miR-30a-5p preserves cardiac homeostasis by reprogramming metabolic checkpoints in hypertrophic cardiomyopathy

Emerging evidence has established the regulatory role of miR-30a-5p in myocardial infarction through multifaceted mechanisms. However, its functional significance in pathological cardiac hypertrophy remains incompletely elucidated. This study systematically investigates the therapeutic potential and molecular underpinnings of miR-30a-5p in cardiac hypertrophy using complementary experimental approaches. We employed transgenic knockout murine models combined transverse aortic constriction (TAC)- and an angiotensin II (Ang II)-induced cardiac hypertrophy paradigms to evaluate the functional consequences of miR-30a-5p modulation on cardiac function, cardiac remodeling, and mitochondrial homeostasis. Multidisciplinary strategies incorporating cellular assays, RNA-sequencing profiling, and mitochondrial functional analysis were implemented to decipher mechanistic pathways. Notably, myocardial miR-30a-5p expression was significantly upregulated in both murine and cellular hypertrophy models. Genetic ablation of miR-30a-5p spontaneously developed a hypertrophic phenotype, while miR-30a-5p deficiency exacerbated TAC- or Ang II-induced pathological cardiac remodeling. Conversely, miR-30a-5p overexpression conferred significant protection against hypertrophy-associated ventricular dysfunction and interstitial fibrosis. Transcriptomic profiling revealed distinctive enrichment of mitochondrial bioenergetics and metabolic reprogramming pathways in knockout mice following TAC challenge, positioning mitochondrial integrity as a critical mediator of miR-30a-5p-dependent cardioprotection. Mechanistic studies further demonstrated that miR-30a-5p preserves myocardial mitochondrial function, enhances respiratory chain efficiency, and attenuates reactive oxygen species generation during hypertrophic stress. Collectively, our findings demonstrate that miR-30a-5p confers protection against pathological cardiac hypertrophy, mediated through the preservation of mitochondrial bioenergetic regulation and redox homeostasis.