Pyroptosis, A Double-Edged Sword in Respiratory Diseases: A Narrative Review.

Pyroptosis is an inflammatory form of programmed cell death (PCD) driven by the gasdermin protein family. This process begins when danger- or damage-associated molecular patterns (DAMPs) are recognized, triggering either the canonical Caspase-1 or non-canonical Caspase-4/5/11 pathways. These pathways activate the cleavage of gasdermin D (GSDMD), releasing N-terminal fragments that form pores in cell membranes. This pore formation increases membrane permeability, leading to cell swelling and eventual lytic rupture. Pyroptosis serves as a double-edged sword in innate immunity: it defends against pathogens but can cause excessive inflammation and tissue damage if dysregulated. Evidence suggests that pyroptosis is involved in various respiratory diseases. The roles of pyroptosis and the Gasdermin family are complex, often exhibiting dual effects that complicate clinical interpretations. This review explores the molecular mechanisms and regulatory networks of pyroptosis, focusing on recent findings related to its role in pulmonary infections, acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS), allergic asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), and lung cancer. We also examine therapeutic strategies targeting pyroptotic pathways and recent advancements in their development, aiming to provide a theoretical foundation and new directions for mechanistic research and clinical translation in respiratory immune-inflammatory diseases.