CircClint1/miR-378b/NPDC1 axis: A novel therapeutic target and biomarker for myocardial infarction.

Myocardial infarction (MI) remains a leading cause of global morbidity, often progressing to irreversible ischemic cardiomyopathy due to the limitations of current pharmacological interventions in arresting adverse remodeling. Here, we combined whole-transcriptome sequencing with bioinformatic prioritization in a murine MI model to identify circClint1 as a pivotal, upregulated mediator within the infarcted microenvironment. Mechanistically, luciferase reporter assays and RNA pull-down confirmed that circClint1 functions as a competitive endogenous RNA (ceRNA) for miR-378b, thereby sequestering the miRNA and preventing the targeted degradation of its downstream effector, NPDC1. Notably, both in vivo Western blot and immunofluorescence revealed that ischemic stress triggers a dramatic and spatiotemporal accumulation of NPDC1 protein, particularly within the cytoplasm of peri-infarct cardiomyocytes. Functionally, we established an AAV9-mediated myocardial-specific overexpression model to evaluate the pathological consequences of sustained NPDC1 elevation. Our results demonstrated that NPDC1 accumulation significantly exacerbates post-infarction damage by promoting TUNEL-positive cardiomyocyte apoptosis, intensifying fibrotic remodeling, and impairing the myocardial microcirculation. Conversely, siRNA-mediated genetic silencing of NPDC1 in HL-1 cardiomyocytes effectively attenuated hypoxia-induced oxidative stress, preserved mitochondrial membrane potential, and improved cell viability. Collectively, this study provides definitive evidence that the circClint1/miR-378b/NPDC1 axis is a master detrimental driver of post-MI progression. By elucidating the multi-dimensional role of NPDC1 in coordinating cell death and impaired revascularization, our findings identify this axis as a promising therapeutic target for mitigating myocardial injury and improving long-term cardiovascular outcomes.