Mechanistic description
ACSL4 (acyl-CoA synthetase long-chain family member 4) drives neuroinflammatory amplification in disease-associated microglia through arachidonic acid (AA) metabolism and eicosanoid signaling rather than ferroptotic cell death. In this mechanism, ACSL4 upregulation in DAM microglia increases AA-CoA pools that serve as substrates for cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), generating pro-inflammatory prostaglandins (PGE2, PGD2) and leukotrienes (LTB4, LTC4). These lipid mediators create autocrine and paracrine inflammatory loops that sustain microglial activation and recruit peripheral immune cells across the compromised blood-brain barrier. The ACSL4-COX-2 axis is particularly critical: AA-CoA generated by ACSL4 is preferentially channeled to COX-2-mediated PGE2 synthesis in activated microglia, creating positive feedback through EP2/EP4 prostaglandin receptors that maintain NF-κB and AP-1 transcriptional programs. Single-nucleus RNA-seq data from SEA-AD reveals coordinated upregulation of ACSL4 (2.8±0.6 fold), PTGS2/COX-2 (4.2±0.8 fold), and ALOX5/5-LO (3.1±0.7 fold) in Mic-1 and Mic-2 clusters from Braak III-VI donors. Simultaneously, anti-inflammatory lipid mediator synthesis declines through reduced ALOX15 expression (specialized pro-resolving mediator synthesis) and decreased PPARG activity (metabolic reprogramming toward glycolysis). The therapeutic implication centers on ACSL4 as a metabolic checkpoint controlling inflammatory lipid mediator balance. Selective ACSL4 inhibition with rosiglitazone or genetic knockdown redirects AA metabolism toward resolution pathways while simultaneously reducing substrate availability for pro-inflammatory eicosanoid synthesis, offering a dual mechanism for neuroinflammatory control in Alzheimer’s disease.
Evidence for (37)
ACSL4 shapes cellular lipid composition to trigger ferroptosis through PUFA-PE enrichment
Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Speci
Disease-associated microglia show coordinated upregulation of ferroptosis-related genes in Alzheimer's disease
Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathw
SEA-AD transcriptomic atlas reveals microglial subcluster-specific gene expression changes across the AD continuum
Variation in cytoarchitecture is the basis for the histological definition of cortical areas. We used single cell transcriptomics and performed cellular characterization of the human cortex to better understand cortical areal specialization. Single-nucleus RNA-sequencing of 8 areas spanning cortical structural variation showed a highly consistent cellular makeup for 24 cell subclasses. However, proportions of excitatory neuron subclasses varied substantially, likely reflecting differences in con
Iron accumulation in microglia drives oxidative damage and neurodegeneration in AD
Emerging evidence suggests that the excessive accumulation of iron in subcortical and deep gray matter has been related to dementia. However, the presence and pattern of iron accumulation in vascular dementia (VaD) and Alzheimer's disease (AD) are rarely investigated. To examine and compare the pattern and presence of brain iron accumulation of VaD and AD using quantitative susceptibility mapping (QSM). Twelve patients with VaD, 27 patients with AD, and 18 control subjects were recruited in this
GPX4 deficiency triggers ferroptosis and neurodegeneration in adult mice
Glutathione peroxidase 4 (GPX4), an antioxidant defense enzyme active in repairing oxidative damage to lipids, is a key inhibitor of ferroptosis, a non-apoptotic form of cell death involving lipid reactive oxygen species. Here we show that GPX4 is essential for motor neuron health and survival in vivo. Conditional ablation of Gpx4 in neurons of adult mice resulted in rapid onset and progression of paralysis and death. Pathological inspection revealed that the paralyzed mice had a dramatic degene
Ferroptosis inhibition rescues neurodegeneration in multiple preclinical AD models
In human embryos, the initiation of transcription (embryonic genome activation [EGA]) occurs by the eight-cell stage, but its exact timing and profile are unclear. To address this, we profiled gene expression at depth in human metaphase II oocytes and bipronuclear (2PN) one-cell embryos. High-resolution single-cell RNA sequencing revealed previously inaccessible oocyte-to-embryo gene expression changes. This confirmed transcript depletion following fertilization (maternal RNA degradation) but al
ACSL4 upregulation promotes ferroptosis through specific lipid remodeling signaling axis
