The MicroRNAs-STAT3-cyclophilin D-cell apoptosis axis: a novel pathway for phosphocreatine treatment in heart disease.

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, with heart failure representing a major end-stage condition characterized by profound myocardial energy deficiency. Cellular signaling in heart disease is highly complex, particularly within pathways involving microRNAs (miRNAs), signal transducer and activator of transcription 3 (STAT3), and Cyclophilin D, which together form regulatory networks governing cardiomyocyte survival and apoptosis. This review examines the emerging miRNAs-STAT3-Cyclophilin D-apoptosis axis as a potential molecular framework through which phosphocreatine (PCr) may exert cardioprotective effects in heart failure. Current literature on the roles of miRNAs and STAT3 in cardiac function and apoptotic regulation is systematically summarized, with particular emphasis on evidence linking PCr to modulation of these signaling pathways. Experimental and preclinical studies suggest that PCr may influence cardiomyocyte survival by modulating STAT3 activity through miRNA-mediated mechanisms and by affecting Cyclophilin D-dependent mitochondrial pathways. Several STAT3-associated miRNAs have been implicated in the cytoprotective effects observed in PCr-treated cardiomyocytes. Collectively, the available evidence supports the concept that the miRNAs-STAT3-Cyclophilin D-apoptosis pathway represents a relevant regulatory axis in heart failure pathophysiology and a potential target for PCr-based therapeutic strategies. Further experimental and clinical studies are required to clarify the mechanistic details and translational relevance of this proposed pathway.