Inhibition of super-enhancer-driven lncRNA SHC alleviates coronary microembolization-induced myocardial injury by inhibiting cardiac ferroptosis.

Coronary microembolization (CME) is associated with an adverse prognosis in patients with acute coronary syndrome. However, the roles of long noncoding RNAs (lncRNAs) driven by super-enhancers (SEs) in the heart following CME have not been well elucidated. Here, we identified SE-associated lncRNA SHC (SE-regulated lncRNA highly expressed in CME) from histone H3 lysine-27 acetylation (H3K27ac) ChIP-seq data derived from rat hearts subjected to CME. A significant upregulation of lncRNA SHC was found in heart tissue following CME and Erastin-induced H9c2 cardiomyocytes. High levels of lncRNA SHC contributed to cardiac ferroptosis and subsequent myocardial injury following CME, while lncRNA SHC knockdown reversed this effect. Mechanistically, transcription factor specific protein 1 (SP1) binds to the SE at the lncRNA SHC locus and induces transcription. Furthermore, lncRNA SHC acted as a sponge for miR-26b-3p to promote oxidized low-density lipoprotein receptor 1 (Olr1) expression, which partially accounted for ferroptosis-dependent myocardial injury. In conclusion, these data suggest that the lncRNA SHC, driven by SE, contributes to cardiac ferroptosis and myocardial injury by targeting the miR-26b-3p/Olr1 cascade, and thus may be a promising therapeutic target to improve the prognosis of patients with CME.