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
  • 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. [email protected].
  • 7. School of Pharmacy, Zunyi Medical University, Zunyi, China. [email protected].
  • 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. [email protected].
  • 9. School of Pharmacy, Zunyi Medical University, Zunyi, China. [email protected].
  • # 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.

Products