JAK/STAT pathway in myocardial infarction: Crossroads of immune signaling and cardiac remodeling

Abstract

Myocardial infarction (MI) initiates a robust immune-inflammatory response in which dysregulated cytokine signaling exacerbates tissue damage and adverse cardiac remodeling. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway serves as a key mediator of cytokine signaling and immune cell activation, playing a dual role in post-MI outcomes. On one hand, JAK/STAT activation supports cardioprotective mechanisms such as angiogenesis and anti-apoptotic signaling; on the other hand, its excessive or prolonged activation contributes to maladaptive inflammation, fibrosis, and heart failure. This review examines how pro-inflammatory cytokines (e.g., IL-6, TNF-α) and immune cells (e.g., macrophages, neutrophils) activate the JAK/STAT pathway in ischemic myocardium. We discuss the pathway’s crosstalk with inflammatory signaling networks, including NF-κB, MAPK, and PI3K/Akt, and evaluate the potential of repurposing JAK inhibitors (e.g., ruxolitinib) to modulate immune responses after MI, drawing insights from clinical trials in autoimmune diseases. Unresolved challenges such as cell-specific effects of JAK/STAT modulation and the need for biomarker-driven therapies are also highlighted. By synthesizing current preclinical and clinical evidence, this review proposes a framework for immune-targeted strategies aimed to improving cardiac outcomes following MI.