ZBP1-Mediated PANoptosis: Mechanisms and Therapeutic Potential in Inflammatory Lung Diseases.

Abstract

Inflammatory lung injuries such as acute lung injury (ALI) and severe pneumonia remain life‑threatening critical illnesses. PANoptosis, an integrated inflammatory programmed cell death that synchronously activates pyroptosis, apoptosis and necroptosis, acts as a core driver of pulmonary inflammatory injury. The interferon‑inducible cytoplasmic sensor Z‑DNA‑binding protein 1 (ZBP1) detects Z‑conformation nucleic acids to initiate PANoptosome assembly and subsequent PANoptosis. This review outlines ZBP1 structural characteristics, the regulatory molecular network of ZBP1‑PANoptosome, and its pathological effects in alveolar macrophages, epithelial and endothelial cells. Circulating and bronchoalveolar lavage ZBP1‑associated proteins hold promise as novel diagnostic and prognostic biomarkers. We summarize available intervention approaches covering genetic modulation, small‑molecule inhibitors and traditional Chinese‑medicine‑derived bioactive components, and discuss key translational obstacles including inter‑species ZBP1 signaling differences and ZBP1's dual protective‑pathogenic roles in host anti‑pathogen immunity. Spatial single‑cell multi‑omics and lung‑targeted nanomedicines are highlighted as prospective directions to balance anti‑inflammatory protection and antimicrobial defence for inflammatory lung disorders.

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