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

Ischemia-reperfusion injury (IRI) remains a primary driver of primary graft dysfunction (PGD) following lung transplantation, yet effective therapeutic strategies are currently limited. Early IRI is driven by coordinated oxidative and inflammatory responses, highlighting the need for therapeutic strategies capable of targeting both processes simultaneously. Using integrated human multi-omics analysis, in silico target prediction, and experimental validation, we identified barbaloin as a dual-target lead compound acting on interleukin-6 (IL-6) and purine nucleoside phosphorylase (PNP). In vitro, barbaloin suppressed IL-6 and PNP expression, inhibited PNP activity, reduced reactive oxygen species (ROS) accumulation, and attenuated NF-κB/NLRP3 inflammatory signaling. Crucially, in vivo validation in a C57BL/6J mouse model demonstrated that barbaloin (15 mg/kg) attenuated pulmonary edema and histological injury, partially restored respiratory mechanics, and reduced IL-6 and PNP expression. Collectively, these findings support the IL-6/PNP axis as a critical mediator of early lung IRI and identify barbaloin as a promising dual-target therapeutic candidate for mitigating oxidative and inflammatory injury during lung transplantation.