Crosstalk among cell death pathways in ARDS (IMAGE)
Caption
Diverse initiator and effector molecules involved in various RCD types are interchangeably used to execute cell death. For example, activated CASP8 not only induces apoptosis but also promotes GSDMD cleavage to trigger pyroptotic cell death. Additionally, procaspase-8 assembly with RIPK1 and FADD can activate necroptosis, indicating connectivity between apoptosis and necroptosis. Lipid peroxidation is an emerging mechanism linking various forms of cell death. Excessive lipid peroxidation, the prominent feature of ferroptosis, can activate executioners of pyroptosis (e.g., GSDMD) and necroptosis (e.g., MLKL). Autophagy is also involved in lipid peroxidation through ferritinophagy and lipophagy while promoting NLRP3 degradation, suggesting that autophagy is an important regulatory mechanism for pyroptosis and ferroptosis. NETosis occurs downstream of other RCD patterns and can be triggered by activated GSDMD. Released NE and NETs, in turn, induce necroptosis and ferroptosis, respectively. Ultimately, these cell death patterns coordinate and cooperate to promote ARDS development. ARDS: acute respiratory distress syndrome; RCD: regulated cell death; CASP: caspase; GSDMD: gasdermin D; RIPK1: receptor-interacting protein kinase 1; FADD: Fas-associated protein with death domain; MLKL: mixed lineage kinase domain-like; NLRP3: NOD-like receptor family, pyrin domain-containing protein 3; NE: neutrophil elastase; NETs: neutrophil extracellular traps.
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© Yongxin Zheng, Nanshan Zhong, Ling Sang, Yongbo Huang 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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