ACSL4 in Alzheimer’s disease: Pathogenetic mechanisms and potential therapeutic targets

Iron metabolism plays a vital role in maintaining physiological homeostasis, and its dysregulation is implicated in a range of pathological consequences and illnesses, including Alzheimer’s disease (AD). Prior studies have demonstrated that Tau protein and amyloid precursor protein are involved in iron homeostasis disorder. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key contributor to AD pathogenesis and a promising therapeutic target. Acyl-CoA synthetase long-chain family 4 (ACSL4) is a lipid metabolizing enzyme that enhances ferroptosis sensitivity by promoting the incorporation of oxidizable polyunsaturated fatty acids into membrane phospholipids. Beyond ferroptosis, ACSL4 also plays crucial roles in neuroinflammation and oxidative stress, which are implicated in AD progression. Therefore, targeting ACSL4 is fantastic and has a lot of promise for treating AD. Nevertheless, the precise mechanisms through which ACSL4 contributes to AD pathology have yet to be fully elucidated. This review reveals a potentially vital role of ACSL4 in AD, focusing on its involvement in ferroptosis, oxidative stress, and neuroinflammation. Additionally, we describe some natural and synthetic compounds targeting ACSL4 with therapeutic potential in AD. Building on the theoretical findings of earlier studies about focused interventions of the ACSL4 path, our evaluation provided a broad basis for the clinical transformation in the treatment of AD strategies.