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Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review)

  • Authors:
    • Yunlong Sun
    • Kaifang Wei
    • Xudong Liao
    • Jian'an Wang
    • Li'na Gao
    • Bo Pang
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    Affiliations: College of Pharmacy, Jining Medical University, Rizhao, Shandong 276826, P.R. China, Gao Shixian National Famous Chinese Medicine Expert Inheritance Studio, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
    Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 139
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    Published online on: July 8, 2025
       https://doi.org/10.3892/ijmm.2025.5580
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Abstract

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and neuroinflammation, with microglial dysfunction emerging as a central driver of pathogenesis. Microglia, the central nervous system‑resident immune cells, exhibit dual pro‑inflammatory and anti‑inflammatory phenotypes, dynamically regulated by lipid metabolic reprogramming. Chronic activation of M1 microglia exacerbates neuronal damage, while M2 microglia promote tissue repair via phagocytic clearance and neurotrophic factor secretion. Lipid dysregulation‑marked by ceramide accumulation, cholesterol esterification defects and oxidized lipid‑driven neuroinflammation‑critically modulates microglial polarization. Mechanistic studies reveal that mitochondrial dysfunction, lysosomal stress and ferroptosis intersect with lipid metabolic pathways to amplify neurotoxicity. Therapeutic strategies targeting lipid homeostasis, such as TREM2 agonism, demonstrate efficacy in preclinical models by restoring microglial function and mitigating pathology. This review synthesizes emerging evidence linking microglial lipid metabolism to NDD progression, highlighting novel biomarkers and therapeutic avenues to disrupt the lipid‑neuroinflammation axis in neurodegeneration.
View Figures

Figure 1

Dual pro-inflammatory and
anti-inflammatory roles of microglia. M1 microglia secrete
pro-inflammatory factors such as IL-1β, IL-18, sTREM2 and IL-6.
These mediators cause neuronal injury and concurrently promote the
transformation of astrocytes into the neurotoxic A1 phenotype,
which secretes complement component C3 and mediates aberrant
synaptic pruning. In addition, M1 microglia produce NO, which
modifies Tau protein, thereby enhancing its phosphorylation and
facilitating the formation of neurofibrillary tangles. Upon IL-4
stimulation, microglia activate the STAT6 signaling pathway to
secrete Arg1 and Ym1, promoting polarization toward the M2
phenotype. M2 microglia, in turn, secrete cytokines such as BDNF
and TGF-β to enhance synaptic plasticity and mitigate Aβ burden via
TREM2 signaling. TREM2, triggering receptor expressed on myeloid
cells 2; NO, nitric oxide; BDNF, bone-derived neurotrophic factor;
sTREM2, soluble triggering receptor expressed on myeloid cells 2;
IL-6, interleukin-6; CX3CL1, C-X3-C motif chemokine ligand 1;
CX3CR1, C-X3-C motif chemokine receptor 1; OXPHOS, oxidative
phosphorylation; C3, complement component 3; STAT6, signal
transducer and activator of transcription 6; TGF-β, transforming
growth factor β; Arg1, arginase 1; Ym1, chitinase-like protein
3.

Figure 2

Link between lipid metabolism and the
pro-inflammatory and anti-inflammatory phenotypes of microglia.
CD36 recognizes oxLDL and Aβ; its binding with Aβ drives the
assembly of the NLRP3 inflammasome, accelerating amyloid plaque
deposition and neuronal injury. Furthermore, activation of CD36 can
trigger a MyD88-dependent signaling cascade via the TLR4/6 complex,
promoting the release of pro-inflammatory cytokines IL-1β and
TNF-α. Aβ and APOE competitively bind to TREM2, thereby regulating
microglial lipid uptake. LAL degrades lipoproteins in lysosomes to
release cholesterol, while intracellular cholesterol is hydrolyzed
into FFA by LPL. Myelin debris is internalized and degraded in
lysosomes to produce FFAs, which further activate nuclear receptors
LXR and PPARγ, inducing the expression of the lipid efflux
transporter ABCA1. This promotes reverse cholesterol transport and
suppresses inflammatory responses. Under pathological conditions,
excessive accumulation of myelin debris leads to lipid droplet
formation and mitochondrial dysfunction. Normally, mitochondria
generate ATP via β-oxidation, which is associated with the
anti-inflammatory phenotype; however, in pathological states,
abnormal accumulation of citrate in the TCA cycle occurs within
mitochondria, followed by its transport to the cytosol where it is
converted into acetyl-CoA. This drives DNL, leading to abnormal
lipid droplet accumulation and excessive release of inflammatory
mediators. oxLDL, oxidized LDL; LAL, lysosomal acid lipase; LPL,
lipoprotein lipase; FFA, free fatty acids; DNL, de novo
lipogenesis; NLRP3, NOD-like receptor family, pyrin
domain-containing 3; MyD88, myeloid differentiation primary
response 88; TLR4/6, toll-like receptor 4/6; IL-1β, interleukin-1β;
TNF-α, tumour necrosis factor α; APOE, apolipoprotein E; LXR, liver
x receptor; PPARγ, peroxisome proliferator-activated receptor γ;
ABCA1, ATP-binding cassette transporter A1; TAG, triacylglycerol;
PS, phosphatidylserine; MerTK, MER tyrosine-protein kinase; LDs,
lipid droplets.

