piR-45962 promotes autophagy-apoptosis crosstalk in myocardial ischemia-reperfusion injury via the HNRNPH1/GATA5 axis

Myocardial ischemia-reperfusion (IR) injury significantly impairs prognostic outcomes in patients with acute myocardial infarction (AMI), as reperfusion therapy itself can trigger cardiomyocyte death. Autophagic apoptosis-the interplay between autophagy and apoptosis-constitutes a pivotal mechanism contributing to IR-induced myocardial injury, yet its regulatory mechanisms remain incompletely elucidated. Piwi-interacting RNAs (piRNAs) have emerged as important regulators in cardiovascular diseases; however, their involvement in autophagic apoptosis during IR injury remains largely unexplored. In this study, using murine IR and H9c2 cell hypoxia-reoxygenation (HR) models, we identified differentially expressed piRNAs and found that piR-45962 was markedly upregulated. Functional experiments demonstrated that piR-45962 promotes autophagic apoptosis by enhancing the expression of LC3-II, Atg5, Bax, and Caspase-3, while reducing levels of p62 and Bcl-2. RNA pull-down assays and complementary approaches confirmed that piR-45962 directly interacts with Heterogeneous nuclear ribonucleoprotein 1(HNRNPH1), an RNA-binding protein implicated in apoptotic regulation. Moreover, HNRNPH1 was shown to interact with GATA binding protein 5(GATA5), a transcription factor whose knockout exacerbates autophagic apoptosis, whereas its overexpression ameliorates this effect. Mechanistically, piR-45962 downregulates GATA5 expression through upregulation of HNRNPH1, thereby establishing a novel piR-45962-HNRNPH1-GATA5 regulatory axis that contributes to myocardial injury during IR. These findings uncover a previously unknown molecular pathway and highlight a potential therapeutic target for mitigating IR-induced myocardial damage.