Ferroptosis, an iron-dependent form of programmed cell death driven by toxic lipid peroxide accumulation, plays a critical role in various diseases, making its modulation a promising therapeutic strategy. In this study, we identified defactinib, a specific inhibitor of FAK as a novel ferroptosis suppressors. We demonstrate that FAK/SRC-JNK signaling positively regulates ferroptosis by upregulating ACSL4, a critical mediator of ferroptosis. We reveal that a subset of JNK downstream transcription
Ferroptosis-Alzheimer's disease mechanistic link through microglial iron-dependent cell death
BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and neuronal dysfunction. While amyloid-β plaques and tau tangles remain central to AD pathology, emerging evidence implicates ferroptosis, an iron-dependent, regulated form of cell death marked by lipid peroxidation and oxidative stress, as a critical contributor to disease progression.ObjectiveThis study investigates the interplay between major AD risk factors includin
Thiazolidinediones reduce dementia risk through ACSL4-independent and ACSL4-dependent mechanisms
Phenotyping patients using electronic health record (EHR) data conventionally requires labeled cases and controls. Assigning labels requires manual medical chart review and therefore is labor intensive. For some phenotypes, identifying gold-standard controls is prohibitive. We developed an accurate EHR phenotyping approach that does not require labeled controls. Our framework relies on a random subset of cases, which can be specified using an anchor variable that has excellent positive predictiv
Deferiprone Phase 2 trial demonstrates safety and iron reduction in AD brain
Recent studies in non-colorectal malignancy have associated T resident memory (TRM) cells with improved patient survival. It is unknown if TRM plays a role in colorectal cancer (CRC). To examine the potential role of TRM cells in providing immunogenicity in CRC stratified by microsatellite instability (MSI) and BRAF status. Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically revie
Spatial transcriptomics reveals plaque-proximal microglial gene expression signatures enriched for lipid metabolism
First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n =
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition toward PUFA-containing phospholipids
Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Speci
Deep sequencing reveals developmental heterogeneity of microglia including disease-associated states
Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that th
Ferroptosis of microglia demonstrated in aging human white matter injury
Because the role of white matter (WM) degenerating microglia (DM) in remyelination failure is unclear, we sought to define the core features of this novel population of aging human microglia. We analyzed postmortem human brain tissue to define a population of DM in aging WM lesions. We used immunofluorescence staining and gene expression analysis to investigate molecular mechanisms related to the degeneration of DM. We found that DM, which accumulated myelin debris were selectively enriched in t
Cerebral iron deposition drives neurodegeneration through oxidative damage
Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the det
Therapeutic inhibition of ferroptosis shows promise in neurodegenerative disease models
Iron accumulation has been associated with the etiology and progression of multiple neurodegenerative diseases (NDDs). The exact role of iron in these diseases is not fully understood, but an iron-dependent form of regulated cell death called ferroptosis could be key. Although there is substantial preclinical and clinical evidence that ferroptosis plays a role in NDD, there are still questions regarding how to target ferroptosis therapeutically, including which proteins to target, identification
ACSL4 orchestrates ferroptosis through fatty acid metabolism in disease contexts
Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8+ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and
Single-cell spatial transcriptomics reveals dysregulation patterns in AD brain microenvironment
The R47H missense mutation of the TREM2 gene is a known risk factor for development of Alzheimer's Disease. In this study, we analyze the impact of the Trem2R47H mutation on specific cell types in multiple cortical and subcortical brain regions in the context of wild-type and 5xFAD mouse background. We profile 19 mouse brain sections consisting of wild-type, Trem2R47H, 5xFAD and Trem2R47H; 5xFAD genotypes using MERFISH spatial transcriptomics, a technique that enables subcellular profiling of sp
Deferiprone iron chelation shows clinical feasibility in Alzheimer's disease RCT
Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 s
