# Oxysterol signaling in the central nervous system: cellular mechanisms and implications for neurodegeneration

**Authors:** Raphael P. Ricci, Cheng Xiang Foo, Katharina Ronacher, Carlie L. Cullen

PMC · DOI: 10.3389/fnmol.2026.1709065 · Frontiers in Molecular Neuroscience · 2026-02-12

## TL;DR

Oxysterols influence brain function and may offer new treatment strategies for neurodegenerative diseases by affecting glial cells and myelination.

## Contribution

This review highlights novel insights into oxysterol signaling's role in glial function and neurodegeneration.

## Key findings

- Oxysterols modulate glial activity and neuroinflammation in the CNS.
- Dysregulated oxysterol signaling contributes to neurodegenerative disorders.
- Targeting oxysterol metabolism could improve glial health and myelin repair.

## Abstract

Oxysterols, oxidized derivatives of cholesterol, are key modulators of central nervous system (CNS) function. Acting as both signaling molecules and cytotoxic mediators, oxysterols can influence glial activity, neuroinflammation and myelination. Glial cells (astrocytes, oligodendrocytes, and microglia) maintain neuronal homeostasis, support synaptic plasticity and mediate CNS repair. Dysregulated glial function contributes to chronic neuroinflammation, a hallmark of neurodegenerative and neuropsychiatric disorders such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. In this review article, we discuss the roles of oxysterols in the CNS with a particular focus on their impact on glial cells, neuroinflammation, myelination and neural circuit function. Therapeutically targeting oxysterol metabolism may mitigate oxidative stress, limit apoptosis, enhance glial health and influence myelin repair. Elucidating oxysterol signaling in glia and neurons provides critical insight into neural circuit regulation and identifies promising strategies for treating demyelinating, neurodegenerative and neuropsychiatric disorders.

## Linked entities

- **Diseases:** Alzheimer’s disease (MONDO:0004975), Parkinson’s disease (MONDO:0005180), multiple sclerosis (MONDO:0005301)

