WSTF nuclear autophagy regulates chronic but not acute inflammation

doi:10.1038/s41586-025-09234-1

. 2025 Jul 2.

doi: 10.1038/s41586-025-09234-1. Online ahead of print.

WSTF nuclear autophagy regulates chronic but not acute inflammation

Yu Wang^{1

2

3

4}, Vinay V Eapen⁵, Yaosi Liang^{1

2

3

6}, Athanasios Kournoutis⁴, Marc Samuel Sherman⁷, Yanxin Xu^{1

2

3}, Angelique Onorati^{1

2

3}, Xianting Li^{8

9

10

11}, Xiaoting Zhou^{8

9

10

11}, Kathleen E Corey⁷, Kuo Du¹², Ana Maria Cabral Burkard^{1

2

3}, Chia-Kang Ho^{1

2

3

13}, Jing Xie¹⁴, Hui Zhang¹⁴, Raquel Maeso-Díaz¹², Xinyi Ma^{6

14}, Ulrike Rieprecht^{1

2

3}, Tara O'Brien^{1

2

3}, Murat Cetinbas^{15

16}, Lu Wang¹⁷, Jihe Liu¹⁸, Corey Bretz¹⁹, Aaron P Havas¹⁹, Zhuo Zhou²⁰, Shannan J Ho Sui¹⁸, Srinivas Vinod Saladi²¹, Ruslan I Sadreyev^{15

16}, Peter D Adams¹⁹, Robert E Kingston^{22

23}, Anna Mae Diehl¹², Benjamin Alman¹⁴, Wolfram Goessling⁷, Zhenyu Yue^{8

9

10

11}, Xiao-Fan Wang²⁴, Terje Johansen²⁵, Zhixun Dou^{26

27

28

29}

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
³ Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Autophagy Research Group, Department of Medical Biology, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.
⁵ Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁶ Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
⁷ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Center for Parkinson's Disease Neurobiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Medicine, Duke University, Durham, NC, USA.
¹³ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁴ Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
¹⁵ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Department of Biochemistry and Structural Biology, Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX, USA.
¹⁸ Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁹ Aging, Cancer and Immuno-oncology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
²⁰ State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.
²¹ Department of Cell and Cancer Biology, University of Toledo, College of Medicine and Life Sciences, Toledo, OH, USA.
²² Department of Molecular Biology and MGH Research Institute, Massachusetts General Hospital, Boston, MA, USA.
²³ Department of Genetics, Harvard Medical School, Boston, MA, USA.
²⁴ Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. xiao.fan.wang@duke.edu.
²⁵ Autophagy Research Group, Department of Medical Biology, University of Tromsø-The Arctic University of Norway, Tromsø, Norway. terje.johansen@uit.no.
²⁶ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. zdou@mgh.harvard.edu.
²⁷ Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. zdou@mgh.harvard.edu.
²⁸ Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. zdou@mgh.harvard.edu.
²⁹ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. zdou@mgh.harvard.edu.

PMID: 40604282
DOI: 10.1038/s41586-025-09234-1

WSTF nuclear autophagy regulates chronic but not acute inflammation

Yu Wang et al. Nature. 2025.

. 2025 Jul 2.

doi: 10.1038/s41586-025-09234-1. Online ahead of print.

Authors

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
³ Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Autophagy Research Group, Department of Medical Biology, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.
⁵ Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁶ Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
⁷ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Center for Parkinson's Disease Neurobiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Medicine, Duke University, Durham, NC, USA.
¹³ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁴ Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
¹⁵ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Department of Biochemistry and Structural Biology, Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX, USA.
¹⁸ Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁹ Aging, Cancer and Immuno-oncology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
²⁰ State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.
²¹ Department of Cell and Cancer Biology, University of Toledo, College of Medicine and Life Sciences, Toledo, OH, USA.
²² Department of Molecular Biology and MGH Research Institute, Massachusetts General Hospital, Boston, MA, USA.
²³ Department of Genetics, Harvard Medical School, Boston, MA, USA.
²⁴ Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. xiao.fan.wang@duke.edu.
²⁵ Autophagy Research Group, Department of Medical Biology, University of Tromsø-The Arctic University of Norway, Tromsø, Norway. terje.johansen@uit.no.
²⁶ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. zdou@mgh.harvard.edu.
²⁷ Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. zdou@mgh.harvard.edu.
²⁸ Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. zdou@mgh.harvard.edu.
²⁹ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. zdou@mgh.harvard.edu.

PMID: 40604282
DOI: 10.1038/s41586-025-09234-1

Abstract

Acute inflammation is an essential response that our bodies use to combat infections¹. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies^2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008). - PubMed
1. Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘Garb-aging’. Trends Endocrinol. Metab. 28, 199–212 (2017). - PubMed
1. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006). - PubMed
1. Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019). - PubMed - PMC
1. Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). - PubMed - PMC

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[1] Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008). - PubMed

[2] Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008). - PubMed

[3] Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘Garb-aging’. Trends Endocrinol. Metab. 28, 199–212 (2017). - PubMed

[4] Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘Garb-aging’. Trends Endocrinol. Metab. 28, 199–212 (2017). - PubMed

[5] Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006). - PubMed

[6] Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006). - PubMed

[7] Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019). - PubMed - PMC

[8] Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019). - PubMed - PMC

[9] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). - PubMed - PMC

[10] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). - PubMed - PMC

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WSTF nuclear autophagy regulates chronic but not acute inflammation

Affiliations

WSTF nuclear autophagy regulates chronic but not acute inflammation

Authors

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Abstract

Conflict of interest statement

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Abstract

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