Nature. 2025 Jul 02.
Yu Wang,
Vinay V Eapen,
Yaosi Liang,
Athanasios Kournoutis,
Marc Samuel Sherman,
Yanxin Xu,
Angelique Onorati,
Xianting Li,
Xiaoting Zhou,
Kathleen E Corey,
Kuo Du,
Ana Maria Cabral Burkard,
Chia-Kang Ho,
Jing Xie,
Hui Zhang,
Raquel Maeso-Díaz,
Xinyi Ma,
Ulrike Rieprecht,
Tara O'Brien,
Murat Cetinbas,
Lu Wang,
Jihe Liu,
Corey Bretz,
Aaron P Havas,
Zhuo Zhou,
Shannan J Ho Sui,
Srinivas Vinod Saladi,
Ruslan I Sadreyev,
Peter D Adams,
Robert E Kingston,
Anna Mae Diehl,
Benjamin Alman,
Wolfram Goessling,
Zhenyu Yue,
Xiao-Fan Wang,
Terje Johansen,
Zhixun Dou.
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 pathologies2,3. 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.