Hu Chen, Geng Jichuan, Shan Peipei, Zhang Tongqing, Zhang Zhuqing, Zhang Xiaoyu, Lin Menghan, Zhang Xiaoxia, Chang Dong, He Baokun, Jia Deshui, Zhang Mary, Wang Chuangui, Zhang Shengping
Biomedical Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo, 255049, China.
Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, 38 Dengzhou Rd, Qingdao, 266021, China.
Commun Biol. 2025 May 27;8(1):813. doi: 10.1038/s42003-025-08255-w.
Programmed necrosis involves three consecutive stages: initiation, propagation, and execution. The initiation of necrosis has been widely studied, but due to the diversity and pleiotropy of the initiating pathways, it is difficult to identify ideal targets for necrosis inhibition from upstream necrosis pathways. Genetic evidence suggests that caspase-independent chromatinolysis, an execution process in multiple forms of necrosis, could be targeted to inhibit necrosis, but its regulatory mechanisms remain unclear. Previous studies suggest that the apoptosis-inducing factor AIF promotes chromatinolysis and caspase-independent necrosis, and its cytosol-to-nucleus translocation induces irreversible chromatinolysis. Here we report that AIF acetylation at lysine 295 is required for its cytosol-to-nucleus translocation and conduction of caspase-independent chromatinolysis upon necrotic stimuli, the SIRT1 deacetylase blocks necrotic chromatinolysis via deacetylating AIF, and pharmacological activation of SIRT1 inhibits AIF-dependent chromatinolysis and necrotic brain injury. Our results reveal a reversible blocking mechanism for AIF-dependent chromatinolysis and caspase-independent necrosis, supporting that targeting the late necrosis stage is a promising therapeutic strategy for treatment of necrosis-associated diseases.
起始、传播和执行。坏死的起始已得到广泛研究，但由于起始途径的多样性和多效性，很难从上游坏死途径中确定抑制坏死的理想靶点。遗传学证据表明，半胱天冬酶非依赖性染色质溶解是多种形式坏死中的一个执行过程，可作为抑制坏死的靶点，但其调控机制仍不清楚。先前的研究表明，凋亡诱导因子AIF促进染色质溶解和半胱天冬酶非依赖性坏死，其从细胞质到细胞核的易位会诱导不可逆的染色质溶解。在此我们报告，赖氨酸295处的AIF乙酰化是其在坏死刺激后从细胞质到细胞核易位以及传导半胱天冬酶非依赖性染色质溶解所必需的，SIRT1脱乙酰酶通过使AIF脱乙酰来阻断坏死性染色质溶解，并且SIRT1的药理学激活可抑制AIF依赖性染色质溶解和坏死性脑损伤。我们的结果揭示了一种针对AIF依赖性染色质溶解和半胱天冬酶非依赖性坏死的可逆阻断机制，支持靶向坏死后期是治疗坏死相关疾病的一种有前景的治疗策略。
