# Myocardial Ischemia–Reperfusion Injury—Mechanistic Insights and Novel Therapeutics

## TL;DR

This paper reviews the mechanisms and new treatments for heart damage caused by restoring blood flow after a heart attack.

## Contribution

The paper provides mechanistic insights and highlights novel therapeutic strategies targeting multiple pathways in myocardial ischemia–reperfusion injury.

## Key findings

- Reperfusion after ischemia causes metabolic, ionic, and mitochondrial disturbances leading to cardiomyocyte injury.
- Multiple forms of cell death, including apoptosis and ferroptosis, are interconnected through inflammatory and oxidative pathways.
- Emerging therapies focus on antioxidants, immune modulation, and anti-ferroptotic interventions to improve outcomes in heart attacks.

## Abstract

Myocardial ischemia–reperfusion (I/R) injury remains a major contributor to infarct expansion and adverse cardiac remodeling despite advances in timely reperfusion therapy. Although restoration of blood flow is essential for myocardial salvage, the abrupt transition from ischemia to reperfusion paradoxically exacerbates cardiomyocyte injury through profound metabolic, ionic, and mitochondrial disturbances. Reperfusion should be viewed not simply as restoration of blood flow, but as a critical biological transition that converts ischemic stress into a self-amplifying injury network. Reperfusion induces excessive reactive oxygen species generation, calcium overload, endothelial barrier disruption, and dysregulated innate immune activation, which converge on mitochondrial dysfunction and diverse forms of cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Emerging evidence highlights that these pathological processes are tightly interconnected through damage-associated molecular pattern signaling, microvascular leakage, and inflammatory amplification, underscoring the limitations of single-target therapeutic approaches. This review summarizes the molecular and cellular mechanisms underlying myocardial I/R injury with a particular focus on oxidative stress, immune modulation, vascular integrity, and ferroptosis. We further discuss current and emerging cardioprotective strategies, including antioxidant therapies, modulation of neutrophil recruitment, microvascular leakage blockade, and anti-ferroptotic interventions. Finally, we address key translational challenges and future perspectives for developing integrated cardioprotective therapies aimed at improving clinical outcomes in acute myocardial infarction.