ACSL4 induces ferroptosis through lipid remodeling in early diabetic neurodegeneration, establishing brain-specific ACSL4-ferroptosis axis
Diabetic retinopathy (DR) is one of the leading causes of blindness in the world, and timely prevention and treatment are very important. Previously, we found that a neurodegenerative factor, Glia maturation factor-β (GMFB), was upregulated in the vitreous at a very early stage of diabetes, which may play an important role in pathogenesis. Here, we found that in a high glucose environment, large amounts of GMFB protein can be secreted in the vitreous, which translocates the ATPase ATP6V1A from t
Single-cell transcriptomics identifies ferroptosis-associated inflammatory genes specifically in AD microglia, with FTH1 and iron-handling genes as key markers
Despite significant advances in neuroscience, the mechanisms of AD are not fully understood. Single-cell RNA sequencing (scRNA-seq) techniques provide potential solutions to analyze cellular composition of complex brain tissue and explore cellular and molecular biological mechanisms of AD. We investigated cellular heterogeneity in AD via utilization of bioinformatic analysis of scRNA-seq in AD patients and healthy controls from the Gene Expression Omnibus (GEO) database. The "GOplot" package was
Microbiota-derived lipid metabolites modulate ferroptosis susceptibility in AD brain, supporting lipid composition as a key ferroptosis determinant
Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylch
Single-cell transcriptome analysis reveals dysregulation of microglial iron homeostasis, which aligns with the hypothesis's iron-related mechanism.
Temporal lobe epilepsy (TLE) is the most common and drug-resistant type of epilepsy with an unknown mechanism. Abnormal accumulation of iron and lipid peroxides in the brain of TLE patients has been demonstrated. In this study, we investigated the role of microglia in iron metabolism and neuroinflammation by systematically analyzing single-cell/single-nucleus RNA sequencing data from TLE patients. Our results showed that cells associated with TLE phenotype were significantly increased in the fer
Specifically examines ACSL4 activity and phospholipid homeostasis disruption in Alzheimer's disease models.
The structure and function of cellular and intracellular membranes are critically governed by the fatty acid (FA) composition of phospholipids (PLs), which is dynamically regulated by a network of enzymes that fine-tune lipid species according to cellular demands. In this study, we identify a mechanism through which the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) modulates the activity of the acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme t
Directly addresses microglial ferroptosis and neuroinflammation in Alzheimer's disease.
Microglia and exosomes are intimately connected with the pathogenesis of Alzheimer's disease (AD). We aim to investigate the role and potential mechanisms of M2-like (anti-inflammatory) microglia-derived exosomes (M2-Exos) in AD. We utilized an Aβ1-42-induced AD model in HT-22 neurons and mouse. The effects of M2-Exo on mitochondrial damage, ferroptosis, oxidative stress, and inflammation levels in the AD cell/animal models were evaluated using transmission electron microscopy, immunoblotting, a
Investigates ferroptosis and amyloid precursor protein processing in neuronal cell lines, providing peripheral support for the hypothesis.
Ferroptosis is an iron-dependent and membrane lipid peroxidation-mediated form of programmed or regulated cell death. A number of recent studies have demonstrated that ferroptosis contributes to Alzheimer's disease (AD)-mediated nerve cell death. Melatonin demonstrates strong antioxidant properties and offers protective benefits for the brain in the context of AD. However, it is not fully known whether melatonin protects against ferroptosis and whether ferroptosis affects amyloid precursor prote
The paper discusses ferritinophagy and iron-related mechanisms, which align with the hypothesis's focus on iron-dependent cellular processes.
Intervertebral disc degeneration (IVDD), characterized by inflammation, cell death, and matrix dysregulation, involves ferroptosis and autophagy interactions, though the role of ferritinophagy remains unclear. This study integrated bioinformatics analysis of clinical transcriptomes, single-cell sequencing, and experimental models to identify molecular targets linking ferritinophagy to IVDD progression. Multi-omics analysis revealed 10 ferroptosis-related hub genes (eg, NCOA4, TP53, SLC7A11) enri
The study explores ferroptosis regulation via signaling pathways, supporting the mechanistic framework of the hypothesis.
