2. Academic Validation
  3. Mechanisms and targeted intervention of mitochondria-dependent ferroptosis and abnormal ductular reaction caused by benzo(a)pyrene

Mechanisms and targeted intervention of mitochondria-dependent ferroptosis and abnormal ductular reaction caused by benzo(a)pyrene

  • Free Radic Biol Med. 2025 Oct 1:241:543-555. doi: 10.1016/j.freeradbiomed.2025.10.001.
Xinru Du 1,  Sisi Song 2,  Jing Wang 3,  Hongquan Zhang 4,  Yue Ma 2,  Zhendong Wang 2,  Qinliang Mo 4,  Mengyue Ji 3,  Sha Liu 2,  Ziyi Wang 2,  Moyan Wang 2,  Chunxiao Zhou 5,  Yuan Li 6,  Chengwu Tang 7
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China; School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education in Stitutions in Jiangsu Province, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
  • 2 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China; School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education in Stitutions in Jiangsu Province, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
  • 3 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China.
  • 4 Department of Hepatopancreatobiliary Surgery, Huzhou Key Laboratory of Translational Medicine, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang Province, China; Zhejiang Key Laboratory of Digital Technology in Medical Diagnostics, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang Province, China.
  • 5 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China. Electronic address: zhouchunxiao@njmu.edu.cn.
  • 6 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China; School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education in Stitutions in Jiangsu Province, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China. Electronic address: liyuan@njmu.edu.cn.
  • 7 Department of Hepatopancreatobiliary Surgery, Huzhou Key Laboratory of Translational Medicine, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang Province, China; Zhejiang Key Laboratory of Digital Technology in Medical Diagnostics, The First Affiliated Hospital of Huzhou University, Huzhou, 313000, Zhejiang Province, China. Electronic address: dr_tcw@zjhu.edu.cn.
PMID: 41043626 DOI: 10.1016/j.freeradbiomed.2025.10.001
Abstract

Chronic hepatobiliary diseases (CHDs), the second leading disease burden worldwide, are closely related to the occurrence and development of abnormal ductular reaction (DR). Tobacco smoking is an important pathogenic risk factor for CHDs, however, the functions and molecular mechanisms underlying in the tobacco smoking-induced abnormal DR, remain largely uninvestigated. Benzo[a]pyrene (B[a]P) is a representative hepatobiliary toxic substance among tobacco carcinogens. Our present study revealed that, B[a]P drove the DR occurrence through inducing the Ferroptosis in bile duct epithelial cells (BECs). For the molecular mechanisms, the metabolic activation product of B[a]P, benzo[a]pyrene diol epoxide (BPDE) could directly bind to the Lys123 site of 14-3-3ε protein, which in turn inhibited its ubiquitination degradation. The abnormally elevated 14-3-3ε in turn activated voltage dependent anion channel 1 (VDAC1) through phosphoserine binding/regulation, leading to an abnormal coupling between endoplasmic reticulum (ER) and mitochondria. The shortened distance between the ER and mitochondria caused the mitochondrial CA2+ overload, inducing the overproduction of Reactive Oxygen Species (ROS). These processes ultimately caused the Ferroptosis in BECs and initiated the DR progression. In terms of targeted intervention, we further innovatively screened and identified a small molecule of traditional Chinese medicine monomer, quercetin, which could efficiently target the phosphoserine binding region of 14-3-3ε protein. Finally, we confirmed that targeted intervention of 14-3-3ε by quercetin significantly inhibited the B[a]P-induced Ferroptosis and abnormal DR.

Keywords

Benzo[a]pyrene; Ductular reaction; Ferroptosis; Molecular mechanisms; Targeted intervention.

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