NF-κB signaling in acute myocardial infarction: pathophysiology, inflammation, and therapeutic implications

Figures

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  Figure 1. Hypoxic/ischemic activation of NF-κB signaling in cardiomyocytes during acute myocardial infarction. Under hypoxic/ischemic stress, cardiomyocytes undergo ATP depletion, mitochondrial dysfunction, ROS accumulation, Ca2⁺ overload, and membrane injury, leading to the release of danger-associated molecular patterns, including HMGB1, extracellular ATP, HSPs, and mtDNA. These signals activate TLR4, RAGE, TNFR1, and IL-1R-related pathways, which converge on the MyD88–IRAK–TRAF6–TAK1–IKK axis. IKK-mediated phosphorylation and degradation of IκBα releases NF-κB p65/p50 dimers, allowing their nuclear translocation and transcriptional activation of inflammatory cytokines, chemokines, adhesion molecules, inflammasome-priming genes, and cell-death-related programs. This cardiomyocyte-centered response links ischemic injury to inflammatory amplification and adverse post-infarction remodeling.

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  Figure 2. NF-κB activation leads to the transcription of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), promoting immune cell recruitment. It also upregulates anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1) for cell survival. NF-κB regulates cell death through apoptosis, pyroptosis (IL-1β, IL-18 release), and necroptosis. In cancer, NF-κB induces immune checkpoint molecules (PD-L1, CTLA-4) to evade immune detection, contributing to chronic inflammation and tumor progression.

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  Figure 3. NF-κB links ischemic injury to the inflammatory cascade in acute myocardial infarction (AMI). Ischemia-induced danger signals activate pattern recognition receptors, leading to NF-κB nuclear translocation and transcription of pro-inflammatory mediators. Acute activation promotes immune cell recruitment, clearance of necrotic tissue, and initiation of repair. However, persistent NF-κB activation sustains inflammation, drives fibrosis and adverse cardiac remodeling, and contributes to heart failure progression.

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  Figure 4. NF-κB regulates myocardial cell death in acute myocardial infarction (AMI) by coordinating apoptosis and pyroptosis. Upon activation, NF-κB drives transcriptional programs that promote mitochondrial apoptotic signaling and inflammatory cell death. Apoptosis contributes to cardiomyocyte loss and impaired contractile function, whereas pyroptosis amplifies inflammation through cytokine release. Excessive or persistent NF-κB activation exacerbates myocardial injury, linking cell death to inflammatory amplification and adverse cardiac outcomes.

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  Figure 5. Long non-coding RNAs (lncRNAs) modulate NF-κB signaling in acute myocardial infarction (AMI), fine-tuning inflammatory and fibrotic responses. By interacting with components of the NF-κB pathway, lncRNAs such as DANCR and Mirt1 regulate transcriptional programs that control cytokine expression, cell survival, and extracellular matrix remodeling. Through this regulatory axis, lncRNAs influence the balance between adaptive repair and maladaptive inflammation, highlighting their potential as therapeutic targets and biomarkers in AMI.