Authors
Mengzhen Xu, Kai Gong, Jiang Zhu, Tianying Sun, Qingjun Zhu, Li Xiao, Xiaolong Wang
Published in
Phytomedicine : international journal of phytotherapy and phytopharmacology. Volume 159. Pages 158552. Jul 06, 2026. Epub Jul 06, 2026.
Abstract
Influenza A virus (IAV) infection characteristically induces lung injury through acute inflammation and epithelial barrier breakdown. Among the pathogenic mechanisms involved, Z-DNA binding protein 1 (ZBP1)-dependent PANoptosis plays a central role. While Shashen Maidong decoction (SMD) demonstrates clinical efficacy in respiratory conditions, the molecular mechanisms by which it modulates this particular mode of cell death require further elucidation.
This study was designed to evaluate the protective effects of SMD against IAV-induced lung injury and to elucidate the underlying molecular mechanisms, with particular emphasis on the ZBP1-PANoptosis pathway.
The protective effects of SMD were evaluated in an IAV-induced lung injury mouse model. The chemical profile and absorbed constituents of SMD were identified using UPLC-MS/MS. Key signaling pathways were predicted through an integrated analysis of network pharmacology and transcriptomics, followed by in silico assessment of the binding potential to ZBP1 using molecular docking and dynamics simulations. To systematically examine the mechanism, specifically the modulation of ZBP1-PANoptosome complex formation and cell death markers, we utilized a series of molecular assays including Western blotting, immunofluorescence, and co-immunoprecipitation (Co-IP).
SMD treatment significantly ameliorated multiple IAV-induced pathologies, including body weight loss, pulmonary edema, histological injury, and pro-inflammatory cytokine release. Unlike oseltamivir, which significantly reduced infectious viral titers, SMD did not markedly alter viral NP and M mRNA levels or viral titers under these experimental conditions. Nevertheless, SMD substantially improved alveolar barrier function, as demonstrated by reduced BALF protein content and enhanced expression of tight junction (TJ) proteins. Integrated analysis of network pharmacology and transcriptomics revealed significant enrichment of inflammation-, programmed cell death-, apoptosis-, and necroptosis-related pathways, while ZBP1 emerged as a convergent candidate target. Based on the established role of ZBP1 in IAV-induced PANoptosis, ZBP1-mediated PANoptosis signaling was therefore selected as a candidate mechanistic axis for subsequent experimental assessment. Molecular dynamics (MD) simulations suggested a potential interaction between ZBP1 and 18β-glycyrrhetinic acid, a representative serum-absorbed candidate constituent of SMD. Mechanistic investigations revealed that SMD suppressed ZBP1 expression and attenuated downstream activation of pyroptotic, apoptotic, and necroptotic markers. Furthermore, Co-IP and triple-immunofluorescence analyses showed reduced association and colocalization among ZBP1, RIPK3, and Caspase-8, consistent with reduced PANoptosome assembly.
SMD exerted protective effects against IAV-induced lung injury in association with ZBP1 downregulation, reduced association of PANoptosome-related components, preserved alveolar epithelial barrier function, and dampened inflammatory cascades. This study provides preliminary evidence for the molecular basis of SMD in modulating the ZBP1-PANoptosis pathway, providing scientific rationale for host-directed traditional Chinese medicine (TCM) strategies in severe influenza management.
PMID:
42424678
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 2
- Comments 0