## Full-text entities

- **Genes:** Cdh5 (cadherin 5) [NCBI Gene 12562] {aka 7B4, Cd144, VE-Cad, VECD, VEcad, Vec}, Il17a (interleukin 17A) [NCBI Gene 16171] {aka Ctla-8, Ctla8, IL-17, IL-17A, Il17}, Gpr183 (G protein-coupled receptor 183) [NCBI Gene 321019] {aka Ebi2}, Acox1 (acyl-Coenzyme A oxidase 1, palmitoyl) [NCBI Gene 11430] {aka AOX, Acox, D130055E20Rik, Paox}, Casp3 (caspase 3) [NCBI Gene 12367] {aka A830040C14Rik, AC-3, CASP-3, CC3, CPP-32, CPP32}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, Trem2 (triggering receptor expressed on myeloid cells 2) [NCBI Gene 83433] {aka TREM-2, Trem2a, Trem2b, Trem2c}, Ccl2 (C-C motif chemokine ligand 2) [NCBI Gene 20296] {aka HC11, JE, MCAF, MCP-1, MCP1, SMC-CF}, Jun (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 16476] {aka AP-1, Junc, c-jun}, Cspg4 (chondroitin sulfate proteoglycan 4) [NCBI Gene 121021] {aka 4732461B14Rik, AN2, Cspg4a, NG2}, Parp1 (poly (ADP-ribose) polymerase family, member 1) [NCBI Gene 11545] {aka 5830444G22Rik, ARTD1, Adprp, Adprt1, PARP, PPOL}, Cd44 (CD44 antigen) [NCBI Gene 12505] {aka HERMES, Ly-24, Pgp-1}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, GPR183 (G protein-coupled receptor 183) [NCBI Gene 1880] {aka EBI2, hEBI2}, Itgal (integrin alpha L) [NCBI Gene 16408] {aka (p180), Cd11a, LFA-1, LFA-1A, Ly-15, Ly-21}, Axl (AXL receptor tyrosine kinase) [NCBI Gene 26362] {aka Ark, Tyro7, Ufo}, Casp8 (caspase 8) [NCBI Gene 12370] {aka CASP-8, FLICE, MACH, Mch5}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, Lamp2 (lysosomal-associated membrane protein 2) [NCBI Gene 16784] {aka CD107b, LGP-B, Lamp II, Lamp-2, Lamp-2a, Lamp-2b}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Abca1 (ATP-binding cassette, sub-family A member 1) [NCBI Gene 11303] {aka ABC-1, Abc1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, Pla2g2a (phospholipase A2, group IIA (platelets, synovial fluid)) [NCBI Gene 18780] {aka EF, Mom1, Pla2, sPLA2, sPla2-IIA}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, Grin2b (glutamate receptor, ionotropic, NMDA2B (epsilon 2)) [NCBI Gene 14812] {aka GluN2B, GluRepsilon2, NR2B, Nmdar2b}, Abl1 (Abl proto-oncogene 1, non-receptor tyrosine kinase) [NCBI Gene 11350] {aka Abl, E430008G22Rik, c-Abl}, Ager (advanced glycosylation end product-specific receptor) [NCBI Gene 11596] {aka RAGE}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, Iba1 (induction of brown adipocytes 1) [NCBI Gene 114737], H2 (histocompatibility-2, MHC) [NCBI Gene 111364] {aka H-2, MHC-II}, Grik4 (glutamate receptor, ionotropic, kainate 4) [NCBI Gene 110637] {aka 6330551K01Rik, GluK4, GluRgamma1, KA-1, KA1}, Trp53 (transformation related protein 53) [NCBI Gene 22059] {aka Tp53, bbl, bfy, bhy, p44, p53}, Nos2 (nitric oxide synthase 2, inducible) [NCBI Gene 18126] {aka MAC-NOS, NOS-II, Nos-2, Nos2a, i-NOS, iNOS}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 216799] {aka AGTAVPRL, AII/AVP, Cias1, FCAS, FCU, MWS}, Il4 (interleukin 4) [NCBI Gene 16189] {aka BSF-1, Il-4}, Icam1 (intercellular adhesion molecule 1) [NCBI Gene 15894] {aka CD54, Icam-1, Ly-47, MALA-2}, Plp1 (proteolipid protein (myelin) 1) [NCBI Gene 18823] {aka DM20, Plp, jimpy, jp, msd, rsh}, Lrp1 (low density lipoprotein receptor-related protein 1) [NCBI Gene 16971] {aka A2mr, CD91, Lrp, b2b1554Clo}, Bcl2 (B cell leukemia/lymphoma 2) [NCBI Gene 12043] {aka Bcl-2, C430015F12Rik, D630044D05Rik, D830018M01Rik}, Tas2r134 (taste receptor, type 2, member 134) [NCBI Gene 295589] {aka GPCR, T2R134, T2R23, T2R34}, Ptges (prostaglandin E synthase) [NCBI Gene 64292] {aka 2410099E23Rik, D2Ertd369e, Pges, mPGES, mPGES-1}, Kars1 (lysyl-tRNA synthetase 1) [NCBI Gene 85305] {aka D8Ertd698e, D8Wsu108e, Kars, LysRS, mKIAA0070}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, Hmox1 (heme oxygenase 1) [NCBI Gene 15368] {aka D8Wsu38e, HO-1, HO1, Hemox, Hmox, Hsp32}, Gnai2 (G protein subunit alpha i2) [NCBI Gene 14678] {aka Galphai2, Gia, Gnai-2, Hg1c}, Ceacam1 (CEA cell adhesion molecule 1) [NCBI Gene 26365] {aka Bgp, Bgp1, C-CAM, CD66a, Cc1, Cea-1}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, Pdgfra (platelet derived growth factor receptor, alpha polypeptide) [NCBI Gene 18595] {aka CD140a, Pdgfr-2}, Cat (catalase) [NCBI Gene 24248] {aka CS1, Cas1, Cat01, Catl, Cs-1}, Csf2 (colony stimulating factor 2 (granulocyte-macrophage)) [NCBI Gene 12981] {aka CSF, Csfgm, GMCSF, Gm-CSf, MGI-IGM}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, Sp1 (trans-acting transcription factor 1) [NCBI Gene 20683] {aka 1110003E12Rik, Sp1-1}, Cd68 (CD68 antigen) [NCBI Gene 12514] {aka Lamp4, Scard1, gp110}
