Srsf7 stabilization by the PIWI-interacting RNA AB352916 enhances Pkm alternative splicing to orchestrate cardiac...

Cardiac fibrosis is a key pathological process following in myocardial infarction (MI), involves excessive extracellular matrix deposition and scar formation, leading to increased ventricular stiffness and reduced compliance. Our team recently identified a highly conserved PIWI-interacting RNA, AB352916 (termed CRAPIR), critical for cardiac regeneration. However, its role in post-MI cardiac fibrosis remains unclear. In this study, we demonstrated that myofibroblast-specific overexpression of AB352916 significantly exacerbated post-MI cardiac function and fibrosis. Conversely, adeno-associated virus (AAV)-mediated knockdown of AB352916 in myofibroblasts notably improved cardiac function and ameliorated pathological cardiac fibrosis. Furthermore, AB352916 overexpression promoted fibroblast activation, whereas its inhibition significantly attenuates TGF-β1-regulated fibrotic response. Mechanistically, AB352916 specifically bound to the RNA recognition motif (RRM) domin of serine and arginine-rich splicing factor 7 (Srsf7) and inhibited Srsf7 ubiquitination, thereby facilitating Srsf7-mediated alternative splicing of pyruvate kinase (Pkm), leading to a pro-fibrotic metabolic shift characterized by enhanced glycolysis and mitochondrial respiration that drives the progression of cardiac fibrosis. Importantly, myofibroblast-specific overexpression of Srsf7 abrogates the rescue effect of AB352916 knockdown on post-MI cardiac fibrosis. Moreover, overexpression of PkmΔE2 could attenuate the protective effects of the AB352916 antagomir or Srsf7 siRNA on TGF-β1-induced fibroblast activation and metabolic dysregulation. Collectively, our findings indicate that AB352916 drives post-MI cardiac fibrosis through Srsf7-dependent alternative splicing of Pkm, inducing a metabolic switch towards enhanced glycolysis and mitochondrial respiration, highlighting the AB352916/Srsf7/PkmΔE2 axis as a potential therapeutic target for fibrotic remodeling.