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142 学报 Journal of China Pharmaceutical University 2026, 57(2): 133 − 143 第 57 卷

的选择性 FIH 抑制剂、共价不可逆抑制剂等多样化 [9] Elkins JM, Hewitson KS, McNeill LA, et al. Structure of factor-
inhibiting hypoxia-inducible factor (HIF) reveals mechanism of
体系。这些工具化分子的开发不仅深化了我们对
oxidative modification of HIF-1 alpha[J]. J Biol Chem, 2003,
FIH 结构与功能的理解，也为其在复杂生理病理情 278(3): 1802-1806.
境中的作用解析提供了技术支撑。尽管目前仍处 [10] Masson N, Singleton RS, Sekirnik R, et al. The FIH hydroxy-
lase is a cellular peroxide sensor that modulates HIF transcrip-
于早期研究阶段，已有多项证据表明，抑制 FIH 活 tional activity[J]. EMBO Rep, 2012, 13(3): 251-257.
性可显著改善高脂饮食或肥胖模型中的脂质代谢 [11] Dhillon S. Roxadustat: first global approval[J]. Drugs, 2019,
79(5): 563-572.
紊乱，为代谢性疾病的干预提供了新的治疗思路。
[12] Wu Y, Li ZH, McDonough MA, et al. Inhibition of the oxygen-
未来，FIH 抑制剂的研究有望在以下几个方向 sensing asparaginyl hydroxylase factor inhibiting hypoxia-in-
实现突破。在分子层面，应进一步优化其靶向性、 ducible factor: a potential hypoxia response modulating strate-
gy[J]. J Med Chem, 2021, 64(11): 7189-7209.
药代性质及成药性，发展具有更好体内活性的候选 [13] Markolovic S, Leissing TM, Chowdhury R, et al. Structure-
化合物。在机制层面亟须厘清 FIH 在脂肪组织、骨 function relationships of human JmjC oxygenases-demethy-
骼肌、肝脏等关键代谢器官中的细胞特异性功能， lases versus hydroxylases[J]. Curr Opin Struct Biol, 2016, 41:
62-72.
明确其对代谢通路的直接或间接调控机制。在应 [14] McNeill LA, Hewitson KS, Claridge TD, et al. Hypoxia-in-
用层面，随着对 FIH 蛋白不断深入探索和研究，以 ducible factor asparaginyl hydroxylase (FIH-1) catalyses hy-
droxylation at the beta-carbon of asparagine-803[J]. Biochem J,
及不断迭代出具有更优活性、选择性和组织分别特
2002, 367(Pt 3): 571-575.
异性的 FIH 抑制剂，相信 FIH 抑制剂有望用于治疗 [15] Dann CE 3rd, Bruick RK, Deisenhofer J. Structure of factor-in-
包括肥胖、非酒精性脂肪肝等脂质代谢性疾病。 hibiting hypoxia-inducible factor 1: an asparaginyl hydroxylase
involved in the hypoxic response pathway[J]. Proc Natl Acad
尽管 FIH 抑制剂在代谢性疾病等领域展现出 Sci U S A, 2002, 99(24): 15351-15356.
广阔的应用前景，但其临床应用仍面临诸多挑战。 [16] Chan MC, Ilott NE, Schödel J, et al. Tuning the transcriptional
response to hypoxia by inhibiting hypoxia-inducible factor
当前存在组织选择性不足及多种底物干扰的潜在
(HIF) prolyl and asparaginyl hydroxylases[J]. J Biol Chem,
风险，可能影响抑制剂的安全性和有效性。未来研 2016, 291(39): 20661-20673.
究需利用类器官模型和单细胞测序技术，深入验证 [17] Stolze IP, Tian YM, Appelhoff RJ, et al. Genetic analysis of the
role of the asparaginyl hydroxylase factor inhibiting hypoxia-in-
FIH 在不同器官和细胞类型中的特异性功能，以增 ducible factor (FIH) in regulating hypoxia-inducible factor
强抑制剂的靶向性和减少副作用，推动其临床转化 (HIF) transcriptional target genes [corrected[J]. J Biol Chem,
2004, 279(41): 42719-42725.
进程。
[18] Tian YM, Yeoh KK, Lee MK, et al. Differential sensitivity of
hypoxia inducible factor hydroxylation sites to hypoxia and hy-
droxylase inhibitors[J]. J Biol Chem, 2011, 286(15): 13041-
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