- **Diseases:** acute monocytic leukemia (MESH:D007948), monocytic leukemia (MESH:D007951), demyelinated lesions (MESH:D003711), mitochondrial damage (MESH:D028361), atherosclerosis (MESH:D050197), PD (MESH:D010300), Inflammatory (MESH:D007249), demyelinating, neurodegenerative and neuropsychiatric disorders (MESH:D019636), neuropsychiatric disease (MESH:D004194), ischaemic injury (MESH:D014947), ALS (MESH:D000690), epilepsy (MESH:D004827), Cytotoxic (MESH:D064420), CF (MESH:D003550), tauopathy (MESH:D024801), schizophrenia (MESH:D012559), neuroinflammation (MESH:D000090862), RRMS (MESH:D020529), infection (MESH:D007239), neurotoxic (MESH:D020258), AD (MESH:D000544), neurological and psychiatric disorders (MESH:D001523), neurogenic defects (MESH:D001750), neurovascular dysfunction (MESH:D013901), Huntington's disease (MESH:D006816), learning and memory deficits (MESH:D007859), cognitive and mood symptoms (MESH:D019954), mitochondrial and peroxisomal dysfunction (MESH:D018901), amyloid (MESH:C000718787), glutamate excitotoxicity (MESH:C537425), loss of oligodendrocytes (MESH:D056784), neuronal and glial injury (MESH:D016472), mood disorders (MESH:D019964), neuron degeneration (MESH:D009410), depression (MESH:D003866), hypercholesterolemia (MESH:D006937), Cholinergic (MESH:C535672), excitotoxic damage (MESH:D020263), cognitive decline (MESH:D003072), neuroaxonal damage (MESH:D019150), MS (MESH:D009103), seizure (MESH:D012640), synaptic dysfunction (MESH:C536122), neurological disorders (MESH:D009461), neuroblastoma (MESH:D009447), neurodevelopmental disorders (MESH:D002658), myelin and neuron damage (MESH:D020279)
- **Chemicals:** potassium (MESH:D011188), 24S-hydroxycholesterol (MESH:C044563), polyunsaturated fatty acids (MESH:D005231), acid (MESH:D000143), eicosanoid (MESH:D015777), 7-KC (MESH:C003001), 24-OHC (-), superoxide (MESH:D013481), hydrogen peroxide (MESH:D006861), vitamin D (MESH:D014807), 24(S),25-epoxycholesterol (MESH:C028358), cuprizone (MESH:D003471), MDL29,951 (MESH:C000588735), coenzyme Q10 (MESH:C024989), 27-OHC (MESH:C076996), MDA (MESH:D008315), apocynin (MESH:C056165), lipid hydroperoxides (MESH:D008054), 5alpha,6alpha-epoxycholesterol (MESH:C119784), NIBR189 (MESH:C000722993), oxi (MESH:D000068759), vitamin E (MESH:D014810), N (MESH:D009584), choline (MESH:D002794), His (MESH:D006639), Lipid (MESH:D008055), Cys (MESH:D003545), arachidonic acid (MESH:D016718), minocycline (MESH:D008911), very long-chain fatty acids (MESH:C017364), TO901317 (MESH:C423915), LPS (MESH:D008070), Mito-Q (MESH:C429014), clotrimazole (MESH:D003022), sterol (MESH:D013261), 25-hydroxycholesterol (MESH:C007997), endocannabinoids (MESH:D063388), ACh (MESH:D000109), water (MESH:D014867), polyphenols (MESH:D059808), ATP (MESH:D000255), Luxol fast blue (MESH:C018588), 26-hydroxycholesterol (MESH:C007042), steroid hormones (MESH:D013256), GSH (MESH:D005978), 7alpha-hydroxycholesterol (MESH:C011724), nitric oxide (MESH:D009569), Cholesterol (MESH:D002784), glucose (MESH:D005947), 5-HT (MESH:D012701), aldehydes (MESH:D000447), cyclic AMP (MESH:D000242), calcium (MESH:D002118), ROS (MESH:D017382), Dopamine (MESH:D004298), NMDA (MESH:D016202), lysolecithin (MESH:D008244), sphingolipid (MESH:D013107), Lys (MESH:D008239), GABA (MESH:D005680)
- **Species:** Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090]
- **Cell lines:** SK-N-BE — Homo sapiens (Human), Neuroblastoma, Cancer cell line (CVCL_0528), -1 — Mus musculus (Mouse), Hybridoma (CVCL_C7RB), THP-1 — Homo sapiens (Human), Childhood acute monocytic leukemia, Cancer cell line (CVCL_0006), NT-2 — Mus musculus (Mouse), Malignant neoplasms of the mouse mammary gland, Cancer cell line (CVCL_JA57), 27-OHC — Mus musculus (Mouse), Hybridoma (CVCL_C5HZ), MSN — Homo sapiens (Human), Neuroblastoma, Cancer cell line (CVCL_9882), MO3.13 — Homo sapiens (Human), Hybrid cell line (CVCL_D357), SH-SY5Y — Homo sapiens (Human), Neuroblastoma, Cancer cell line (CVCL_0019), C6 glioma — Rattus norvegicus (Rat), Rat malignant glioma, Cancer cell line (CVCL_3581), C6 — Rattus norvegicus (Rat), Rat malignant glioma, Cancer cell line (CVCL_0194), HMC3 — Homo sapiens (Human), Transformed cell line (CVCL_II76), BV-2 — Mus musculus (Mouse), Transformed cell line (CVCL_0182), PC12 neuronal — Homo sapiens (Human), Finite cell line (CVCL_3284)

## Full text

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## Figures

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## References

237 references — full list in the complete paper: https://tomesphere.com/paper/PMC12936014/full.md

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Source: https://tomesphere.com/paper/PMC12936014