中国药理学与毒理学杂志2026，Vol.40Issue(1)：67-78,12.DOI:10.3867/j.issn.1000-3002.2026.08718
靶向脂质自由基抑制剂在铁死亡中的作用机制与构效关系研究进展
Advances in research on inhibitors targeting lipid radicals in ferroptosis mechanisms and their structure-activity relationships
摘要
Abstract
Ferroptosis is an iron-dependent form of regulated cell death driven by dysregulated lipid peroxidation.A distinct chemical feature is the formation and chain propagation of lipid radicals(L·),leading to excessive lipid peroxide accumulation and loss of membrane integrity.Targeting lipid radi-cals(TLR)inhibitors suppress ferroptosis by rapidly trapping L·and terminating the lipid peroxidation chain reaction,and thus represent a promising class of small-molecule anti-ferroptotic agents.Despite robust tissue-protective effects of diverse disease models,the in vivo mechanisms,structure-activity relationships(SAR),and systemic toxicological profiles of many TLR inhibitors remain incompletely defined,and no representative agent has yet received U.S.FDA approval for ferroptosis-related indica-tions.This review summarizes radical generation and propagation in ferroptosis,classify reported small-molecule TLR inhibitors by scaffold,and integrate mechanistic insights with SAR trends,with emphasis on neurodegenerative and cerebrovascular disease models.This article also highlights translational bottlenecks involving selectivity,metabolic liabilities,and pharmacokinetic behavior,and propose ratio-nal design strategies to improve potency and developability by optimizing hydrogen-donating capacity,membrane partitioning,metabolic stability,and cooperative antioxidant motifs.关键词
脂质过氧化/铁死亡/氢原子转移/自由基清除剂/构效关系/神经退行性疾病/药物设计Key words
lipid peroxidation/ferroptosis/hydrogen abstraction/free radical scavengers/struc-ture-activity relationship/neurodegenerative diseases/drug design分类
医药卫生引用本文复制引用
吴登峰,盛卸晃,毛近隆..靶向脂质自由基抑制剂在铁死亡中的作用机制与构效关系研究进展[J].中国药理学与毒理学杂志,2026,40(1):67-78,12.基金项目
山东省自然科学基金(ZR2020MH087) Shandong Provincial Natural Science Foundation(ZR2020MH087) （ZR2020MH087）
