AhR-mediated histone lactylation drives cellular senescence during benzo[a]pyrene-evoked chronic obstructive pulmonary disease.

Benzo[a]pyrene (BaP) and the end-product BaP-7,8-diol-9,10-epoxide (BPDE) are representative environmental contaminants. In the present study, chronic BPDE exposure decreased pulmonary function and evoked chronic obstructive pulmonary disease (COPD)-like lung lesions. In addition, the expression of p53, p21, and p16, β-galactosidase-positive cells, and the mRNA levels of senescence-associated secretory phenotype (SASP) were all elevated in mouse lungs and mouse lung epithelial type II (MLE-12) cells after chronic BPDE. Moreover, BPDE elevated (lactate dehydrogenase B) LDHB expression and lactate production. Additionally, the pharmacological inhibition or knockdown of LDHB alleviated BPDE-evoked cellular senescence and COPD. Mechanistically, BPDE induced histone H4K12 lactylation (H4K12la) at the promoter of the p53 gene, which facilitated cellular senescence and COPD. In addition, BPDE activated the aryl hydrocarbon receptor (AhR) in pulmonary epithelial cells. A dual-luciferase reporter assay revealed that AhR is a direct transcription factor of LDHB. AhR antagonists or knockdown attenuated BPDE-induced LDHB transcription and H4K12la. A casecontrol study confirmed that the BaP concentration was elevated in COPD patients. Furthermore, the number of AhR-positive nuclei was positively correlated with H4K12la and cellular senescence in the lung tissues of COPD patients. Collectively, these findings reveal that BaP exposure contributes to COPD by inducing pulmonary epithelial cell senescence via AhR-mediated histone H4K12 lactylation.