Gut microbiota-ferroptosis signaling as a putative feed-forward amplifier of pulmonary immunometabolic reprogramming in acute respiratory distress syndrome: actionable therapeutic targets

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.