in model rats. Sodium butyrate suppressed macrophage M1 polarization, reduced pro-inflammatory cytokine secretion, and inhibited cardiac fibroblast activation. Mechanistically, butyrate downregulated the expression of the chemokine CXCL3 and blocked the JAK2/STAT3 signaling pathway, thereby alleviating myocardial fibrosis. In vivo, butyrate supplementation ameliorated myocardial structural damage and collagen deposition. Collectively, our findings reveal that butyrate attenuates right heart failure-associated myocardial fibrosis by inhibiting CXCL3-mediated macrophage M1 polarization via the JAK2/STAT3 pathway, highlighting a novel therapeutic target for pathological cardiac remodeling.
PMID:42628891 | DOI:10.1016/j.cellsig.2026.112836