IFIT3 Knockdown Attenuates Pressure-Overload-Induced Cardiac Inflammation and Remodeling Through a JNK/H3K9 Lactylation-Associated Mechanism

Aims: Heart failure (HF) is characterized by sustained inflammation and adverse cardiac remodeling, yet the mechanisms underlying macrophage-associated inflammatory activation remain incompletely understood. This study investigated whether the interferon-induced protein IFIT3 contributes to pressure-overload-induced HF and explored the potential involvement of JNK signaling and histone H3 lysine 9 lactylation (H3K9la). Methods and Results: We performed integrated bioinformatics analyses of publicly available single-cell RNA sequencing data from human failing hearts (GEO: GSE145154) and identified IFIT3 as a macrophage-enriched hub gene. In vivo , we used AAV-mediated IFIT3 knockdown in a transverse aortic constriction (TAC) mouse model. In vitro , we performed siRNA-mediated IFIT3 silencing in RAW264.7 macrophage-like cells and rescue treatments with anisomycin and sodium lactate. Single-cell transcriptomic analysis revealed that IFIT3 was significantly upregulated in macrophages from failing human hearts. In TAC-induced heart failure in mice, myocardial IFIT3 expression was increased and showed partial colocalization with CD68-positive cells. AAV-mediated IFIT3 knockdown improved cardiac function, reduced inflammatory cytokine production, and attenuated myocardial fibrosis in vivo . In RAW264.7 macrophage-like cells, IFIT3 silencing suppressed lipopolysaccharide-induced inflammatory cytokine secretion and reduced JNK phosphorylation and H3K9la levels. Rescue experiments showed that anisomycin partially restored p-JNK, H3K9la, and inflammatory cytokine expression, whereas sodium lactate supplementation partially rescued H3K9la levels and inflammatory responses in IFIT3 -silenced cells. Conclusion: These findings suggest that IFIT3 contributes to pressure-overload-induced cardiac inflammation and remodeling and that this effect is associated with JNK activation and H3K9 lactylation. IFIT3 may represent a potential target for immunoinflammatory modulation in heart failure.