image: 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.
Credit: © 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.
Acute respiratory distress syndrome (ARDS) remains one of the deadliest complications of severe infections, sepsis, trauma, and viral pneumonia, yet decades of research have produced few targeted therapies capable of improving patient outcomes.
A new review published in Ferroptosis and Oxidative Stress suggests one reason for this therapeutic gap: researchers may have been focusing on individual cell death pathways while overlooking the complex network that connects them.
The review proposes a new perspective on ARDS pathogenesis, arguing that multiple forms of regulated cell death (RCD)—including apoptosis, necroptosis, pyroptosis, ferroptosis, and other programmed death mechanisms—do not act independently. Instead, they communicate through extensive molecular crosstalk, forming a dynamic network that collectively drives lung inflammation, alveolar injury, and respiratory failure.
Traditionally, studies have investigated each cell death pathway separately, seeking to identify a single dominant mechanism responsible for acute lung injury. However, mounting genetic and biochemical evidence indicates that these pathways are highly interconnected. Blocking one form of cell death may activate another, while shared signaling molecules coordinate multiple death programs simultaneously. This remarkable plasticity may help explain why therapies targeting individual pathways have shown limited clinical success.
The authors comprehensively summarize the molecular mechanisms underlying different regulated cell death modalities and integrate emerging evidence showing how these pathways interact throughout ARDS development. Rather than viewing apoptosis, ferroptosis, pyroptosis, or necroptosis as isolated events, the review presents them as components of a coordinated biological network that amplifies tissue injury following infection or inflammatory insults.
Understanding this crosstalk could fundamentally change therapeutic strategies for ARDS. Instead of inhibiting a single cell death mechanism, future treatments may need to target common regulatory nodes shared across multiple pathways, reducing excessive lung injury while preserving essential immune defense against pathogens. Such network-based approaches may also improve the effectiveness of combination therapies and support the development of precision medicine for critically ill patients.
Beyond highlighting current knowledge, the review identifies several important challenges for future research, including defining how different cell death pathways interact over time, identifying biomarkers that distinguish dominant death programs in individual patients, and discovering master regulators capable of coordinating multiple forms of regulated cell death simultaneously.
As interest in ferroptosis and other programmed cell death mechanisms continues to expand across biomedical research, this review provides an integrated framework for understanding how cell death crosstalk contributes to ARDS. By shifting attention from individual pathways to an interconnected regulatory network, the work offers new directions for therapeutic development against one of intensive care medicine's most challenging disorders.
Why this matters
- ARDS affects millions of patients worldwide and continues to carry a high mortality rate despite advances in supportive care.
- The review introduces a network-based view of regulated cell death, challenging the traditional strategy of targeting a single death pathway.
- Understanding how apoptosis, pyroptosis, necroptosis, ferroptosis, and other programmed cell death pathways interact may accelerate the development of more effective therapies for ARDS and other inflammatory lung diseases.
Journal
Ferroptosis and Oxidative Stress
Method of Research
Literature review
Subject of Research
Human tissue samples
Article Title
The role of multiple modes of cell death in the pathogenesis of acute respiratory distress syndrome
Article Publication Date
13-Apr-2026
COI Statement
The authors declare no conflicts of interest.