Gut microbiota-ferroptosis signaling as a putative feed-forward amplifier of pulmonary immunometabolic reprogramming in acute respiratory distress syndrome: actionable therapeutic targets
5 affiliations
- 1Department of Respiratory and Critical Care Medicine, Liuzhou People’s Hospital, Guangxi Medical University
- 2Key Laboratory of Diagnosis, Treatment and Research of Asthma and Chronic Obstructive Pulmonary Disease, Liuzhou People’s Hospital, Guangxi Medical University
- 3Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University
- 4Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University
- 5Fever Clinic, Liuzhou People’s Hospital, Guangxi Medical University
Abstract
Acute respiratory distress syndrome (ARDS) is characterized by dysregulated pulmonary immune responses, and effective targeted therapeutic strategies remain an unmet clinical need. Accumulating preclinical and clinical correlative data reveal complex interconnections between gut microbiota and ferroptosis-driven immunopathology in ARDS, yet an integrated mechanistic understanding of the gut-lung pathological axis remains incomplete. This review puts forward a testable conceptual temporal framework for ARDS-related gut-lung crosstalk. Evidence supporting the gut-to-lung limb is comparatively more abundant, whereas the full sequential pathogenic cascade has not been rigorously validated. Gut-derived metabolites remodel pulmonary cell phenotypes, macrophage functional states, neutrophil extracellular trap formation and T-cell homeostasis, potentially sustaining a self-amplifying ferroptosis-inflammatory vicious cycle that may drive pulmonary immunometabolic reprogramming. Targeting this regulatory cascade may yield promising conceptual therapeutic avenues, including microbiota-modulating interventions, anti-ferroptotic strategies and multi-omics-guided precision approaches. Major knowledge gaps persist: most mechanistic observations are extrapolated from non-ARDS animal models; temporally-separated preclinical experiments that induce lung injury prior to gut-targeted manipulation are scarce; and well-controlled human studies disentangling pulmonary-driven effects from ICU confounders are urgently required. This sequence represents an etiology-dependent working model rather than a uniform chronological hierarchy for all ARDS. In direct-pulmonary ARDS, alveolar injury may precede gut dysbiosis; in indirect/sepsis-associated ARDS, systemic inflammation, intestinal hypoperfusion and antibiotic exposure may occur before, or simultaneously with, overt pulmonary ferroptotic injury.
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BibTeX
@article{dong2026microbiotaferroptosis,
title = {{Gut microbiota-ferroptosis signaling as a putative feed-forward amplifier of pulmonary immunometabolic reprogramming in acute respiratory distress syndrome: actionable therapeutic targets}},
author = {Biying Dong and Weitong Zeng and Bing Zhong and Longxiong Liao and Yi Wei and Lihua Liao and Dongwei Zhang and Xianming Fan},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1900118},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1900118/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Gut microbiota-ferroptosis signaling as a putative feed-forward amplifier of pulmonary immunometabolic reprogramming in acute respiratory distress syndrome: actionable therapeutic targets
AU - Biying Dong
AU - Weitong Zeng
AU - Bing Zhong
AU - Longxiong Liao
AU - Yi Wei
AU - Lihua Liao
AU - Dongwei Zhang
AU - Xianming Fan
PY - 2026
DA - 2026/10/28
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1900118
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1900118/full
AB - Acute respiratory distress syndrome (ARDS) is characterized by dysregulated pulmonary immune responses, and effective targeted therapeutic strategies remain an unmet clinical need. Accumulating preclinical and clinical correlative data reveal complex interconnections between gut microbiota and ferroptosis-driven immunopathology in ARDS, yet an integrated mechanistic understanding of the gut-lung pathological axis remains incomplete. This review puts forward a testable conceptual temporal framework for ARDS-related gut-lung crosstalk. Evidence supporting the gut-to-lung limb is comparatively more abundant, whereas the full sequential pathogenic cascade has not been rigorously validated. Gut-derived metabolites remodel pulmonary cell phenotypes, macrophage functional states, neutrophil extracellular trap formation and T-cell homeostasis, potentially sustaining a self-amplifying ferroptosis-inflammatory vicious cycle that may drive pulmonary immunometabolic reprogramming. Targeting this regulatory cascade may yield promising conceptual therapeutic avenues, including microbiota-modulating interventions, anti-ferroptotic strategies and multi-omics-guided precision approaches. Major knowledge gaps persist: most mechanistic observations are extrapolated from non-ARDS animal models; temporally-separated preclinical experiments that induce lung injury prior to gut-targeted manipulation are scarce; and well-controlled human studies disentangling pulmonary-driven effects from ICU confounders are urgently required. This sequence represents an etiology-dependent working model rather than a uniform chronological hierarchy for all ARDS. In direct-pulmonary ARDS, alveolar injury may precede gut dysbiosis; in indirect/sepsis-associated ARDS, systemic inflammation, intestinal hypoperfusion and antibiotic exposure may occur before, or simultaneously with, overt pulmonary ferroptotic injury.
SN - 1664-3224
ER -