HSP22 Alleviates Lung Ischemia–Reperfusion Injury Following Pulmonary Embolism by Suppressing Inflammation, Oxidative Stress, and Apoptosis Through HIF-1α/NOX4 Pathway

Abstract

Heat shock protein 22 (HSP22) is a molecular chaperone known to protect against tissue damage in ischemic conditions. However, its role in lung ischemia–reperfusion injury (LIRI) following pulmonary embolism (PE) remains unclear. This study aimed to investigate the protective effects and molecular mechanisms of HSP22 in LIRI, focusing on its regulation of the HIF-1α/NOX4 signaling pathway. We found that HSP22 expression was significantly downregulated in LIRI mouse lung tissues and hypoxia/reoxygenation (H/R)-exposed pulmonary microvascular endothelial cells (PMVECs). HSP22 overexpression improved pulmonary function, reduced lung edema, and alleviated apoptosis, inflammation, and oxidative stress in LIRI mice. Similarly, in PMVECs, HSP22 overexpression restored cell viability, suppressed apoptosis, and decreased TNF-α, IL-6, and ROS levels under H/R exposure. Mechanistically, HSP22 directly interacted with HIF-1α and promoted its ubiquitination, leading to proteasomal degradation and downregulation of NOX4 expression. Notably, NOX4 overexpression abolished the protective effects of HSP22, restoring apoptosis, inflammation, and oxidative stress both in vivo and in vitro. Collectively, our study demonstrates that HSP22 protects against LIRI by promoting HIF-1α ubiquitination and inhibiting the HIF-1α/NOX4 pathway, thereby reducing oxidative stress, inflammation, and apoptosis. These findings suggest that targeting HSP22 may represent a promising therapeutic strategy for preventing LIRI in PE patients undergoing reperfusion therapy.