Barbaloin Alleviates Lung Ischemia-Reperfusion Injury by Dual-targeting IL‑6 and PNP

Ischemia-reperfusion injury (IRI) is a primary driver of graft dysfunction following lung transplantation, yet effective therapeutic strategies remain limited. Through integrated multi-omics analysis, target prediction, and experimental validation, this study identifies barbaloin as a potent dual-target agent that alleviates lung IRI by simultaneously inhibiting interleukin-6 (IL-6) and purine nucleoside phosphorylase (PNP). Mechanistically, barbaloin reduces intracellular Reactive Oxygen Species (ROS) accumulation by suppressing both IL-6 and PNP, thereby abrogating the ROS-dependent NF-κB/NLRP3 signaling cascade and subsequent immune-inflammatory responses. These findings highlight the pivotal role of the IL-6/PNP axis in mediating barbaloin’s antioxidant and anti-inflammatory effects. Furthermore, barbaloin’s favorable ADMET profile supports its potential as a novel therapeutic candidate for lung transplantation and other oxidative stress-driven inflammatory disorders.