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

Zhiqiang Yan,1,2,* Jiayun Wang,3,4,* Jiayi Qiao,1,2,* Zhongju Xu,5 Suwan Wu,3,4 Shun Wang,3,4 Liangbo Jiao,3,4 Tao Guo,3,4 Bo Tan,1,2 Aidong Yang3,4 1The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosecurity, School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 5Department of Traditional Chinese Medicine, Shanghai Pudong New Area Gongli Hospital, Shanghai, 200120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Tan, Email [email protected] Aidong Yang, Email [email protected]: 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