美国马萨诸塞州总医院研究组揭示了WSTF核自噬调节慢性而非急性炎症。这一研究成果于2025年7月2日发表在国际顶尖学术期刊《自然》上。

在这里，该课题组人员确定了一种分离这两种反应的机制：在慢性而非急性炎症期间，染色质重塑受到核自噬的影响，其中ISWI染色质重塑复合体的WSTF蛋白与核细胞中的ATG8自噬蛋白家族相互作用。这种相互作用导致WSTF核输出并随后被细胞质中的自噬体和溶酶体降解。WSTF的缺失导致炎症基因上的染色质打开，从而放大炎症。在motheme模型和患者样本中，阻断WSTF-ATG8相互作用的细胞穿透肽不影响急性炎症，但抑制衰老以及MASH和骨关节炎的慢性炎症。特异性靶向慢性炎症而不钝化急性炎症的能力为治疗常见的慢性炎症性疾病提供了一种方法。

据了解，急性炎症是人体对抗感染的一种基本反应。然而，在没有感染的情况下，慢性炎症可能在慢性疾病的发生和进展中发挥关键作用，如关节炎、癌症、自身免疫性疾病、代谢功能障碍相关脂肪性肝炎（MASH）和大多数与年龄相关的病理。区分慢性炎症和急性炎症的潜在机制尚不清楚，这对开发针对这些主要疾病的靶向治疗提出了挑战。

附：英文原文

Title: WSTF nuclear autophagy regulates chronic but not acute inflammation

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

Issue&Volume: 2025-07-02

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 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.

DOI: 10.1038/s41586-025-09234-1

Source: https://www.nature.com/articles/s41586-025-09234-1