KDM4B enhances immune surveillance via demethylating cGAS

作者：Qiao Peng, Huimin Zhuo, Minkang Wu, Yun Hao, Yiyi Zhang, Yuying Zheng, Yu Lei, Lin Han, Hui Ren, Yingcong Wang, Zhijie Gao, Lei‐Lei Wu, Qi Lin, Chunhua Lu, Jinghua Li, Ping Wang, Lan Fang, Haihong Yu, Meiling Lu · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07792-w · 被引用次数：1 · 研究领域：interferon and immune responses、RNA modifications and cancer、Immune cells in cancer

Cyclic GMP-AMP synthase (cGAS) serves as a crucial sentinel in innate immunity by sensing cytosolic DNA, yet the molecular mechanisms governing its activation remain incompletely understood. Here, we identify lysine demethylase 4B (KDM4B) as the specific demethylase that erases cGAS K350 methylation, facilitating its chromatin release and subsequent activation. Genetic ablation of Kdm4b compromised both antiviral immunity against HSV-1 infection and antitumor responses, while also diminishing the efficacy of anti-PD-1 immunotherapy. Mechanistically, KDM4B-mediated cGAS demethylation proved crucial for its proper subcellular distribution and activation. In the context of autoimmune diseases, we found that targeting KDM4B-cGAS axis through either genetic approaches or pharmacological inhibition of KDM4B with JIB-04 effectively ameliorated disease manifestations in both Trex1-deficient mice and peripheral blood mononuclear cells from Aicardi-Goutieres syndrome (AGS) patients. Collectively, this study demonstrated that KDM4B functions as a specific demethylase for cGAS, controlling its chromatin dissociation and subsequent activation, thereby providing a therapeutic rationale for targeting cGAS methylation in human diseases.