miR-454-3p alleviates LPS-induced cardiomyocyte damage by negatively regulating STAT3 in sepsis-induced cardiomyopathy.

Abstract

Sepsis-induced cardiomyopathy (SICM) contributes greatly to high mortality in critically ill patients. Accumulating evidence indicates that miRNAs play key roles in sepsis-related organ injury. This work investigated the function and molecular mechanism of miR-454-3p in SICM, along with its potential clinical utility. A total of 100 healthy controls and 210 sepsis patients were enrolled. Sepsis patients were categorized into non-cardiomyopathy group (non-CM, n=105) and SICM group (n=105). Receiver operating characteristic (ROC) curve analysis, multivariate logistic regression, and Cox regression were performed to assess the clinical value of miR-454-3p. In vitro functional experiments were conducted using LPS-stimulated AC16 cardiomyocytes. The dual-luciferase reporter assay verified the targeting relationship between miR-454-3p and STAT3. miR-454-3p expression decreased progressively from healthy controls to non-CM patients and further to SICM patients. miR-454-3p demonstrated good diagnostic performance for SICM. Multivariate analysis identified miR-454-3p as both an independent protective factor against SICM and an independent predictor of favorable prognosis. Cellular experiments revealed that miR-454-3p directly binds to the 3'UTR of STAT3 and suppresses STAT3 expression. Functional assays indicated that miR-454-3p attenuates LPS-induced cardiomyocyte apoptosis, inflammation, and oxidative stress, whereas STAT3 overexpression reverses these protective phenotypes. Furthermore, western blot analysis showed that miR-454-3p inhibits activation of the JAK2/STAT3/NF-κB inflammatory cascade. In vitro assays suggest that miR-454-3p alleviates LPS-triggered cardiomyocyte damage by negatively regulating STAT3 and suppressing the JAK2/STAT3/NF-κB inflammatory cascade. Our single-center observational data indicate that circulating miR-454-3p correlates independently with SICM incidence and 28-day all-cause mortality, implying its potential value as a candidate diagnostic and prognostic biomarker for SICM. Nevertheless, correlational findings from this cross-sectional cohort cannot confirm causal relationships, and large-scale multicenter prospective cohorts are needed for external validation to verify its clinical utility.