The Role of Histone Modifications in Acute Lung Injury: Molecular Mechanisms and Potential of Traditional Chinese Medicine Treatment

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterized by excessive inflammation, alveolar-capillary barrier disruption, and immunothrombosis. Mortality remains persistently high due to the lack of effective targeted therapies. Emerging evidence indicates that histone post-translational modifications (PTMs) play dual regulatory roles by modulating intranuclear gene transcription and, upon extracellular release, amplifying damage-associated molecular pattern (DAMP) signaling. Scope: This review proposes a unified pathological framework termed the “Nuclear Epigenetic Remodeling‒Extracellular DAMP Amplification Circuit.” By conceptualizing this as an inside-out pathological cascade, we integrate four principal histone modifications—acetylation, methylation, lactylation, and citrullination—and evaluate three-tiered therapeutic strategies alongside the unique multi-target potential of traditional Chinese medicine (TCM). Key Findings: Mechanistically, intranuclear HDAC3/6 drive inflammatory gene expression and pyroptosis, while cytoprotective SIRT1/3/6 suppress inflammasome activation and ferroptosis; concurrently, histone lactylation at H3K18 and H3K14 bridges glycolytic metabolism with ferroptosis and glycocalyx degradation; ultimately, externalized citrullinated histone H3 (CitH3) propagates a thrombo-inflammatory cascade driving NET-mediated immunothrombosis. Corresponding to this cascade, TCM-derived interventions collectively show promising potential to act across all therapeutic tiers by modulating the HDAC/SIRT acetylation axis, suppressing the PAD4–CitH3–NETs cascade, and regulating lactylation-linked metabolic pathways. Conclusion: We propose a precision medicine approach integrating dynamic epigenetic biomarkers (eg, serum CitH3 and H3K18la) with a multi-tiered intervention framework. This paradigm aims to shift ALI/ARDS treatment from empirical supportive care toward mechanism-based, individualized targeted therapies. Keywords: acute lung injury, acute respiratory distress syndrome, histone modifications, extracellular histones, neutrophil extracellular traps, immune-related thrombosis, traditional Chinese medicine