Shim Minki, San Thin Thin, Shin Bohyun, Lee Hyojeong, Han Sang Beom, Lee Dong-Kyu, Kim Hyun-Jung
College of Pharmacy, Chung-Ang University, 84, Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea.
Sci Rep. 2025 Feb 13;15(1):5409. doi: 10.1038/s41598-025-88636-7.
Lysine-specific histone demethylase (KDM) 5 inhibition by KDM5-C70 induces astrocytogenesis and highlights the importance of modulation of histone methylation in cell fate specification. This study investigated the role of the histone demethylase inhibitor KDM5-C70 in modulating the metabolic and lipidomic landscape during astrocyte differentiation of rat neural stem cells (NSCs). Using chemical derivatisation combined with gas chromatography-mass spectrometry, 42 metabolites were detected, indicating potential regulation of phospholipid metabolism. Subsequent lipidomic analysis, employing reverse-phase liquid chromatography with high-resolution quadrupole time-of-flight mass spectrometry, identified 180 lipid species and 9 lipid subclasses. Integrative analysis revealed that KDM5-C70 promoted astrocytogenesis through epigenetic changes linked to the attenuation of phosphatidylethanolamine (PE) biosynthesis pathways. The reduced expression of transcripts related to PE highlighted the significance of the PE pathway in influencing cell fate decisions. These quantitative metabolomic and lipidomic analyses not only advance our understanding of NSC differentiation but also lay the groundwork for potential therapeutic strategies targeting metabolic pathways in neurodegenerative diseases and neural injuries.
赖氨酸特异性组蛋白去甲基化酶（KDM）5-C70对KDM5的抑制作用可诱导星形胶质细胞生成，并突出了组蛋白甲基化调节在细胞命运决定中的重要性。本研究调查了组蛋白去甲基化酶抑制剂KDM5-C70在大鼠神经干细胞（NSC）向星形胶质细胞分化过程中对代谢和脂质组格局的调节作用。通过化学衍生化结合气相色谱-质谱联用技术，检测到42种代谢物，表明磷脂代谢存在潜在调控。随后采用反相液相色谱与高分辨率四极杆飞行时间质谱联用的脂质组分析方法，鉴定出180种脂质种类和9个脂质亚类。综合分析表明，KDM5-C70通过与磷脂酰乙醇胺（PE）生物合成途径减弱相关的表观遗传变化促进星形胶质细胞生成。与PE相关转录本的表达降低突出了PE途径在影响细胞命运决定中的重要性。这些定量代谢组学和脂质组学分析不仅增进了我们对NSC分化的理解，也为针对神经退行性疾病和神经损伤中代谢途径的潜在治疗策略奠定了基础。
