Context-dependent roles of palmitoylation in acute respiratory distress syndrome: integrating inflammation, cell death and repair.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by dysregulated inflammation, immune imbalance and impaired alveolar repair. Despite advances in supportive care, effective targeted therapies remain limited. Palmitoylation, a reversible lipid-based post-translational modification, has recently emerged as a regulatory mechanism in ARDS pathogenesis. Acting in a context-dependent manner, palmitoylation affects key processes, including immune activation, programmed cell death and epithelial remodelling. Accumulating evidence suggests that palmitoylation may exert dual roles in ARDS: it can promote inflammation and immune evasion in the early phase, while contributing to resolution and tissue repair during later stages. This review summarises current findings regarding the spatial and temporal regulation of palmitoylation in immune and structural cells involved in ARDS, including its effects on inflammasome activation, epithelial-immune interactions and fibrotic progression. Therapeutic approaches under investigation include selective inhibition of palmitoyltransferases (zinc finger aspartate-histidine-histidine-cysteine motif-containing-type palmitoyltransferase family), modulation of depalmitoylation enzymes and substrate-targeted strategies. Several preclinical studies support the feasibility of targeting palmitoylation to reduce lung injury and improve immune regulation. Overall, palmitoylation represents a potential regulatory node in ARDS pathophysiology. Further research is required to clarify its cell-specific functions and to assess the translational potential of palmitoylation-based interventions.