LILRB4 Recruits SHP ‐1 to Enhance Oxidative Stress and Apoptosis, Aggravating Myocardial Ischemia–Reperfusion Injury

ABSTRACT Ischemia–reperfusion (I/R) leads to high levels of ROS, leading to cell death. The role of leukocyte immunoglobulin‐like receptor B4 (LILRB4) in MIRI is unclear, despite its importance in oxidative stress and apoptosis regulation. In this study, we found that cardiac overexpression of LILRB4 increased the oxidative stress levels, promoted the expression of apoptotic cascade proteins, exacerbated I/R‐induced cardiac dysfunction and myocardial injury in rats. LILRB4 also exacerbated H/R‐induced cardiomyocyte injury, oxidative stress, and apoptosis. LILRB4 specifically binds to SH2‐containing protein tyrosine phosphatase 1 (SHP‐1), inhibiting the PI3K‐Nrf2 signaling pathway and suppressing STAT3 phosphorylation and activation in cardiomyocytes. Compared to wild‐type (WT) mice, LILRB4 −/− mice exhibited significantly reduced levels of myocardial oxidative stress and apoptosis induced by I/R, improved cardiac function, and a smaller area of myocardial infarction. In summary, LILRB4 recruits SHP‐1, enhancing oxidative stress by inhibiting the PI3K‐Nrf2 pathway and promoting apoptosis by suppressing the STAT3 pathway, thereby aggravating MIRI.