Hydroxysafflor yellow A alleviates ischemic myocardial injury by targeting SF3A1 to improve mitochondrial energy metabolism.

Myocardial ischemia/reperfusion injury (MIRI) significantly contributes to the increased mortality associated with cardiovascular diseases; however, there are no effective therapeutic agents. Hydroxysafflor yellow A (HSYA) is a natural small molecule that possesses potent anti-ischemic myocardial injury properties. However, precise molecular targets remain unclear. In this study, we identified splicing factor 3A subunit 1 (SF3A1) as a direct target of HSYA through thermal proteome profiling. SF3A1 participates in spliceosome assembly and it has been reported to mediate the alternative splicing of precursor messenger RNA. Based on this function, we used RNA sequencing to investigate the downstream mechanisms of SF3A1 and found that the most strongly correlated genes and pathways were associated with mitochondrial injury and energy metabolism. Furthermore, the results demonstrated that in MIRI, HSYA could clear the accumulation of reactive oxygen species, thereby restoring mitochondrial polarization and membrane potential. HSYA further drove oxidative phosphorylation in the electron transport chain and promoted ATP synthesis. Additionally, we silenced the SF3A1 gene and confirmed that SF3A1 played a regulatory role in mitochondrial energy metabolism and HSYA-mediated therapeutic effects. In vivo, HSYA also demonstrated significant therapeutic efficacy in acute myocardial mouse infarction models, with the ability to enhance mitochondrial energy metabolism in myocardial tissue. In summary, our research suggests that SF3A1, through the pharmacological targeting of mitochondrial energy metabolism, may emerge as a novel therapeutic target for MIRI. Moreover, specific modulation of SF3A1 by HSYA may provide a new perspective for designing cardiovascular protectants with novel mechanisms, facilitating the development of precise therapies for MIRI.