Penehyclidine hydrochloride, a common anticholinergic drug, shows protective effects on ischemia-reperfusion injury (IRI) in various organs. However, the effects of penehyclidine hydrochloride on lung IRI induced by lung transplantation (LTx) have not been known, especially during the cold ischemia phase. Therefore, this study aimed to explore the effect of penehyclidine hydrochloride on lung IRI in a rat model of LTx.Rats were randomly divided into sham group, control group, and penehyclidine hydrochloride group (PHC group). Rats in the sham group only underwent thoracotomies without LTx. Rats in the C group and PHC group established LTx model and received no treatment or penehyclidine hydrochloride respectively during the cold ischemia phase. At 120 minutes after LTx, the blood gas analysis, wet to dry ration (W/D), inflammatory reaction, oxidative stress injury, and lung structure were detected. Additionally, the type II alveolar epithelial cells observed by transmission electron microscopy were also explored.Compared with C group, the oxygenation, W/D, inflammatory markers, oxidative stress markers and lung structure in the C group and PHC group deteriorated, which improved in the PHC group compared with those in the C group (P < .05). Additionally, the type II alveolar epithelial cells were also less damaged in the PHC group compared with the C group (P < .05).Penehyclidine hydrochloride applied during the cold ischemia phase improved lung IRI caused by LTx via inhibiting inflammatory response and oxidative stress injury, and maintained the integrity of organizational structure in the type II alveolar epithelial cells.Copyright © 2025 Elsevier Inc. All rights reserved.