Chronic inflammation occurs when the immune system is stuck in attack-mode, sending cell after cell to defend and repair the body for months or even years. Diseases associated with chronic inflammation, like arthritis or cancer or autoimmune disorders, weigh heavily on human health—and experts anticipate their incidence is on the rise. A new study by investigators from Mass General Brigham identified a protein called WSTF that could be targeted to block chronic inflammation. Crucially, this strategy would not interfere with acute inflammation, allowing the immune system to continue responding appropriately to short-term threats, such as viral or bacterial infection. Results are published in Nature .
"Chronic inflammatory diseases cause a great deal of suffering and death, but we still have much to learn about what drives chronic inflammation and how to treat it," said senior author Zhixun Dou, PhD, of the Center for Regenerative Medicine and Krantz Family Center for Cancer Research at Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system. "Our findings help us separate chronic and acute inflammation, as well as identify a new target for stopping chronic inflammation that results from aging and disease."
Using chronically inflamed human cells, the researchers found that WSTF interacts with other proteins inside cell nuclei, which prompts its excretion and degradation. Since WSTF is responsible for concealing pro-inflammatory genes, this nucleus-eviction reveals those genes and, in turn, amplifies inflammation. They confirmed that WSTF loss could promote inflammation in mouse models of aging and cancer. They also found, using human cells, that WSTF loss only occurred in chronic inflammation, not acute. Using these findings, the researchers designed a WSTF-restoring therapeutic to suppress chronic inflammation and observed preliminary success in mouse models of aging, metabolic dysfunction-associated steatohepatitis (MASH), and osteoarthritis.
The researchers went further to examine tissue samples from patients with MASH or osteoarthritis. They found that WSTF is lost in the livers of patients with MASH, but not in the livers of healthy donors. Using cells from the knees of osteoarthritis patients undergoing joint replacement surgery, they showed that WSTF-restoring therapeutic reduces chronic inflammation from the inflamed knee cells. These findings highlight the potential of developing new treatments targeting WSTF to combat chronic inflammatory diseases.
Further research is needed to validate the therapeutic potential of WSTF restoration in broader settings and to develop specific strategies to target WSTF. Additionally, the findings suggest other similar proteins may be involved in chronic inflammation, opening a promising new avenue for studying and treating inflammation in the future.
Authorship: In addition to Dou, Mass General Brigham authors include Yu Wang, Yaosi Liang, Marc Samuel Sherman, Yanxin Xu, Angelique Onorati, Kathleen E. Corey, Ana Maria Cabral Burkard, Chia-Kang Ho, Ulrike Rieprecht, Tara O'Brien, Murat Cetinbas, Ruslan I. Sadreyev, Robert E. Kingston, and Wolfram Goessling. Additional authors include Vinay V. Eapen, Athanasios Kournoutis, Xianting Li, Xiaoting Zhou, Kuo Du, Jing Xie, Hui Zhang, Raquel Maeso-Díaz, Xinyi Ma, Lu Wang, Jihe Liu, Corey Bretz, Aaron P. Havas, Zhuo Zhou, Shannan J. Ho Sui, Srinivas Vinod Saladi, Peter D. Adams, Anna Mae Diehl, Benjamin Alman, Zhenyu Yue, Xiao-Fan Wang, and Terje Johansen.
Paper cited: Wang, Y et al. "WSTF nuclear autophagy regulates chronic but not acute inflammation" Nature DOI: 10.1038/s41586-025-09234-1
