铁死亡在神经退行性疾病发病机理中的研究进展OA

Driven by the global trend of population aging,the prevalence of neurodegenerative diseases,including Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS),has been rising consistently.The pathogenic mechanisms of these disorders are complex,and effective disease-modifying therapies remain an unmet clinical need.Ferroptosis,a regulated cell death modality driven by iron-dependent lipid peroxidation,has been widely implicated in the occurrence and evolution of the aforementioned conditions.Under pathological states,both perturbed iron metabolism and reactive oxygen species(ROS)accumulation can precipitate ferroptosis.Specifically,iron overload exacerbates oxidative injury via the Fenton reaction,disrupts the glutathione(GSH)-based antioxidant defense system,and induces extensive peroxidation of polyunsaturated fatty acids(PUFAs),ultimately culminating in neuronal damage.Furthermore,ferroptosis interacts synergistically with other pathological hallmarks,such as oxidative stress,neuroinflammation,aberrant protein aggregation,and apoptosis,thereby accelerating disease progression.A synthesis of current evidence indicates that disrupted iron homeostasis,enhanced lipid peroxidation,GSH depletion,and impaired glutathione peroxidase 4(GPX4)activity constitute the common basis for ferroptosis in these neurodegenerative diseases.Concurrently,ferroptosis also displays certain disease-specific characteristics by engaging distinct pathogenic proteins and regulatory pathways in each disorder.In this review,we delineate the molecular regulatory framework of ferroptosis,summarize its research progress in AD,PD,HD,and ALS,and highlight both shared mechanisms and divergent regulatory pathways across these diseases,with the goal of informing future investigations into disease pathogenesis and the discovery of novel strategies.