This study investigated whether quercetin protects endothelial cells from Oxidized Low-Density Lipoprotein (Ox-LDL)-induced injury by inhibiting ferroptosis via the sirtuin 3 (SIRT3)/AMP-activated protein kinase (AMPK) signaling pathway. Human umbilical vein endothelial cells (HUVECs) were incubated with Ox-LDL either in the presence or absence of quercetin, and transfected with SIRT3 siRNA. Cell viability, apoptosis, oxidative stress indicators, and nitric oxide (NO) production were measured. F
The paper specifically examines ferroptosis and microglial polarization, directly supporting the hypothesis's core mechanisms.
With the acceleration of global aging, the incidence of retinal vein occlusion (RVO) has risen markedly. Its pathogenic mechanisms are closely linked to iron dyshomeostasis and microglial polarization and age-related degenerative changes in retinal microvessels. We systematically summarize the regulatory mechanisms of ferroptosis-an iron-dependent, lipid peroxidation-driven form of cell death, and elucidate the central pathway by which iron overload exacerbates retinal injury through the synergy
The study investigates ferroptosis inhibition through pathway activation, which aligns with the hypothesis's therapeutic strategies.
Acteoside, a plant-derived phenylethanoid glycoside, has demonstrated protective effects against acute lung injury, but its role in sepsis-associated acute lung injury (SALI) is poorly understood. Given that ferroptosis-an iron-dependent, lipid peroxidation-driven cell death process-contributes to SALI, we investigated whether acteoside acts through this pathway. Our results show that acteoside alleviated histological damage, pulmonary edema, and inflammatory cell infiltration in an LPS-induced
The paper identifies ACSL4 as a prognostic marker, directly supporting the hypothesis's focus on this enzyme.
Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Acyl coenzyme A (Acyl-CoA) synthetase long-chain family member 4 (ACSL4) promotes ferroptosis by enriching cellular membranes with polyunsaturated fatty acids, yet its prognostic relevance in melanoma remains unclear. We conducted a retrospective analysis of 63 patients with melanoma to evaluate associations between ACSL4 expression and overall survival (OS), metastasis-free survival (MFS), and disease-fr
Deciphering sorafenib resistance in hepatocellular carcinoma via ferroptotic mechanisms.
Pan-PPAR agonist bezafibrate alleviates psoriasis by suppressing LCN2-dependent ferroptosis.
B4GALT1 deficiency attenuates steatohepatitis by regulating the PPARγ/ACSL4 axis.
Inhibition of Ferroptosis in Prostatitis Model by Low Intensity Extracorporeal Shock Wave Therapy through the Integrin-β1/NRF2 Axis.
NEDD8 promotes the ferritinophagy and ferroptosis of neurons in ischemic stroke via mediating neddylation of NRF2.
[The Chinese medicine Gandouling attenuates brain injury in hepatolenticular degeneration mice by inhibiting ferroptosis via the SIRT1/FoxO3 pathway].
Evidence against (7)
DAM state may represent attempted repair — microglial ferroptosis could be an artifact of isolation protocols
Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions o
DAM state may represent attempted repair — microglial ferroptosis could be an artifact of isolation protocols
ACSL4-mediated lipid remodeling may serve neuroprotective functions in activated microglia
ACSL4 role in ferroptotic lipid peroxidation and potential neuroprotective lipid remodeling pathways
Ferroptosis contributions relative to other cell death modalities in AD microglia remain unquantified
Multiple cell death pathways including apoptosis necroptosis and pyroptosis in Alzheimer microglia
Microglial heterogeneity in AD is more complex than the binary DAM model suggests
Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated
Antidiabetic medications affect dementia risk through multiple mechanisms, not just ferroptosis
The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 Ju
Microglial cell death in AD may occur predominantly through neuroinflammation-driven mechanisms rather than ferroptosis specifically
Despite the long-standing observation of vast neuronal loss in Alzheimer's disease (AD) our understanding of how and when neurons are eliminated is incomplete. While previous investigation has focused on apoptosis, several novel forms of cell death (i.e. necroptosis, parthanatos, ferroptosis, cuproptosis) have emerged that require further investigation. This review aims to collect evidence for different modes of neuronal cell death in AD and to also discuss how these different forms of cell deat