2. Academic Validation
  3. Mechanisms and targeted prevention of abnormal ductular reaction caused by a low concentration of Benzo(a)pyrene

Mechanisms and targeted prevention of abnormal ductular reaction caused by a low concentration of Benzo(a)pyrene

  • Cell Death Dis. 2025 Oct 7;16(1):714. doi: 10.1038/s41419-025-08043-8.
Xinru Du # 1 2 3,  Yancheng Gao # 1 2 3,  Sisi Song 2 3,  Qinming Hui 2 3,  Zhendong Wang 2 3,  Mengyue Ji 1,  Maoxuan Li 2 3,  Shuoke Duan 2 3,  Sha Liu 2 3,  Ziyi Wang 2 3,  Yue Ma 2 3,  Ye Yang 4 5,  Chunxiao Zhou 6,  Yuan Li 7 8 9
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China.
  • 2 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China.
  • 3 School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu Province, China.
  • 4 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China. yangye@njmu.edu.cn.
  • 5 School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu Province, China. yangye@njmu.edu.cn.
  • 6 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China. zhouchunxiao@njmu.edu.cn.
  • 7 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China. liyuan@njmu.edu.cn.
  • 8 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, China. liyuan@njmu.edu.cn.
  • 9 School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu Province, China. liyuan@njmu.edu.cn.
  • # Contributed equally.
PMID: 41057340 DOI: 10.1038/s41419-025-08043-8
Abstract

The impact of long-term exposure to low concentrations of environmental pollutants on hepatobiliary diseases is a major public health issue. Benzo(a)pyrene (B[a]P) is a common environmental toxin classified by the International Agency for Research on Cancer as a Group I carcinogen. Abnormal ductular reaction (DR) is a major pathological feature of hepatobiliary diseases; however, the underlying molecular mechanisms of B[a]P-induced abnormal DR remain unclear. This study revealed that chronic exposure to a low concentration of B[a]P increased the expression of a glucose-regulated protein (GRP75) in cholangiocytes. As GRP75 is a bridge protein for the endoplasmic reticulum (ER)-mitochondrial junction, the overexpression of GRP75 abnormalizes ER-mitochondria coupling. These biological processes facilitated CA2+ release from the ER into the mitochondria and caused mitochondrial CA2+ overload, leading to the overproduction of Reactive Oxygen Species (ROS). The increased ROS activates epithelial-mesenchymal transition (EMT) and ultimately induces a profibrotic phenotype in bile duct cells (BECs). These cells secreted Collagen and activated hepatic stellate cells through paracrine activity, which synergistically promoted the development and progression of fibrosis. Finally, via drug screening and functional analysis, we innovatively revealed a traditional Chinese medicine monomer, luteolin, which could prevent B[a]P-induced abnormal DR and hepatic fibrosis by targeting GRP75. Our study offers new insights into environmental toxin-induced hepatobiliary diseases and suggests a potential key interventional target or approach for the prevention of abnormal DR.

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