Histone H4 Lysine 12 Lactylation Promotes the Senescence of Alveolar Epithelial Type II Cells in Chronic Obstructive Pulmonary Disease by Modulating the CD38-NAD+ Signaling Pathway

In chronic obstructive pulmonary disease, the senescence of type II alveolar epithelial cells is a key driver of disease progression, severely impacting lung function and structure. Lactate accumulation, a common feature of chronic hypoxic conditions such as COPD, is increasingly recognized for its role in modulating cellular functions via epigenetic mechanisms. This study aimed to investigate the specific effects of lactate-induced histone lactylation on AEC2 senescence and its contribution to COPD progression. Our experiments revealed a significant increase in histone lactylation levels in COPD models, with site-specific screening identifying histone H4 lysine 12 lactylation as a predominant modification. Using the Cleavage Under Targets and Tagmentation technique (CUT&Tag) sequencing, we demonstrated that H4K12la modulates the CD38-nicotinamide adenine dinucleotide (NAD⁺) signaling pathway, thereby promoting AEC2 senescence and exacerbating COPD progression. Further in vitro and in vivo analyses confirmed that elevated H4K12la expression was associated with increased CD38 levels and decreased NAD⁺ concentrations. To interrogate this pathway, we employed the p300/CBP inhibitor A485, which specifically inhibits H4K12la levels. This intervention significantly improved AEC2 senescence and reduced COPD-related pathology. Subsequently, we explored additional therapeutic strategies using the CD38 inhibitor 78c and the NAD⁺ precursor β-nicotinamide mononucleotide (NMN), both of which effectively reduced senescence markers and further ameliorated COPD symptoms. These findings highlight the critical role of lactate-induced histone lactylation, specifically H4K12la, in COPD pathogenesis. Targeting the H4K12la-CD38-NAD⁺ axis, with strategies such as p300/CBP inhibition, offers promising therapeutic avenues for managing the disease.