Mettl1 mitigates sepsis-induced cardiomyopathy via inhibition of FDX1-dependent cuproptosis.

Abstract

Sepsis-induced cardiomyopathy (SICM) significantly contributes to sepsis-related mortality, yet its molecular mechanisms remain incompletely understood. Here, we identify cuproptosis-a copper-dependent mitochondrial cell death pathway-as a critical driver of SICM pathogenesis. In a murine SICM model induced by lipopolysaccharide (LPS), cardiac dysfunction was accompanied by myocardial copper accumulation and dysregulation of cuproptosis regulators. RNA sequencing (RNA-seq) analysis revealed cuproptosis as one of the top enriched pathways. Crucially, we demonstrate that the m7G methyltransferase Mettl1 functions as a cardioprotective factor. Mettl1 expression was upregulated in septic hearts and positively correlated with copper levels. In vitro, Mettl1 knockdown exacerbated LPS-induced cytotoxicity in cardiomyocytes and amplified intracellular copper overload. Mechanistically, Mettl1 deficiency potentiated LPS-triggered upregulation of FDX1-a key executor of cuproptosis-and suppressed PDHA1 expression. Our findings establish Mettl1 as a novel suppressor of cuproptosis that confers protection against sepsis-induced cardiotoxicity by restraining FDX1-mediated copper-dependent cell death. Targeting the Mettl1-FDX1 axis may offer a promising therapeutic strategy for SICM.