Figure 3

Impact of cholesterol and its
metabolites on microglial function. ACAT1 catalyzes the
esterification of myelin-derived cholesterol into CE, which are
stored in lipid droplets. Loss of TREM2 signaling leads to reduced
APOE expression, thereby decreasing cholesterol efflux and
resulting in intracellular CE accumulation and axonal degeneration.
Increased cholesterol levels enhance the activity of lipid-gated
potassium channels. The cholesterol metabolite 25-HC can induce
iNOS, disrupting membrane permeability. Additionally, 27-HC
activates the IL-6/STAT3 pathway, leading to cellular senescence,
while 7-KC mediates neuronal injury by inhibiting peroxisomes
through the action of ROS. CE, cholesterol esters; ROS, reactive
oxygen species; TREM2, triggering receptor expressed on myeloid
cells 2; LDs, lipid droplets; 7-KC, 7-ketocholesterol; 25-HC,
25-hydroxycholesterol; IL-6, interleukin-6; STAT3, signal
transducer and activator of transcription 3; iNOS, inducible nitric
oxide synthase; ACAT1, acyl-CoA cholesterol acyltransferase 1;
SREBP2, sterol regulatory element-binding protein 2.

Figure 4

Regulatory network of ferroptosis in
microglia and its association with neuroinflammation. The complex
formed by 15-LOX and PEBP1 catalyzes the conversion of ETE-PE into
the pro-ferroptotic signal 15-HpETE-PE via its 'oxygen channel'.
This process relies on the redox activity of iron and the
competitive binding of oxygen and NO•. In M1 microglia, the high
levels of NO• produced by iNOS inhibit 15-LOX activity, thereby
preventing ferroptosis; by contrast, M2 microglia, due to their
lack of iNOS, accumulate lipid peroxides, which trigger
ferroptosis. ACSL4 facilitates ferroptosis by esterifying PUFAs
into PUFA-CoA, increasing the oxidative sensitivity of the cell
membrane. LPS stimulation upregulates ACSL4 expression via NF-κB,
exacerbating neuroinflammation, whereas propofol can
dose-dependently inhibit ACSL4, thereby alleviating neuronal injury
in a sepsis-associated encephalopathy model. Overexpression of HO-1
depletes GSH and inhibits GPX4 activity, resulting in the
accumulation of lipid peroxides and iron deposition. This process
drives microglia toward a pro-inflammatory M1 phenotype,
characterized by upregulated expression of inflammatory mediators
including iNOS, IL-1β, TNF-α, NLRP3 and caspase-1. Ferroptosis
inhibitors can reverse this phenotypic transition by scavenging
free radicals. 15-LOX, 15-lipoxygenase; PUFAs, polyunsaturated
fatty acids; GSH, glutathione; ETE-PE,
eicosatetraenoyl-phosphatidylethanolamine; 15-HpETE-PE,
15-hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine; PEBP1,
phosphatidylethanolamine-binding protein 1; PLOHs, phospho-lipid
hydroxides; PLOOHs, phospho-lipid hydroperoxides; ACSL4, acyl-CoA
synthetase long-chain family member 4; HO-1, heme oxygenase-1; NO,
nitric oxide; GPX4, glutathione peroxidase 4.
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Copy and paste a formatted citation
Spandidos Publications style
Sun Y, Wei K, Liao X, Wang J, Gao L and Pang B: Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review). Int J Mol Med 56: 139, 2025.
APA
Sun, Y., Wei, K., Liao, X., Wang, J., Gao, L., & Pang, B. (2025). Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review). International Journal of Molecular Medicine, 56, 139. https://doi.org/10.3892/ijmm.2025.5580
MLA
Sun, Y., Wei, K., Liao, X., Wang, J., Gao, L., Pang, B."Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 56.3 (2025): 139.
Chicago
Sun, Y., Wei, K., Liao, X., Wang, J., Gao, L., Pang, B."Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 139. https://doi.org/10.3892/ijmm.2025.5580
Copy and paste a formatted citation
x
Spandidos Publications style
Sun Y, Wei K, Liao X, Wang J, Gao L and Pang B: Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review). Int J Mol Med 56: 139, 2025.
APA
Sun, Y., Wei, K., Liao, X., Wang, J., Gao, L., & Pang, B. (2025). Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review). International Journal of Molecular Medicine, 56, 139. https://doi.org/10.3892/ijmm.2025.5580
MLA
Sun, Y., Wei, K., Liao, X., Wang, J., Gao, L., Pang, B."Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 56.3 (2025): 139.
Chicago
Sun, Y., Wei, K., Liao, X., Wang, J., Gao, L., Pang, B."Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review)". International Journal of Molecular Medicine 56, no. 3 (2025): 139. https://doi.org/10.3892/ijmm.2025.5580
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