Analysis of mechanism, therapeutic strategies, and potential natural compounds against atherosclerosis by targeting iron overload-induced oxidative stress
Jing Zhang, Chunxia Nie, Yang Zhang, Lina Yang, Xinke Du, Li Liu, Ying Chen, Qing Yang, Xiaoxin Zhu, Qi Li
Abstract
Ferroptosis is a novel form of cell demise characterized primarily by the reduction of trivalent iron to divalent iron, leading to the release of reactive oxygen species (ROS) and consequent induction of intense oxidative stress. In atherosclerosis (AS), highly accumulated lipids are modified by ROS to promote the formation of lipid peroxides, further amplifying cellular oxidative stress damage to influence all stages of atherosclerotic development. Macrophages are regarded as pivotal executors in the progression of AS and the handling of iron, thus targeting macrophage iron metabolism holds significant guiding implications for exploring potential therapeutic strategies against AS. In this comprehensive review, we elucidate the potential interplay among iron overload, inflammation, and lipid dysregulation, summarizing the potential mechanisms underlying the suppression of AS by alleviating iron overload. Furthermore, the application of Traditional Chinese Medicine (TCM) is increasingly widespread. Based on extant research and the pharmacological foundations of active compounds of TCM, we propose alternative therapeutic agents for AS in the context of iron overload, aiming to diversify the therapeutic avenues. • Iron overload depletes the cellular antioxidant system and thus drives lesions. • Iron overload accelerates plaque rupture due to damaging mitochondrial and efferocytosis functions. • Targeting NCOA4 to inhibit ferritinophagy without disrupting autophagy function. • Targeting DHODH to relieve antioxidant system and lipid metabolism inhibition. • Therapeutic potential of Traditional Chinese Medicine for atherosclerosis characterized by iron overload.