Targeting PANoptosis: a promising therapeutic strategy for ALI/ARDS.

Abstract

Acute lung injury (ALI) is a complex, high-mortality pulmonary disease triggered by multiple etiological factors, potentially progressing to acute respiratory distress syndrome (ARDS). During the development of ALI/ARDS, a key pathological feature involves the disruption of the intact alveolar-capillary barrier, which is formed by alveolar epithelium, pulmonary interstitium, and microvascular endothelium. Under physiological conditions, cell death removes excess or dysfunctional cells, defends against pathogenic microorganisms, and thus plays a protective role while maintaining homeostasis. However, excessive clearance reactions can lead to pathological loss of pulmonary epithelial cells, endothelial cells, or macrophage-immune cells, eventually exacerbating tissue structural damage. With the discovery of various programmed cell death mechanisms, researchers have consistently uncovered the participation of cell death modes such as apoptosis, pyroptosis, necroptosis, and PANoptosis in the pathological processes underlying ALI/ARDS. Modulating these critical death pathways presents opportunities for therapeutic intervention in disease progression. Among these, PANoptosis is an independent lytic inflammatory cell death pathway initiated by innate immune sensors and driven by the PANoptosome complex, playing a core role in lung injury and infectious diseases. This review summarizes recent advancements in PANoptosis research in the context of ALI/ARDS, providing a reliable framework and direction for the targeted development of drugs acting on the PANoptosis axis to more effectively prevent and treat ALI/ARDS.