# Astrocyte Heterogeneity and Metabolic Reprogramming: Mechanisms Governing Retinal Ganglion Cell Damage in Glaucoma

**Authors:** Yufei Hao, Dongran Liang, Mengjie Ren, Fang Kuang, Mingmei Wu

PMC · DOI: 10.3390/cells15060487 · 2026-03-10

## TL;DR

This paper reviews how different types of astrocytes and their metabolic changes contribute to retinal cell damage in glaucoma, offering new ideas for potential treatments.

## Contribution

The paper provides a novel theoretical framework linking astrocyte heterogeneity and metabolic changes to retinal ganglion cell damage in glaucoma.

## Key findings

- Astrocyte heterogeneity and metabolic reprogramming significantly impact retinal ganglion cell survival in glaucoma.
- Fatty acid metabolism and neuroinflammation are key mechanisms in astrocyte-mediated RGC injury.
- Current challenges include characterizing astrocyte subtypes and identifying therapeutic targets in metabolic/inflammatory pathways.

## Abstract

Glaucoma, a leading cause of irreversible visual impairment, is driven by progressive retinal ganglion cell (RGC) degeneration. Emerging evidence highlights astrocytes as pivotal players in its pathogenesis, with their heterogeneity and pathological metabolic reprogramming profoundly impacting RGC survival. This review synthesizes current insights into astrocyte diversity and metabolic alterations during glaucoma-related RGC injury, emphasizing molecular mechanisms from proteomic studies. Key focuses include fatty acid metabolism, neuroinflammation, and signaling pathways that modulate astrocyte function and contribute to neurodegeneration. Despite advances, challenges remain—particularly in characterizing astrocyte subtypes and identifying actionable targets within astrocyte-mediated metabolic/inflammatory cascades. By unraveling the interplay between astrocyte heterogeneity, metabolic reprogramming, and RGC vulnerability, this review provides novel theoretical frameworks to inform targeted glaucoma therapies.

## Linked entities

- **Diseases:** glaucoma (MONDO:0005041)

