Paeoniflorin Ameliorates Cecal Ligation and Puncture-Induced Acute Lung Injury in Mice by Modulating Oxidative Stress, Apoptosis, and Inflammation: Shedding Light on the Role of the JAK2/STAT3 Pathway

Background: Acute lung injury (ALI) is a major complication of sepsis, driven by oxidative stress, inflammation, and apoptosis. Paeoniflorin, a monoterpenoid glycoside, has demonstrated notable antioxidant and anti-inflammatory properties, suggesting potential therapeutic value in ALI. Methods: Sepsis-induced ALI was established in mice using the cecal ligation and puncture (CLP) model. The protective effects of paeoniflorin were evaluated by measuring oxidative stress markers (SOD, GSH, and MDA) and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) using biochemical assays and RT-PCR. Histopathological examination and apoptosis assessment (Bax and Bcl-2 expression) were performed. Western blot analysis was conducted to investigate the involvement of the JAK2/STAT3 signaling pathway. Network pharmacology analysis was used to identify potential molecular targets, and molecular docking was performed to explore binding interactions. Results: CLP-induced ALI resulted in increased oxidative stress and inflammatory responses, as evidenced by elevated MDA and cytokine levels, along with reduced SOD and GSH levels. Paeoniflorin treatment significantly ameliorated these alterations. Histological damage and apoptosis were markedly reduced, accompanied by the downregulation of Bax and upregulation of Bcl-2. Additionally, paeoniflorin inhibited activation of the JAK2/STAT3 pathway. Network pharmacology identified key ALI-related targets, including IL6, TNF, IL1B, HIF1A, STAT3, NFKB1, CCL2, CYBB, CXCL8, and NOX4. Molecular docking revealed strong binding affinity of paeoniflorin toward HIF-1 and JUN, and moderate interactions with IL-1β, TNF-α, and Bax. Conclusions: Paeoniflorin exerts protective effects against sepsis-induced ALI by attenuating oxidative stress, inflammation, and apoptosis, partly through inhibition of the JAK2/STAT3 signaling pathway. These findings highlight its potential as a promising therapeutic candidate for ALI management.