GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis.
GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis.
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GSK-J4 是一种特异性组蛋白赖氨酸去甲基化酶 6A 抑制剂，通过保留 H3K27 甲基化和减少铁死亡来改善心肌细胞的脂毒性
DOI：
10.3389/fcvm.2022.907747
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发表时间：
2022
影响因子：
3.6
通讯作者：
Chen, Juan
中科院分区：
文献类型：
--
作者：
Xu, Kai;Liu, Xiang;Wen, Bin;Liu, Yazhou;Zhang, Wei;Hu, Xiaolin;Chen, Ling;Hang, Weijian;Chen, Juan
现代生活方式的改变引起一系列代谢应激，如高脂血症。过量的游离脂肪酸诱导心肌细胞代谢重编程和心肌细胞脂质含量重排，并促进氧化应激。作为一种新定义的脂质过氧化相关的细胞死亡途径，铁凋亡在代谢应激诱导的心肌细胞损伤中的作用尚不清楚。我们的工作表明，GSK-J 4，一种组蛋白赖氨酸脱甲基酶6A/6 B双重抑制剂，可以减轻棕榈酸（PA）诱导的超敏反应，通过抑制H3 K27去甲基化。从机制上讲，PA刺激降低了H3 K27 me 3水平，因此促进了ACSL 4的表达，ACSL 4是铁凋亡的关键脂质调节剂。GSK-J 4预处理显著地保留了H3 K27 me 3水平并降低了ACSL 4水平。GSK-J 4还减少活性氧以减轻氧化应激，这进一步减少脂质过氧化。综上所述，我们的数据表明，心肌细胞在代谢挑战下经历表观遗传重编程，重新排列脂质含量，并对铁凋亡敏感。GSK-J 4可能通过靶向表观遗传调节而成为治疗高血压诱导的心肌细胞损伤的潜在药物。在PA刺激下，KDM 6A上调，然后使H3 K27 me 3去甲基化，从而促进ACSL 4的转录并诱导铁凋亡。GSK-J 4是KDM 6A的特异性抑制剂，在PA刺激下保留H3 K27 me 3以抑制ACSL 4转录，其最终抑制PA诱导的铁凋亡的发展并表现出心肌细胞保护作用。
Changes in modern lifestyle provoke a series of metabolic stresses such as hyperlipidemia. Excessive free fatty acids induce cardiomyocyte metabolic reprogramming and rearrangement of the lipid content of cardiomyocyte and promote oxidative stress. As a newly defined lipid peroxidation-related cell death pathway, the role of ferroptosis in metabolic stress-induced cardiomyocyte injury is poorly revealed. Our work indicates that GSK-J4, a histone lysine demethylase 6A/6B dual inhibitor, can alleviate palmitic acid (PA)-induced hypersensitivity to ferroptosis by suppressing H3K27 demethylation. Mechanistically, PA stimulation reduces the H3K27me3 level and hence promotes the expression of ACSL4, a key lipid modulator of ferroptosis. GSK-J4 pretreatment significantly preserves the H3K27me3 level and reduces the ACSL4 level. GSK-J4 also reduces reactive oxygen species to alleviate oxidative stress, which further decreases lipid peroxidation. Taken together, our data suggest that cardiomyocyte undergoes epigenetic reprogramming under metabolic challenges, rearranging lipid content, and sensitizing to ferroptosis. GSK-J4 can be a potential drug for treating hyperlipidemia-induced cardiomyocyte injury by targeting epigenetic modulations. KDM6A is upregulated and then demethylases H3K27me3 under PA stimulation, which promotes the transcription of ACSL4 and induces ferroptosis. GSK-J4 is a specific inhibitor of KDM6A and preserves H3K27me3 under PA stimulation to suppress ACSL4 transcription, which ultimately inhibits the development of PA-induced ferroptosis and exhibits a cardiomyocyte protective effect.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
核心调节回路液-液相分离的药理抑制抑制骨肉瘤的转移和化疗耐药性
DOI：
10.1002/advs.202101895
发表时间：
2021-10
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
--
作者：
Lu B;Zou C;Yang M;He Y;He J;Zhang C;Chen S;Yu J;Liu KY;Cao Q;Zhao W
通讯作者：
Zhao W
DOI：
10.1186/s13046-021-02208-x
发表时间：
2022-01-03
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Lu Y;Chan YT;Tan HY;Zhang C;Guo W;Xu Y;Sharma R;Chen ZS;Zheng YC;Wang N;Feng Y
通讯作者：
Feng Y
影响因子：
16.6
作者：
Li F;Jing J;Movahed M;Cui X;Cao Q;Wu R;Chen Z;Yu L;Pan Y;Shi H;Shi H;Xue B
通讯作者：
Xue B
DOI：
10.3390/antiox11020208
发表时间：
2022-01-22
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Molinaro C;Salerno L;Marino F;Scalise M;Salerno N;Pagano L;De Angelis A;Cianflone E;Torella D;Urbanek K
通讯作者：
Urbanek K