Abstract Background Acute respiratory distress syndrome (ARDS) is a biologically heterogeneous condition in which patients exposed to similar injurious stimuli often develop markedly different clinical trajectories and outcomes. While inflammation is central to ARDS pathogenesis, inflammatory burden alone does not fully explain the variability in disease progression, treatment response, or recovery. Emerging evidence suggests that immunometabolic reprogramming, characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and altered metabolite signalling, plays a critical role in shaping immune-cell activation, inflammatory persistence, and tissue repair during critical illness. Main body This narrative review synthesizes current evidence linking immunometabolic reprogramming and mitochondrial dysfunction to the clinical heterogeneity observed in ARDS. During acute lung injury, immune and structural lung cells undergo metabolic shifts characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and accumulation of bioactive metabolites such as lactate, succinate, and extracellular adenosine triphosphate (ATP). Beyond reflecting metabolic stress, these metabolites function as signalling mediators that are associated with amplified inflammatory pathways, compromised alveolar-capillary barrier integrity, and sustained lung injury. Multi-omic studies further demonstrate that distinct metabolic signatures are associated with ARDS phenotypes, disease severity, and treatment responsiveness. We integrate these findings within the concept of metabolic resilience, defined as the host’s capacity to restore coordinated mitochondrial function, redox balance, and substrate utilization following inflammatory stress. Therapeutic strategies aimed at preserving mitochondrial function, restoring nicotinamide adenine dinucleotide (NAD⁺) homeostasis, and modulating maladaptive immunometabolic signalling may offer new avenues for precision-based interventions in ARDS. Conclusions Immunometabolic reprogramming and mitochondrial dysfunction represent central biological axes linking cellular bioenergetics with clinical heterogeneity in ARDS. Understanding metabolic resilience may help refine phenotyping strategies and support development of metabolism-targeted therapies aimed at improving outcomes in this complex syndrome. Clinical trial number Not applicable.
Srinivas et al. (Fri,) studied this question.