# BRG1 orchestrates diabetic corneal neuropathy via PI3K/AKT-mediated glycolytic reprogramming **Authors:** Yuyang Deng, Wenqu Chen, Danling Liao, Jianzhang Hu PMC · DOI: 10.1186/s40662-026-00474-4 · Eye and Vision · 2026-02-01 ## TL;DR This study shows that BRG1, a chromatin remodeler, drives diabetic corneal neuropathy through glycolytic reprogramming and PI3K/AKT signaling. ## Contribution The paper identifies BRG1 as a novel regulator of glycolytic reprogramming in diabetic corneal neuropathy. ## Key findings - BRG1 overexpression worsens corneal nerve damage and epithelial repair defects in diabetic mice. - BRG1 activates PI3K/AKT signaling to enhance glycolytic flux in diabetic corneal neuropathy. - Inhibiting PI3K/AKT rescues BRG1-induced pathologies without affecting BRG1 levels. ## Abstract Mounting evidence indicates metabolic dysregulation in diabetic corneal neuropathy (DCN). This study elucidates how the chromatin remodeler Brahma-related gene 1 (BRG1) orchestrates glycolytic reprogramming to drive neurodegeneration and epithelial repair defects in DCN. Type 1 diabetic mice were established via streptozotocin (STZ) injection. Glycolysis was inhibited using 2-deoxy-D-glucose (2-DG) to assess its role in DCN pathogenesis. BRG1 expression was modulated by subconjunctival plasmid delivery (overexpression/knockdown). Pathway screening identified BRG1 downstream effectors, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) inhibition (LY294002) confirmed regulatory hierarchy. Glycolytic flux was evaluated via Western blotting and immunofluorescence; corneal nerve integrity and epithelial healing were assessed by βIII-tubulin staining and sodium fluorescein assay. Hyperglycemia upregulated BRG1 and glycolytic enzymes in diabetic corneal nerves. BRG1 overexpression exacerbated epithelial repair delay and neurodegeneration, while knockdown partially reversed damage. BRG1 overexpression activated PI3K/AKT transcription, and PI3K/AKT inhibition did not alter BRG1 levels but rescued BRG1-induced pathologies. Glycolytic reprogramming is a critical driver of DCN progression. BRG1 activates PI3K/AKT signaling to enhance glycolytic flux, thereby regulating DCN pathogenesis. Targeting this axis may offer novel therapeutic strategies. The online version contains supplementary material available at 10.1186/s40662-026-00474-4. ## Linked entities - **Genes:** SMARCA4 (SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4) [NCBI Gene 6597], PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) [NCBI Gene 5290], AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] - **Chemicals:** streptozotocin (PubChem CID 29327), 2-deoxy-D-glucose (PubChem CID 108223), LY294002 (PubChem CID 3973) - **Species:** Mus musculus (taxon 10090) ## Full-text entities - **Genes:** PKM (pyruvate kinase M1/2) [NCBI Gene 5315] {aka CTHBP, HEL-S-30, OIP3, PK3, PKM2, TCB}, Cgas (cyclic GMP-AMP synthase) [NCBI Gene 214763] {aka E330016A19Rik, Mb21d1}, Tubb3 (tubulin, beta 3 class III) [NCBI Gene 22152] {aka 3200002H15Rik, M(beta)3, M(beta)6}, POTEF (POTE ankyrin domain family member F) [NCBI Gene 728378] {aka A26C1B, POTE2alpha, POTEACTIN}, Dcn (decorin) [NCBI Gene 13179] {aka DC, DSPG2, PG40, PGII, PGS2, SLRR1B}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, Slc2a1 (solute carrier family 2 (facilitated glucose transporter), member 