Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice

Wen Yin, Heng Xu, Zhonghao Bai, Yue Wu, Yan Zhang, Rui Liu, Zhangzhao Wang, Bei Zhang, Jing Shen, Hao Zhang, Xin Chen, Danting Ma, Xiaofeng Shi, Lihui Yan, Chang Zhang, Hualiang Jiang, Kaixian Chen, Dean Guo, Wenyan Niu, Huiyong Yin, Weiping J. Zhang, Cheng Luo () and Xiangyang Xie ()
Additional contact information
Wen Yin: Tianjin Medical University
Heng Xu: University of Chinese Academy of Sciences
Zhonghao Bai: Tianjin Medical University
Yue Wu: Chinese Academy of Sciences
Yan Zhang: Tianjin Medical University
Rui Liu: Tianjin Medical University
Zhangzhao Wang: Tianjin Medical University
Bei Zhang: Chinese Academy of Sciences
Jing Shen: Tianjin Medical University
Hao Zhang: University of Chinese Academy of Sciences
Xin Chen: Chinese Academy of Sciences (CAS)
Danting Ma: Tianjin Medical University
Xiaofeng Shi: Tianjin Medical University
Lihui Yan: Tianjin Medical University
Chang Zhang: Tianjin Medical University
Hualiang Jiang: Chinese Academy of Sciences
Kaixian Chen: Chinese Academy of Sciences
Dean Guo: Chinese Academy of Sciences
Wenyan Niu: Tianjin Medical University
Huiyong Yin: Chinese Academy of Sciences (CAS)
Weiping J. Zhang: Tianjin Medical University
Cheng Luo: University of Chinese Academy of Sciences
Xiangyang Xie: Tianjin Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Reactive oxygen species exacerbate nonalcoholic steatohepatitis (NASH) by oxidizing macromolecules; yet how they promote NASH remains poorly understood. Here, we show that peroxidase activity of global hepatic peroxiredoxin (PRDX) is significantly decreased in NASH, and palmitic acid (PA) binds to PRDX1 and inhibits its peroxidase activity. Using three genetic models, we demonstrate that hepatic PRDX1 protects against NASH in male mice. Mechanistically, PRDX1 suppresses STAT signaling and protects mitochondrial function by scavenging hydrogen peroxide, and mitigating the oxidation of protein tyrosine phosphatases and lipid peroxidation. We further identify rosmarinic acid (RA) as a potent agonist of PRDX1. As revealed by the complex crystal structure, RA binds to PRDX1 and stabilizes its peroxidatic cysteine. RA alleviates NASH through specifically activating PRDX1’s peroxidase activity. Thus, beyond revealing the molecular mechanism underlying PA promoting oxidative stress and NASH, our study suggests that boosting PRDX1’s peroxidase activity is a promising intervention for treating NASH.

Date: 2025
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DOI: 10.1038/s41467-025-55939-2

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