# Lactylation: a metabolic-epigenetic bridge in diabetic kidney disease and a therapeutic target for TCM **Authors:** Wen Zhang, Xiangdong Zhu, Yan Zhang, Jiahao Yang, Xiaobo Sun, Jianfeng Wang, Bin Zhang PMC · DOI: 10.1186/s13020-026-01361-9 · 2026-03-06 ## TL;DR This paper explores how lactylation, a metabolic-epigenetic process, contributes to diabetic kidney disease and how traditional Chinese medicine may offer new treatment strategies. ## Contribution The paper introduces lactylation as a novel metabolic-epigenetic bridge in DKD and highlights TCM compounds as potential therapeutic agents. ## Key findings - Lactylation links metabolic dysregulation to kidney injury and fibrosis in DKD. - Natural compounds from TCM can reduce lactate and lactylation, mitigating renal damage. - Lactate accumulation modulates immune responses, worsening inflammation in DKD. ## Abstract Lactate-derived lactylation, as an emerging epigenetic mechanism driven by lactic acid metabolism, plays a pivotal bridging role in diabetic kidney disease (DKD), linking metabolic dysregulation to pathological gene expression. Research indicates that lactacidosis exacerbates glomerular injury by promoting mesangial cell activation and podocyte damage, whilst simultaneously disrupting mitochondrial function in the tubules and activating pro-fibrotic pathways, thereby establishing a vicious cycle of metabolic reprogramming and fibrosis. Furthermore, lactate accumulation and lactylation modulate immune cell function, intensifying inflammatory responses. Owing to their multi-targeted properties, natural compounds from traditional Chinese medicine and traditional Chinese medicine compound formulations offer promising intervention strategies for this pathway. Specific agents such as Berberine, baicalin, ginsenoside compound K, and cordycepin have been demonstrated to mitigate renal injury by directly or indirectly reducing lactate production and modulating lactylation levels, thereby suppressing downstream inflammatory and fibrotic responses. This review systematically elucidates the pivotal role of the lactate-lactylation axis in the pathogenesis of DKD, highlighting traditional Chinese medicine's unique potential for precisely regulating this metabolic-epigenetic nexus. It offers innovative insights and strategies for the integrated management of DKD. ## Linked entities - **Chemicals:** Berberine (PubChem CID 2353), baicalin (PubChem CID 64982), ginsenoside compound K (PubChem CID 9852086), cordycepin (PubChem CID 6303) - **Diseases:** diabetic kidney disease (MONDO:0005016), DKD (MONDO:0005016) ## Full-text entities - **Genes:** CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, MSN (moesin) [NCBI Gene 4478] {aka HEL70, IMD50}, AGER (advanced glycosylation end-product specific receptor) [NCBI Gene 177] {aka RAGE, SCARJ1, sRAGE}, PFKM (phosphofructokinase, muscle) [NCBI Gene 5213] {aka ATP-PFK, GSD7, PFK-1, PFK-A, PFK1, PFKA}, Smad5 (SMAD family member 5) [NCBI Gene 59328] {aka Madh5}, P4HB (prolyl 4-hydroxylase subunit beta) [NCBI Gene 5034] {aka CLCRP1, DSI, ERBA2L, GIT, P4Hbeta, PDI}, PKM (pyruvate kinase M1/2) [NCBI Gene 5315] {aka CTHBP, HEL-S-30, OIP3, PK3, PKM2, TCB}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, CD2AP (CD2 associated protein) [NCBI Gene 23607] {aka CMS}, LARS1 (leucyl-tRNA synthetase 1) [NCBI Gene 51520] {aka HSPC192, ILFS1, LARS, LEURS, LEUS, LFIS}, PECAM1 (platelet and endothelial cell adhesion molecule 1) [NCBI Gene 5175] {aka CD31, CD31/EndoCAM, GPIIA', PECA1, PECAM-1, endoCAM}, NOX4 (NADPH oxidase 4) [NCBI Gene 50507] {aka KOX, KOX-1, RENOX}, Crp (C-reactive protein) [NCBI Gene 25419] {aka Aa1249, Ab1-341, Ab2-196, Ac1-114, Ac1262, Ac2-069}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, SLC7A11 (solute carrier family 7 member 11) [NCBI Gene 23657] {aka CCBR1, xCT}, GOT2 (glutamic-oxaloacetic transaminase 2) [NCBI Gene 2806] {aka DEE82, KAT4, KATIV, KYAT4, mitAAT}, LDHA (lactate dehydrogenase A) [NCBI Gene 3939] {aka GSD11, HEL-S-133P, LDHM, PIG19}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, WT1 (WT1 transcription factor) [NCBI Gene 7490] {aka AWT1, GUD, NPHS4, WAGR, WIT-2, WT-1}, Mapk8 (mitogen-activated protein kinase 8) [NCBI Gene 116554] {aka JNK}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, MRE11 (MRE11 double strand break repair nuclease) [NCBI Gene 4361] {aka ATLD, HNGS1, MRE11A, MRE11B}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, Actg2 (actin gamma 2, smooth muscle) [NCBI Gene 25365] {aka ACTGE, SMGA}, SIRT1 (sirtuin 1) [NCBI Gene 23411] {aka SIR2, SIR2L1, SIR2alpha}, Smad3 (SMAD family member 3) [NCBI Gene 25631] {aka Madh3, Smad 3, mad3}, CCN2 (cellular communication network factor 2) [NCBI Gene 1490] {aka CTGF, HCS24, IBP-8, IGFBP8, KMD, NOV2}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 59086] {aka Tgfb}, ACTA1 (actin alpha 1, skeletal muscle) [NCBI Gene 58] {aka ACTA, ASMA, CFTD, CFTD1, CFTDM, CMYO2A}, FOXP3 (forkhead box P3) [NCBI Gene 50943] {aka AIID, DIETER, IPEX, JM2, PIDX, XPID}, ZHX2 (zinc fingers and homeoboxes 2) [NCBI Gene 22882] {aka AFR1, RAF}, TFAM (transcription factor A, mitochondrial) [NCBI Gene 7019] {aka MTDPS15, MTTF1, MTTFA, TCF6, TCF6L1, TCF6L2}, MIR210 (microRNA 210) [NCBI Gene 406992] {aka MIRN210, mir-210}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, LDHB (lactate dehydrogenase B) [NCBI Gene 3945] {aka HEL-S-281, LDH-B, LDH-H, LDHBD, TRG-5}, PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562] {aka AMPK, AMPK alpha 1, AMPKa1}, IKZF1 (IKAROS family zinc finger 1) [NCBI Gene 10320] {aka CVID13, Hs.54452, IK1, IKAROS, LYF1, LyF-1}, ALB (albumin) [NCBI Gene 213] {aka FDAHT, HSA, PRO0883, PRO0903, PRO1341}, PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) [NCBI Gene 5209] {aka IPFK2, PFK2, iPFK-2}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, CGAS (cyclic GMP-AMP synthase) [NCBI Gene 115004] {aka C6orf150, D4, MB21D1, h-cGAS}, ACSL4 (acyl-CoA synthetase long chain family member 4) [NCBI Gene 2182] {aka ACS4, FACL4, LACS4, MRX63, MRX68, XLID63}, METTL3 (methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit) [NCBI Gene 56339] {aka IME4, M6A, MT-A70, Spo8, hMETTL3}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, COL1A1 (collagen type I alpha 1 chain) [NCBI Gene 1277] {aka CAFYD, EDSARTH1, EDSC, OI1, OI2, OI3}, ACSS2 (acyl-CoA synthetase short chain family member 2) [NCBI Gene 55902] {aka ACAS2, ACECS, ACS, ACSA, AceCS1, dJ1161H23.1}, PRRT2 (proline rich transmembrane protein 2) [NCBI Gene 112476] {aka BFIC2, BFIS2, DSPB3, DYT10, EKD1, FICCA}, NBN (nibrin) [NCBI Gene 4683] {aka AT-V1, AT-V2, ATV, NBS, NBS1, P95}, TFRC (transferrin receptor) [NCBI Gene 7037] {aka CD71, IMD46, T9, TFR, TFR1, TR}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, Fn1 (fibronectin 1) [NCBI Gene 