2. Academic Validation
  3. Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury

Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury

  • Commun Biol. 2024 May 23;7(1):621. doi: 10.1038/s42003-024-06243-0.
Yi Wang # 1 2,  Xiaolong Fu # 1 2,  Li Zeng 1 2,  Yan Hu 1 2,  Rongyang Gao 1 2,  Siting Xian 1 2,  Songjie Liao 1 2,  Jianxiang Huang 1 2,  Yonggang Yang 1 2,  Jilong Liu 3,  Hai Jin 4,  James Klaunig 5,  Yuanfu Lu 6 7,  Shaoyu Zhou 8 9
Affiliations

Affiliations

  • 1 Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.
  • 2 School of Pharmacy, Zunyi Medical University, Zunyi, China.
  • 3 Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
  • 4 Institute of Digestive Diseases of Affiliated Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
  • 5 Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, IN, USA.
  • 6 Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China. luyuanfu2000@163.com.
  • 7 School of Pharmacy, Zunyi Medical University, Zunyi, China. luyuanfu2000@163.com.
  • 8 Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China. szhou@zmu.edu.cn.
  • 9 School of Pharmacy, Zunyi Medical University, Zunyi, China. szhou@zmu.edu.cn.
  • # Contributed equally.
PMID: 38783088 DOI: 10.1038/s42003-024-06243-0
Abstract

Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

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