SRPK3 exacerbates cardiac ischemia/reperfusion injury by regulating KLF3-mTOR/P70 S6K-mediated autophagy

Abstract

Myocardial ischemia-reperfusion (I/R) injury remains a leading cause of cardiac dysfunction and mortality worldwide. Serine/arginine-Rich Protein Kinase 3 (SRPK3) is highly expressed in cardiac muscle, yet its specific pathological role in I/R injury has not been fully characterized. In this study, we utilized cardiac-specific knockout mouse models and cardiomyocyte hypoxia/reoxygenation assays to investigate the function of SRPK3. Our results demonstrated that SRPK3 deficiency significantly preserved cardiac function, reduced infarct size, and attenuated apoptosis and oxidative stress. Conversely, SRPK3 overexpression exacerbated these pathological phenotypes. Mechanistically, by integrating transcriptomics, phosphoproteomics, and site-directed mutagenesis, we revealed that SRPK3 directly phosphorylates the Transcription Factor KLF3 at the Ser71 residue. This phosphorylation event disrupts KLF3-mediated transcriptional activation of mTOR, thereby suppressing the mTOR/P70 S6K signaling axis. Consequently, this inhibition unleashes an excessive, maladaptive autophagic flux that transitions from a homeostatic mechanism to a lethal process, further aggravating myocardial injury. Collectively, we systematically elucidate that SRPK3 acts as a detrimental regulator in myocardial I/R injury by inducing lethal autophagy via the KLF3-mTOR axis. These findings identify the SRPK3-KLF3 interaction as a critical molecular switch and offer a promising therapeutic target for managing ischemic heart disease. This figure systematically delineates the mechanistic role of SRPK3 in myocardial ischemia/reperfusion injury. Acting as a critical regulatory factor, SRPK3 phosphorylates KLF3 at the Ser71 residue and concomitantly suppresses the mTOR signaling pathway, thereby inducing excessive pathological autophagy. This dysregulated autophagic flux, characterized by increased autophagosome formation, loses its cytoprotective function and instead exacerbates cardiomyocyte apoptosis and oxidative stress, ultimately leading to deterioration of cardiac function.