Mechanisms and therapeutic strategies of pyroptosis in sepsis‑induced acute lung injury (Review).

Sepsis‑induced acute lung injury (S‑ALI) is a leading cause of respiratory failure and mortality in intensive care units, characterized by profound biological and clinical heterogeneity that explains the repeated failure of uniform anti‑inflammatory therapies. This variability underscores the urgent need for mechanism‑based patient stratification and precision medicine approaches. Pyroptosis, a regulated inflammatory cell death program driven by gasdermin‑mediated membrane pore formation, has emerged as a critical driver of alveolar‑capillary barrier disruption and cytokine amplification in S‑ALI. The activation of canonical and non‑canonical inflammasome pathways, together with molecular crosstalk within the integrated PANoptosome network, promotes context‑dependent pyroptotic responses across pulmonary endothelial, epithelial and immune cells. Notably, recent insights into lineage plasticity and transcriptional heterogeneity further elucidate the dynamic cellular orchestration of these pathways. Pyroptotic effectors, such as circulating gasdermin D fragments and mature IL‑1β/IL‑18, are detectable in patients with sepsis and acute respiratory distress syndrome, being associated with hyperinflammatory endotypes, disease severity and clinical trajectories. By integrating preclinical mechanistic insights with emerging human biomarker and trial data, the present review positions pyroptosis as a clinically actionable, stratification‑relevant target. The present review highlights current advances in pathway‑specific inhibitors and discusses their potential to enable biomarker‑guided, personalized interventions in critically ill patients.