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

Why It Matters

Targeting IFIT3 could break the cycle of inflammation and remodeling that fuels heart‑failure progression, offering a novel immunomodulatory avenue for therapy. Its link to JNK signaling and epigenetic lactylation expands the molecular toolbox for cardiology drug development.

Key Takeaways

• IFIT3 upregulated in macrophages of failing human hearts.
• IFIT3 knockdown improves cardiac function and reduces fibrosis in TAC mice.
• Silencing IFIT3 lowers JNK phosphorylation and H3K9 lactylation in macrophages.
• Anisomycin or lactate partially rescues inflammatory signaling after IFIT3 loss.
• IFIT3 emerges as a therapeutic target for inflammation-driven heart failure.

Pulse Analysis

Heart failure remains a leading cause of morbidity, driven in part by chronic inflammation that remodels cardiac tissue. Recent single‑cell RNA sequencing of human failing hearts has highlighted macrophage heterogeneity, revealing IFIT3 as a previously underappreciated hub gene that spikes in disease‑associated immune cells. This discovery aligns with a growing body of evidence that interferon‑stimulated genes can modulate innate immune pathways, positioning IFIT3 at the crossroads of cytokine signaling and epigenetic regulation.

In preclinical models, silencing IFIT3 via AAV vectors markedly improved left‑ventricular performance after transverse aortic constriction, a standard pressure‑overload paradigm. Mice displayed lower serum natriuretic peptide levels, reduced collagen deposition, and diminished expression of pro‑inflammatory mediators such as IL‑6 and TNF‑α. Parallel experiments in RAW264.7 macrophage‑like cells linked IFIT3 loss to attenuated JNK activation and a drop in H3K9 lactylation, an emerging histone mark that translates metabolic lactate flux into transcriptional outcomes. Pharmacologic re‑activation of JNK with anisomycin or supplementation with sodium lactate partially rescued the inflammatory phenotype, underscoring the pathway’s therapeutic relevance.

The translational implications are significant. By targeting IFIT3, clinicians could intervene upstream of both kinase signaling and epigenetic reprogramming, potentially halting the vicious cycle of inflammation‑driven remodeling. Moreover, the dual mechanistic insight—JNK phosphorylation and H3K9 lactylation—offers biomarkers to monitor treatment response. Future work should explore small‑molecule inhibitors or RNA‑based therapeutics that selectively dampen IFIT3 activity, as well as patient stratification strategies that identify individuals with IFIT3‑high macrophage signatures. Such approaches could reshape heart‑failure management, moving beyond symptomatic relief toward disease‑modifying interventions.