Inhibition of Hsp90 Alleviates Necroptosis and Inflammation in Lung Epithelial Cells During Pulmonary Ischemia–Reperfusion Injury

ABSTRACT Lung ischemia–reperfusion injury (LIRI) is a critical pathological process associated with various clinical conditions, characterised by excessive inflammatory responses and cell death, which can lead to severe respiratory dysfunction and even mortality. However, no effective therapeutic strategy is currently available. This study investigates the protective effects and underlying mechanisms of the Hsp90 inhibitor 17‐dimethylaminoethylamino (17‐DMAG) in LIRI. An in vivo mouse model of LIRI was established by transiently occluding the left pulmonary hilum with a microvascular clamp, followed by reperfusion. In vitro, necroptosis was induced in BEAS‐2B cells using TSZ (TNF‐α, Smac mimetic and z‐VAD‐FMK). Our results demonstrate that 17‐DMAG significantly attenuates lung injury, inflammation and epithelial cell necroptosis in mice. Additionally, 17‐DMAG mitigates TSZ‐induced cell death and inflammatory responses in BEAS‐2B cells. Mechanistically, 17‐DMAG inhibits the phosphorylation of RIPK1, RIPK3 and MLKL—key necroptotic regulators and client proteins of Hsp90—thereby suppressing necroptosis and reducing the associated inflammatory response. In conclusion, 17‐DMAG alleviates LIRI by inhibiting necroptosis and its consequent acute inflammatory cascade. These findings suggest that 17‐DMAG may serve as a promising therapeutic candidate for LIRI treatment.