1) [NCBI Gene 20525] {aka GT1, Glut-1, Glut1, M100200, Rgsc200}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, Hmox1 (heme oxygenase 1) [NCBI Gene 15368] {aka D8Wsu38e, HO-1, HO1, Hemox, Hmox, Hsp32}, Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, LDHA (lactate dehydrogenase A) [NCBI Gene 3939] {aka GSD11, HEL-S-133P, LDHM, PIG19}, Pfkl (phosphofructokinase, liver, B-type) [NCBI Gene 18641] {aka ATP-PFK, PFK-B, PFK-L}, HK2 (hexokinase 2) [NCBI Gene 3099] {aka HKII, HXK2}, Actb (actin, beta) [NCBI Gene 11461] {aka Actx, E430023M04Rik, beta-actin}, Hk2 (hexokinase 2) [NCBI Gene 15277] {aka HKII}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Egf (epidermal growth factor) [NCBI Gene 13645], CGAS (cyclic GMP-AMP synthase) [NCBI Gene 115004] {aka C6orf150, D4, MB21D1, h-cGAS}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, SMARCA4 (SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4) [NCBI Gene 6597] {aka BAF190, BAF190A, BRG1, CSS4, MRD16, OTSC12}, H3c7 (H3 clustered histone 7) [NCBI Gene 260423] {aka H3.2-221, H3c13, H3c14, H3c15, H3c2, H3c3}, Renbp (renin binding protein) [NCBI Gene 19703] {aka Age, Rnbp}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, Smarca4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) [NCBI Gene 20586] {aka BAF190A, Brg1, HP1-BP72, SNF2beta, SW1/SNF, b2b508.1Clo}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, CALCA (calcitonin related polypeptide alpha) [NCBI Gene 796] {aka CALC1, CGRP, CGRP-I, CGRP-alpha, CGRP1, CT}, Ldha (lactate dehydrogenase A) [NCBI Gene 16828] {aka Ldh1, Ldhm, l7R2}, Csnk2a2 (casein kinase 2, alpha prime polypeptide) [NCBI Gene 13000] {aka 1110035J23Rik, CK2} - **Diseases:** TG (MESH:D045888), infection (MESH:D007239), Diabetic keratopathy (MESH:C562399), Hyperglycemia (MESH:D006943), neurodegeneration (MESH:D019636), epithelial (MESH:D009375), type 2 diabetes (MESH:D003924), DCN (MESH:D003929), neuropathological (MESH:D009422), neuronal damage (MESH:D009410), cancer (MESH:D009369), Diabetic (MESH:D003920), Type 1 diabetic (MESH:D003922), diabetic complications (MESH:D048909), punctate keratitis (MESH:D007634), DM (MESH:D009223), metabolic dysregulation (MESH:D021081), pain (MESH:D010146), corneal epithelial defects (MESH:C536444), hyperglycemic (MESH:D006944), metabolic disorders (MESH:D008659) - **Chemicals:** SDS (MESH:D012967), inositol (MESH:D007294), TRIzol (MESH:C411644), LY294002 (MESH:C085911), advanced glycation end-product (MESH:D017127), tribromoethanol (MESH:C062527), pyruvate (MESH:D019289), 4',6-diamidino-2-phenylindole (MESH:C007293), BCA (MESH:C047117), glucose (MESH:D005947), proparacaine hydrochloride (MESH:C005717), DM (-), citrate (MESH:D019343), PMSF (MESH:D010664), 2-DG (MESH:D003847), glucose-6-phosphate (MESH:D019298), Lactate (MESH:D019344), ofloxacin (MESH:D015242), Tween 20 (MESH:D011136), Triton X-100 (MESH:D017830), paraformaldehyde (MESH:C003043), ice (MESH:D007053), ATP (MESH:D000255), VC (MESH:C098534), PVDF (MESH:C024865), sucrose (MESH:D013395), STZ (MESH:D013311), Sodium fluorescein (MESH:D019793), Blood glucose (MESH:D001786), fructose-6-phosphate (MESH:C027618), saline (MESH:D012965) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12861070/full.md ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12861070/full.md --- Source: https://tomesphere.com/paper/PMC12861070