MicroRNA-300-3p promotes cardiac hypertrophy by modulating the ACOX-1/GPX4 pathway

Cardiac hypertrophy (CH) represents a key pathological process in cardiac remodeling and progression toward heart failure. Understanding its underlying molecular mechanisms is essential for developing novel therapeutic strategies. MicroRNAs (miRNAs) play crucial regulatory roles in cardiovascular diseases, however, their specific involvement in CH remains incompletely understood. Here, we demonstrate that miR-300-3p modulates angiotensin II (Ang II)-induced CH through the ACOX1/GPX4 pathway. Functionally, miR-300-3p directly targets ACOX1, leading to its downregulation and subsequent enhancement of Ferroptosis. Overexpression of ACOX1 reversed these effects. Mechanistically, hypomethylation of the miR-300-3p promoter region, mediated by DNMT1, elevated miR-300-3p expression and contributed to Ang II-induced hypertrophic responses. Furthermore, ACOX1 exerted anti-hypertrophic effects via activation of the GPX4 signaling pathway. In conclusion, DNMT1-regulated promoter hypomethylation enhances miR-300-3p expression, suppresses ACOX1, and promotes Ferroptosis in Ang II-induced CH. The miR-300-3p/ACOX1/GPX4 axis uncovers novel molecular pathways in CH and identifies potential therapeutic regulators.