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OA

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.