SRPK3 regulates back-splicing of pre-MYOCD through Phosphorylating SRSF10 to modulate cardiac hypertrophy

Cardiac hypertrophy represents a hallmark of pathological remodeling in heart failure, involving complex molecular networks that remain incompletely defined. While post-transcriptional regulation is increasingly recognized as a key control layer, the role of splicing kinases in this process requires further elucidation. This study identifies serine/arginine-rich protein kinase 3 (SRPK3) as a central regulator of myocardial hypertrophy through its control of circular RNA (circRNA) biogenesis. We observed marked SRPK3 upregulation in phenylephrine/angiotensin II-treated cardiomyocytes, transverse aortic constriction (TAC) rats, and human heart failure datasets. Gain- and loss-of-function studies demonstrated that SRPK3 overexpression exacerbates hypertrophic phenotypes, including increased cell surface area and upregulation of markers (ANP, BNP, Myh7). Conversely, siRNA knockdown or pharmacological inhibition with the pan-SRPK inhibitor MSC-1186 effectively attenuated these pathological features. Mechanistically, SRPK3 interacts with and phosphorylates the splicing factor SRSF10 at specific serine residues (S129, S131, and S133). This phosphorylation event inhibits the back-splicing of pre-MYOCD, resulting in reduced cardioprotective circ-MYOCD levels and a concomitant increase in linear MYOCD expression. The depletion of circ-MYOCD relieves its competitive inhibition on linear splicing, driving the transcriptional activation of pro-hypertrophic signaling pathways. Crucially, restoring circ-MYOCD expression reversed SRPK3-driven pathology, confirming its protective role. These findings establish the SRPK3-SRSF10-circ-MYOCD axis as a critical regulatory circuit in cardiac remodeling. By bridging kinase activity with splicing dynamics, this study highlights RNA processing as a vital therapeutic target. Targeting this axis via SRPK3 inhibition or circ-MYOCD delivery represents a promising dual-modality strategy for treating heart failure.