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

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

  • J Hazard Mater. 2025 Jun 26:495:139083. doi: 10.1016/j.jhazmat.2025.139083.
Li-Hong Chen 1,  Jun-Ping Wei 2,  Meng-Die Li 1,  Xiu Lu 1,  Yi-Cheng Ma 3,  Yu Wang 1,  Ling Zheng 1,  Jun Fei 1,  Wei Cao 3,  De-Xiang Xu 4,  Jin Yang 5,  Hui Zhao 6,  Lin Fu 7
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
  • 2 Department of Respiratory and Critical Care Medicine, Linquan County People's Hospital, Fuyang, Anhui 236499, China.
  • 3 Department of Thoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
  • 4 Department of Toxicology, Anhui Medical University, Hefei, Anhui 230032, China.
  • 5 Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China. Electronic address: yangqj1015@foxmail.com.
  • 6 Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China. Electronic address: zhaohuichenxi@126.com.
  • 7 Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Center for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Department of Respiratory and Critical Care Medicine, Bozhou People's Hospital, Bozhou, Anhui 236800, China. Electronic address: fulindev@126.com.
PMID: 40609471 DOI: 10.1016/j.jhazmat.2025.139083
Abstract

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.

Keywords

Aryl hydrocarbon receptor; Benzo[a]pyrene; Cellular senescence; Chronic obstructive pulmonary disease; Histone lactylation; P53.

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