Acute Lung Injury: From Molecular Circuits to System‐Level Therapeutics

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), remain critical conditions with persistently high mortality. The failure to develop effective pharmacotherapies stems largely from reductionist approaches focused on isolated linear pathways. This review synthesizes recent breakthroughs redefining ALI as dysregulation of integrated pathological networks spanning immunity, metabolism, and cell death. We systematically analyze three interconnected core circuits: cGAS-STING as a central danger signal integrator, immunometabolic reprogramming as fuel for sustained inflammation, and the programmed cell death network-particularly PANoptosis-as executor of tissue damage. We further elucidate how ALI manifests as a multiorgan communication disorder, with the brain and gut actively shaping pulmonary inflammation. The convergence of single-cell technologies, multiomics profiling, and computational modeling has deconstructed ARDS heterogeneity into clinically actionable endotypes (hyperinflammatory C1, hypoinflammatory C2) with differential treatment responses. This network-based understanding is catalyzing a therapeutic shift toward rationally designed poly-pharmacology, precision immunotherapies, and advanced platforms integrating smart nanomaterials with endogenous systems. By embracing this holistic perspective, we chart a course toward mechanism-based, personalized interventions that move beyond supportive care to genuine disease modification.