NAT10 inhibition alleviates astrocyte autophagy by impeding ac4C acetylation of <i>Timp1</i> mRNA in ischemic stroke.

Li YANG; Xiaotong LI; Yaxuan ZHAO; Hao CHEN; Can WANG; Angrong WU; Xintong GUO; Yue HUANG; Qihui WANG; Lingyun HAO; Xiaowen LI; Ying JI; Jin BAN; Guangtian WANG; Junli CAO; Zhiqiang PAN

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NAT10 inhibition alleviates astrocyte autophagy by impeding ac4C acetylation of Timp1 mRNA in ischemic stroke.

Author: Li YANG ¹ ; Xiaotong LI ¹ ; Yaxuan ZHAO ¹ ; Hao CHEN ² ; Can WANG ¹ ; Angrong WU ¹ ; Xintong GUO ¹ ; Yue HUANG ¹ ; Qihui WANG ¹ ; Lingyun HAO ¹ ; Xiaowen LI ² ; Ying JI ² ; Jin BAN ² ; Guangtian WANG ³ ; Junli CAO ¹ ; Zhiqiang PAN ¹
Author Information

1. Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou 221004, China.
2. Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China.
3. Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin 150081, China.
Publication Type:Journal Article
Keywords: Astrocyte; Autophagy; Functional recovery; Ischemic stroke; NAT10; Neuroprotection; Timp1; ac4C
From: Acta Pharmaceutica Sinica B 2025;15(5):2575-2592
CountryChina
Language:English
Abstract: Although a single nucleotide polymorphism for N-acetyltransferase 10 (NAT10) has been identified in patients with early-onset stroke, the role of NAT10 in ischemic injury and the related underlying mechanisms remains elusive. Here, we provide evidence that NAT10, the only known RNA N4-acetylcytidine (ac4C) modification "writer", is increased in the damaged cortex of patients with acute ischemic stroke and the peri-infarct cortex of mice subjected to photothrombotic (PT) stroke. Pharmacological inhibition of NAT10 with remodelin on Days 3-7 post-stroke or astrocytic depletion of NAT10 via targeted virus attenuates ischemia-induced infarction and improves functional recovery in PT mice. Mechanistically, NAT10 enhances ac4C acetylation of the inflammatory cytokine tissue inhibitor of metalloproteinase 1 (Timp1) mRNA transcript, which increases TIMP1 expression and results in the accumulation of microtubule-associated protein 1 light chain 3 (LC3) and progression of astrocyte autophagy. These findings demonstrate that NAT10 regulates astrocyte autophagy by targeting Timp1 ac4C after stroke. This study highlights the critical role of ac4C in the regulation of astrocyte autophagy and proposes a promising strategy to improve post-stroke outcomes via NAT10 inhibition.