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<p>Sepsis-associated lung injury (SALI) remains a leading cause of mortality in critically ill patients, characterized by a complex pathophysiology that involves both dysregulated inflammatory responses and profound damage to pulmonary parenchymal cells. Although apoptosis has traditionally been regarded as the predominant form of cell death, emerging evidence underscores the potential contributions of novel regulated cell death (RCD) pathways—notably pyroptosis and ferroptosis—to the progression of this injury. Pyroptosis is a gasdermin-mediated lytic cell death process driven by inflammasome activation, leading to abundant release of pro-inflammatory cytokines that exacerbate the septic “cytokine storm”. In contrast, ferroptosis is an iron-dependent form of regulated necrosis characterized by the accumulation of lipid peroxides, closely linked to oxidative stress and metabolic disturbances in sepsis. This review systematically outlines the molecular mechanisms and functional crosstalk between pyroptosis and ferroptosis, with a particular emphasis on their cell-type-specific roles in pulmonary endothelial cells, alveolar epithelial cells, and immune cells during sepsis-induced lung injury. Furthermore, we discuss the implications of other emerging RCD modalities, including necroptosis and cuproptosis, and critically evaluate translational prospects of targeting these pathways based on preclinical evidence. By synthesizing current knowledge, this review aims to establish a theoretical framework and propose new directions for future research into therapeutic interventions for sepsis-induced lung injury.</p>

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Pyroptosis, ferroptosis, and beyond: mechanisms of regulated cell death in SALI

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Shuxian Cheng,
  • Hongwei Zhang

摘要

Sepsis-associated lung injury (SALI) remains a leading cause of mortality in critically ill patients, characterized by a complex pathophysiology that involves both dysregulated inflammatory responses and profound damage to pulmonary parenchymal cells. Although apoptosis has traditionally been regarded as the predominant form of cell death, emerging evidence underscores the potential contributions of novel regulated cell death (RCD) pathways—notably pyroptosis and ferroptosis—to the progression of this injury. Pyroptosis is a gasdermin-mediated lytic cell death process driven by inflammasome activation, leading to abundant release of pro-inflammatory cytokines that exacerbate the septic “cytokine storm”. In contrast, ferroptosis is an iron-dependent form of regulated necrosis characterized by the accumulation of lipid peroxides, closely linked to oxidative stress and metabolic disturbances in sepsis. This review systematically outlines the molecular mechanisms and functional crosstalk between pyroptosis and ferroptosis, with a particular emphasis on their cell-type-specific roles in pulmonary endothelial cells, alveolar epithelial cells, and immune cells during sepsis-induced lung injury. Furthermore, we discuss the implications of other emerging RCD modalities, including necroptosis and cuproptosis, and critically evaluate translational prospects of targeting these pathways based on preclinical evidence. By synthesizing current knowledge, this review aims to establish a theoretical framework and propose new directions for future research into therapeutic interventions for sepsis-induced lung injury.