Inhibition of ULK1 attenuates ferroptosis-mediated cardiac hypertrophy via HMGA2/METTL14/SLC7A11 axis in mice.

Abstract

UNC-51-like kinase 1 (ULK1), a primary serine/threonine kinase, is implicated in diverse pathophysiological processes. Previous findings have linked ULK1-dependent autophagy to cardiac hypertrophy. Our study further explored the functional role and molecular mechanisms of ULK1 in non-autophagic signaling pathways. Notably, ULK1 expression was significantly elevated in both transverse aortic constriction (TAC)-induced hypertrophic mouse hearts and Angiotensin II (Ang II)-treated cardiomyocytes, suggesting an increased sensitivity to hypertrophic stimuli potentially mediated by ULK1-induced ferroptosis in hypertrophic cardiomyocytes. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reduced ULK1-induced cardiomyocyte hypertrophy and ferroptosis. Proteomic analysis identified the upregulation of transcription factor High Mobility Group A2 (HMGA2) as a key mechanism in this ferroptotic process. Elevated HMGA2 levels exacerbated ferroptosis, evidenced by increased cell death, lipid peroxidation, ROS production, and reduced GPX4 expression. Furthermore, HMGA2 was shown to promote cardiomyocyte ferroptosis via binding to Methyltransferase-like 14 (METTL14), which in turn enhanced ferroptosis in cardiomyocytes through SLC7A11 m⁶A modification. In vivo, a delivery system using neutrophil membrane (NM)-coated mesoporous silica nanoparticles (MSN) was developed to inhibit cardiac hypertrophy, underscoring the therapeutic potential of targeting ULK1. Overall, this study demonstrates that ULK1 promotes cardiac hypertrophy through HMGA2/METTL14/SLC7A11 axis-mediated cardiomyocyte ferroptosis, suggesting a novel therapeutic approach for cardiac hypertrophy.