The landscape of protein post-translational modifications in the pathogenesis of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) remains one of the most severe forms of acute lung injury, characterized by diffuse alveolar damage and refractory hypoxemia secondary to non-cardiogenic pulmonary edema. After many years of research and incremental improvements in ventilatory and supportive strategies, mortality rates are still disappointingly high and no pharmacological agent has convincingly demonstrated a mortality benefit in large trials. Elucidating the rapid molecular processes driving the acute phase of lung injury, particularly post-translational modifications (PTMs), may be critical for devising targeted therapies and potentially lowering mortality. In this review, we provide a comprehensive synthesis of the multifaceted roles of PTMs in ARDS pathogenesis, bridging molecular mechanisms to clinical relevance. We begin by examining canonical modifications, including phosphorylation and ubiquitination, which serve as swift molecular switches coordinating the cytokine storm, endothelial barrier disruption, and defective alveolar fluid clearance. We then discuss emerging PTMs, including citrullination, lactylation, and succinylation, and highlight their contributions to neutrophil extracellular trap (NET) formation and inflammatory amplification. We examine how metabolic reprogramming of the ARDS lung directly governs PTM enzyme activity and substrate availability, thereby acting as an upstream regulatory layer linking cellular metabolism to PTM dynamics. We further discuss how PTMs do not operate independently but engage in obligatory sequential and competitive crosstalk. Finally, we explore the therapeutic promise of modulating specific PTM-regulating enzymes alongside precision medicine approaches, underscoring the value of multi-omics integration in surmounting current translational barriers against this deadly syndrome.