Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice
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) b...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55939-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544480772063232 |
|---|---|
| author | 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 Xiangyang Xie |
| author_facet | 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 Xiangyang Xie |
| author_sort | Wen Yin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f5cacae11da14c308040890f514b5b72 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f5cacae11da14c308040890f514b5b722025-01-12T12:30:51ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-55939-2Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male miceWen Yin0Heng Xu1Zhonghao Bai2Yue Wu3Yan Zhang4Rui Liu5Zhangzhao Wang6Bei Zhang7Jing Shen8Hao Zhang9Xin Chen10Danting Ma11Xiaofeng Shi12Lihui Yan13Chang Zhang14Hualiang Jiang15Kaixian Chen16Dean Guo17Wenyan Niu18Huiyong Yin19Weiping J. Zhang20Cheng Luo21Xiangyang Xie22NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversitySchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversitySchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesCAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS)NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityDepartment of Pharmacy, General Hospital, Tianjin Medical UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), NHC Key Laboratory of Hormones and Development, Tianjin Medical UniversityCAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS)NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversitySchool of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesNHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-025-55939-2 |
| spellingShingle | 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 Xiangyang Xie Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice Nature Communications |
| title | Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice |
| title_full | Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice |
| title_fullStr | Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice |
| title_full_unstemmed | Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice |
| title_short | Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice |
| title_sort | inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice |
| url | https://doi.org/10.1038/s41467-025-55939-2 |
| work_keys_str_mv | AT wenyin inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT hengxu inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT zhonghaobai inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT yuewu inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT yanzhang inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT ruiliu inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT zhangzhaowang inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT beizhang inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT jingshen inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT haozhang inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT xinchen inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT dantingma inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT xiaofengshi inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT lihuiyan inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT changzhang inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT hualiangjiang inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT kaixianchen inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT deanguo inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT wenyanniu inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT huiyongyin inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT weipingjzhang inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT chengluo inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice AT xiangyangxie inhibitedperoxidaseactivityofperoxiredoxin1bypalmiticacidexacerbatesnonalcoholicsteatohepatitisinmalemice |