## Full-text entities

- **Genes:** 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}, Gja1 (gap junction protein, alpha 1) [NCBI Gene 24392] {aka Cx43, Cxnk1}, Gfap (glial fibrillary acidic protein) [NCBI Gene 14580], Hmgb1 (high mobility group box 1) [NCBI Gene 15289] {aka HMG-1, Hmg1, SBP-1, p30}, Amigo2 (adhesion molecule with Ig like domain 2) [NCBI Gene 105827] {aka AMIGO-2, Ali1}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, Gja1 (gap junction protein, alpha 1) [NCBI Gene 14609] {aka Cnx43, Cx43, Cx43alpha1, Cxnk1, Gja-1, Npm1}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 59086] {aka Tgfb}, Vsnl1 (visinin-like 1) [NCBI Gene 26950] {aka VILIP, Vnsl1}, Lgals1 (lectin, galactose binding, soluble 1) [NCBI Gene 16852] {aka Gal-1, Galbp, L-14.5, L14, Lect14, galectin-1}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, Aqp4 (aquaporin 4) [NCBI Gene 11829] {aka WCH4}, Cd38 (CD38 antigen) [NCBI Gene 12494] {aka ADPRC 1, Cd38-rs1, I-19}, Trim21 (tripartite motif-containing 21) [NCBI Gene 20821] {aka Ro52, Ssa1}, Fabp7 (fatty acid binding protein 7, brain) [NCBI Gene 12140] {aka B-FABP, BFABP, Blbp, MRG}, Spp1 (secreted phosphoprotein 1) [NCBI Gene 25353] {aka OSP}, Cpt1a (carnitine palmitoyltransferase 1a, liver) [NCBI Gene 12894] {aka C730027G07, CPTI, Cpt1}, Srgn (serglycin) [NCBI Gene 19073] {aka Prg, Prg1, Sgc}, Dcn (decorin) [NCBI Gene 29139], Gdnf (glial cell line derived neurotrophic factor) [NCBI Gene 14573] {aka ATF}, Ngf (nerve growth factor) [NCBI Gene 18049] {aka Ngfb, beta-NGF}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Pak1 (p21 (RAC1) activated kinase 1) [NCBI Gene 29431], Gulp1 (GULP, engulfment adaptor PTB domain containing 1) [NCBI Gene 70676] {aka 3110030A04Rik, 5730529O06Rik, CED-6, Ced6, GULP, Gulp-2}, Il1rl1 (interleukin 1 receptor-like 1) [NCBI Gene 17082] {aka DER4, Fit-1, Ly84, ST2L, St2, St2-rs1}, Lcn2 (lipocalin 2) [NCBI Gene 16819] {aka 24p3, NRL, Sip24}, Lgals3 (lectin, galactose binding, soluble 3) [NCBI Gene 16854] {aka GBP, L-34, Mac-2, gal3}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, Abca1 (ATP binding cassette subfamily A member 1) [NCBI Gene 313210], H2-T23 (histocompatibility 2, T region locus 23) [NCBI Gene 15040] {aka 37b, 37c, H-2T23, H2-K1, H2-Qa1, Qa-1}, Il1a (interleukin 1 alpha) [NCBI Gene 24493] {aka IL-1 alpha, IL-1F1}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, Cartpt (CART prepropeptide) [NCBI Gene 27220] {aka Cart}, Serping1 (serine (or cysteine) peptidase inhibitor, clade G, member 1) [NCBI Gene 12258] {aka C1 Inh, C1INH., C1Inh, C1nh}, Pax8 (paired box 8) [NCBI Gene 18510] {aka Pax-8}, Bcl3 (B cell leukemia/lymphoma 3) [NCBI Gene 12051] {aka Bcl-3}, Glul (glutamate-ammonia ligase) [NCBI Gene 14645] {aka GS, Glns}, C4b (complement C4B (Chido blood group)) [NCBI Gene 12268] {aka C4, Ss}, Aldh1l1 (aldehyde dehydrogenase 1 family, member L1) [NCBI Gene 107747] {aka 1810048F20Rik, FDH, Fthfd, Neut2}, Manf (mesencephalic astrocyte-derived neurotrophic factor) [NCBI Gene 74840] {aka 3230402M22Rik, Armet, D18Mgi17}, Acly (ATP citrate lyase) [NCBI Gene 104112] {aka A730098H14Rik}, P2rx7 (purinergic receptor P2X, ligand-gated ion channel, 7) [NCBI Gene 18439] {aka P2X(7), P2X7R}, Fgf2 (fibroblast growth factor 2) [NCBI Gene 14173] {aka Fgf-2, Fgf2a, Fgfb, bFGF}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, Cflar (CASP8 and FADD-like apoptosis regulator) [NCBI Gene 12633] {aka 2310024N18Rik, A430105C05Rik, CLARP, Cash, Casper, FLAME}, Ccl5 (C-C motif chemokine ligand 5) [NCBI Gene 20304] {aka MuRantes, RANTES, SISd, Scya5, TCP228}, Slc1a3 (solute carrier family 1 (glial high affinity glutamate transporter), member 3) [NCBI Gene 20512] {aka B430115D02Rik, Eaat1, GLAST, GLAST-1, GLU-T, GluT-1}, Cav1 (caveolin 1, caveolae protein) [NCBI Gene 12389] {aka Cav, Cav-1}, Ccn2 (cellular communication network factor 2) [NCBI Gene 14219] {aka Ctgf, Fisp12, Hcs24, fisp-12}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, Rac1 (Rac family small GTPase 1) [NCBI Gene 363875], Kcnj10 (potassium inwardly-rectifying channel, subfamily J, member 10) [NCBI Gene 16513] {aka BIR10, BIRK-1, Kir1.2, Kir4.1}, Edn2 (endothelin 2) [NCBI Gene 24324] {aka ET-2, Et2, PPET2, RNEDN2S01, VIC}, S100b (S100 protein, beta polypeptide, neural) [NCBI Gene 20203] {aka Bpb}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Slc1a2 (solute carrier family 1 (glial high affinity glutamate transporter), member 2) [NCBI Gene 20511] {aka 1700091C19Rik, 2900019G14Rik, Eaat2, GLT-1, GLT1, MGLT1}, Eln (elastin) [NCBI Gene 13717] {aka E030024M20Rik}, Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}
- **Diseases:** mitochondrial dysfunction (MESH:D028361), glaucomatous retina (MESH:D019572), retinopathies (MESH:D058437), ischemia (MESH:D007511), glaucomatous neurodegeneration (MESH:D019636), inflammatory cytokines (MESH:D000080424), CNS injury (MESH:D002493), toxicity (MESH:D064420), damage (MESH:D020263), NTG (MESH:D057066), neurotoxic (MESH:D020258), Neuroinflammation (MESH:D000090862), RGC degeneration (MESH:D012162), dysfunction (MESH:D006331), axonal injury (MESH:D001480), RGC injury (MESH:D012173), Glaucoma (MESH:D005901), glaucomatous injury (MESH:D014947), optic nerve damage (MESH:D020221), inherited glaucoma (MESH:C580055), degeneration (MESH:D009410), glutamate excitotoxicity (MESH:C537425), Inflammation (MESH:D007249), hypoxic (MESH:D002534), hypoxia (MESH:D000860), optic neuropathies (MESH:D009901), retinal edema (MESH:D010211), vision loss (MESH:D014786), astrocytosis (MESH:D005911), crush (MESH:D003444), open-angle glaucoma (MESH:D005902), RGC Damage (MESH:D012164), Ocular Hypertension (MESH:D009798), blindness (MESH:D001766), metabolic (MESH:D008659)
- **Chemicals:** K+ (MESH:D011188), lipid (MESH:D008055), LXB4 (MESH:C042651), Iron (MESH:D007501), WAY-100635 (MESH:C090413), resveratrol (MESH:D000077185), crocetin (MESH:C487773), lysophosphatidic acid (MESH:C032881), lactate (MESH:D019344), Fatty Acid (MESH:D005227), glutamine (MESH:D005973), bromfenac (MESH:C053083), prostaglandins (MESH:D011453), carnosic acid (MESH:C018381), calcium (MESH:D002118), FAO (-), cholesterol (MESH:D002784), GABA (MESH:D005680), glucose (MESH:D005947), melatonin (MESH:D008550), Nicotinamide (MESH:D009536), oleic acid (MESH:D019301), baicalein (MESH:C006680), ATP (MESH:D000255), Deferiprone (MESH:D000077543), vitamin C (MESH:D001205), endocannabinoids (MESH:D063388), glutamate (MESH:D018698), naringenin (MESH:C005273), palmitic acid (MESH:D019308), docosahexaenoic acid (MESH:D004281), NAD+ (MESH:D009243), ROS (MESH:D017382), sphingosine 1-phosphate (MESH:C060506)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Rattus norvegicus (brown rat, species) [taxon 10116]
- **Mutations:** E50K
- **Cell lines:** cell — Muntiacus muntjak (Barking deer), Spontaneously immortalized cell line (CVCL_9126), /2J — Homo sapiens (Human), Transformed cell line (CVCL_N185), RGC — Rattus norvegicus (Rat), Transformed cell line (CVCL_8140), C57BL/6J — Mus musculus (Mouse), Transformed cell line (CVCL_C0MW)

## Figures

1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC13025485/full.md

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Source: https://tomesphere.com/paper/PMC13025485