A newly published review article brings fresh attention to ACSL4, a key enzyme increasingly recognized for its central role in the progression of Alzheimer’s disease. By connecting multiple biological processes, the findings position ACSL4 as a compelling focal point for future therapeutic innovation and a potential driver of disease mechanisms.
Alzheimer’s disease, a leading cause of dementia, continues to challenge healthcare systems worldwide due to its complex pathology and rising prevalence. This article underscores how disruptions in iron metabolism and lipid balance contribute to disease progression, with particular emphasis on a form of cell death known as ferroptosis. Unlike other cellular processes, ferroptosis is closely tied to iron accumulation and lipid damage, both of which are strongly implicated in neurodegeneration.
At the center of this process is ACSL4, an enzyme that regulates the incorporation of polyunsaturated fatty acids into cellular membranes, making them more vulnerable to oxidative damage. This activity amplifies oxidative stress, accelerates lipid peroxidation, and contributes to neuronal injury. The article highlights how elevated ACSL4 activity is associated with increased neuroinflammation, another hallmark of Alzheimer’s progression, further linking metabolic dysfunction to cognitive decline.
Beyond its role in ferroptosis, ACSL4 also influences immune responses in the brain, particularly through the activation of inflammatory pathways. These combined effects create a damaging cycle in which oxidative stress, inflammation, and neuronal loss reinforce one another. The integration of these mechanisms provides a more unified understanding of how Alzheimer’s disease develops and advances over time.
Importantly, the article outlines a growing range of natural and synthetic compounds that target ACSL4, suggesting new directions for therapeutic development. These compounds demonstrate the ability to reduce lipid peroxidation, limit neuroinflammation, and improve cognitive function in experimental models. While further validation is needed, these findings highlight the potential of ACSL4-targeted strategies to reshape treatment approaches.
The review also acknowledges current challenges, including the need for improved drug delivery to the brain and a deeper understanding of ACSL4’s role across different cell types. Despite these hurdles, the evidence points to ACSL4 as a critical regulator of disease-driving pathways and a promising avenue for intervention.
By bringing together advances in lipid metabolism, oxidative biology, and neurodegeneration, this work offers a clearer framework for tackling Alzheimer’s disease and opens the door to more targeted and effective therapies in the future.
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Yu Guo, Qingqing Jiang, Zhongya Gu, Huan Cao, Chengchao Zuo, Yaqi Huang, Yu Song, Xiang Chen, Furong Wang, ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets, Genes & Diseases, Volume 13, Issue 4, 2026, 101858, https://doi.org/10.1016/j.gendis.2025.101858

Funding
National Key Research and Development Program of Hubei Province 2020BCA089
National Natural Science Foundation of China 81974218