Sangbaipi Decoction mitigates influenza pneumonia in mice by inhibiting ZBP1-mediated PANoptosis.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia remains a major global health concern. Sangbaipi Decoction (SBPD), a traditional Chinese medicine formula, which is used clinically to treat pneumonia, exhibits antiviral and anti-inflammatory effects. However, its pharmacological basis and mechanism of action (MOA) in vivo remain unclear. AIM OF THE STUDY: This study aimed to evaluate the therapeutic efficacy of SBPD on viral pneumonia and to elucidate its underlying MOA. MATERIALS AND METHODS: The protective effects of SBPD were assessed in H1N1 (A/Puerto Rico/8/1934)-infected mice using histopathology, Western blot, and RT-qPCR. RNA sequencing was performed to identify key pathways modulated by SBPD. PANoptosis-related markers were examined both in vivo and in vitro, and Z-DNA-binding protein 1 (ZBP1) overexpression assays were conducted to verify its role in SBPD-mediated regulation of PANoptosis. A Poly(I:C)-induced acute lung injury model was used for further validation. Blood-absorbed constituents of SBPD were screened to identify bioactive components. RESULTS: SBPD treatment greatly reduced pulmonary viral load, lung index, and pro-inflammatory cytokine levels in H1N1-infected mice, alleviating lung injury. Transcriptomic analysis identified the ZBP1-mediated PANoptosis as a major regulatory target of SBPD. In vivo and in vitro studies demonstrated that SBPD downregulated the expression of ZBP1 and its downstream effectors, suppressing excessive inflammatory cell death. SBPD also attenuated Poly(I:C)-induced acute lung injury through the same pathway. Screening of blood-absorbed constituents of SBPD identified peimine, peiminine, chrysin, wogonin, and apigenin as active constituents that inhibit ZBP1-mediated PANoptosis. CONCLUSION: SBPD mitigates influenza-induced pneumonia by suppressing ZBP1-mediated PANoptosis and excessive inflammation, highlighting its host-directed therapeutic potential for viral pneumonia.