TREM1 as a master regulator of mitophagy-pyroptosis crosstalk in myocardial infarction: A dual-target strategy for precision therapy.

Abstract

Myocardial infarction (MI), a global health crisis driven by dysregulated immune responses and genetic-environmental interplay, remains inadequately addressed by current therapies targeting programmed cell death (PCD). While apoptosis, mitophagy, and pyroptosis collectively orchestrate MI progression. Emerging evidence underscores the pivotal roles of mitophagy and pyroptosis in regulating NLRP3 inflammasome activation, however, the crosstalk between these processes remains a critical unresolved question in cardiovascular immunology. Here, we identify Triggering Receptor Expressed on Myeloid cells 1 (TREM1) as a central molecular nexus governing this axis. Leveraging integrative bioinformatics analysis of the GSE66360 dataset combined with functional validation in macrophage-specific and MI rodent models, we demonstrate that TREM1 overexpression suppresses PINK1/Parkin-mediated mitophagy while paradoxically exacerbating NLRP3-dependent pyroptosis. Moreover, TREM1 knockdown significantly improved post-MI cardiac function and attenuated fibrotic remodeling. These findings establish TREM1 as both a prognostic biomarker for MI and a pleiotropic therapeutic target capable of simultaneously dampening NLRP3 inflammasome hyperactivation and promoting cardiac functional recovery.