Inclisiran attenuates myocardial ischemia/reperfusion injury by inhibiting macrophage M1 polarization

Macrophage polarization is pivotal in myocardial ischemia/reperfusion (I/R) injury. Inclisiran is a small interfering RNA agent that lowers low-density lipoprotein cholesterol by targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). However, whether Inclisiran exerts LDL-C-independent cardioprotective effects within the acute I/R window remains unclear. In this study, wild-type C57BL/6J mice were pretreated with Inclisiran before I/R surgery. Myocardial injury was assessed by echocardiography, laser speckle contrast imaging, and TTC/Evans Blue staining. Macrophage polarization and its direct impact on cardiomyocytes or fibroblasts were investigated in co-culture system in vitro. Target gene screening was performed by chromatin immunoprecipitation (ChIP)-sequencing, and transcriptional regulation was validated by dual-luciferase assay and ChIP-qPCR. Protein interaction was confirmed by molecular docking, surface plasmon resonance, and co-immunoprecipitation. Our results demonstrated that Inclisiran significantly attenuated myocardial injury and dysfunction, inhibited macrophage M1 polarization, reduced cardiomyocyte apoptosis, and suppressed fibroblast activation. Mechanistically, Inclisiran disrupted the direct interaction between PCSK9 and JNK, thereby blocking the HIF-1α-mediated transcriptional regulation of Myo1d, and ultimately suppressing macrophage M1 polarization. In conclusion, Inclisiran alleviates myocardial I/R injury by targeting the JNK–HIF-1α–Myo1d signaling axis. These findings identify a previously unrecognized cardioprotective mechanism that is LDL-C-independent within the acute I/R window, suggesting Inclisiran as a promising therapeutic strategy for ischemic cardiomyopathy.