Intercellular transfer of LncRNA NEAT1 drives post-infarction inflammation by blocking the macrophage IRG1-itaconate metabolic axis.

Authors

Jiacheng Ge, Diankui Ge

Published in

Biochemistry and biophysics reports. Volume 47. Pages 102684. Epub Jul 07, 2026.

Abstract

Post-infarction inflammation and adverse remodeling remain major therapeutic challenges in ischemic heart disease. However, how specific intercellular communication drives macrophage metabolic maladaptation during this process remains unclear. This study aimed to elucidate the mechanisms by which damaged cardiomyocytes epigenetically reprogram macrophage immunometabolism post-myocardial infarction. Here, we identify a novel inter-organelle and inter-cellular signaling axis wherein hypoxic cardiomyocyte-derived exosomal NEAT1 acts as a pivotal epigenetic rheostat of macrophage immunometabolism. Using single-cell RNA sequencing and molecular tracing in a murine MI model, we demonstrate that exosomal NEAT1, rather than endogenous transcription, accumulates in infiltrating macrophages and interacts with nuclear Sox2. This interaction triggers IRG1 promoter hypermethylation, silencing the biosynthesis of the anti-inflammatory metabolite itaconate, thereby exacerbating pro-inflammatory polarization. To exploit this mechanism therapeutically, we employed an AAV9-mediated, cardiomyocyte-specific shNEAT1 delivery system to intercept this pathological exosomal transfer. This genetic intervention successfully restored macrophage itaconate homeostasis, suppressed the surge of pro-inflammatory cytokines (including MCP-1 and IL-1β), and significantly preserved cardiac contractility (LVEF/LVFS) 28 days post-MI. Our findings delineate the Hypoxic Cardiomyocyte-Exosomal NEAT1-Macrophage Sox2-IRG1 pathway as a critical driver of post-ischemic injury and establish AAV-mediated gene silencing of lncRNAs as a potent translational strategy for cardiac immunometabolic reprogramming.

PMID:
42438786
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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