25661] {aka FIBNEC, fn-1}, KAT2A (lysine acetyltransferase 2A) [NCBI Gene 2648] {aka GCN5, GCN5L2, PCAF-b, hGCN5}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, ACSF2 (acyl-CoA synthetase family member 2) [NCBI Gene 80221] {aka ACSMW, AVYV493}, PHB2 (prohibitin 2) [NCBI Gene 11331] {aka BAP, BCAP37, Bap37, PNAS-141, REA, hBAP}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, SIRT2 (sirtuin 2) [NCBI Gene 22933] {aka SIR2, SIR2L, SIR2L2} - **Diseases:** Tumour (MESH:D009369), renal pathological (MESH:D002114), tubular injury (MESH:D000230), diabetes (MESH:D003920), Chronic Kidney Disease (MESH:D051436), inflammation (MESH:D007249), hyperglycemia (MESH:D006943), cardiac fibrosis (MESH:D005355), TCM syndrome (MESH:D013577), mitochondrial (MESH:D028361), renal interstitial (MESH:D007984), metabolic (MESH:D008659), metabolic dysregulation (MESH:D021081), proteinuria (MESH:D011507), spleen-kidney deficiency (MESH:D007680), fibro-inflammatory (MESH:D009810), Tubulointerstitial injury (MESH:D009395), carcinogenesis (MESH:D063646), blood stasis (MESH:D014647), renal function deterioration (MESH:D058186), interstitial (MESH:D065167), immune diseases (MESH:D007154), end-stage renal disease (MESH:D007676), insulin resistance (MESH:D007333), acidosis (MESH:D000138), lactic acid metabolism disorders (MESH:C565446), glomerulosclerosis (MESH:D005921), microvascular dysfunction (MESH:D017566), renal tubular epithelial cell fibrosis (MESH:D009375), renal tubular injury (MESH:D015499), diabetic complications (MESH:D048909), diabetic cardiomyopathy (MESH:D058065), EndoMT (MESH:D008579), DKD (MESH:D003928), tissue injury (MESH:D017695), chronic (MESH:D002908), type 2 diabetes mellitus (MESH:D003924), glomerular injury (MESH:D007674), hepatic and cardiac remodelling (MESH:D020257), hepatic injury (MESH:D056486), liver injury (MESH:D017093), cardiac injury (MESH:D006331) - **Chemicals:** Lactate (MESH:D019344), quercetin (MESH:D011794), pentose phosphate (MESH:D010428), pyruvate (MESH:D019289), Ginsenosides (MESH:D036145), Evodiamine (MESH:C049639), oxygen (MESH:D010100), alkaloid (MESH:D000470), kynurenine (MESH:D007737), Lactyl-CoA. (MESH:C047009), water (MESH:D014867), kaempferol (MESH:C006552), compound K (MESH:C112772), iron (MESH:D007501), streptozotocin (MESH:D013311), oxaloacetic acid (MESH:D062907), acyl-CoA (MESH:D000214), fatty acid (MESH:D005227), D (MESH:D003903), Chinese herbal medicine (-), dichloroacetic acid (MESH:D003999), curcumin (MESH:D003474), lysine (MESH:D008239), tryptophan (MESH:D014364), anthraquinone (MESH:D000880), flavonoid (MESH:D005419), creatinine (MESH:D003404), baicalein (MESH:C006680), glucose (MESH:D005947), Aloe emodin (MESH:C518327), saponins (MESH:D012503), ROS (MESH:D017382), Berberine (MESH:D001599), Baicalin (MESH:C038044), short-chain fatty acid (MESH:D005232), ATP (MESH:D000255), adenosine monophosphate (MESH:D000249), Cordycepin (MESH:C058120), sodium butyrate (MESH:D020148), Triptolide (MESH:C001899), cysteine (MESH:D003545), lipid (MESH:D008055), astragaloside IV (MESH:C052064) - **Species:** Panax ginseng (Asiatic ginseng, species) [taxon 4054], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Tripterygium wilfordii (species) [taxon 458696], Salvia miltiorrhiza (Chinese salvia, species) [taxon 226208] ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12964770/full.md --- Source: https://tomesphere.com/paper/PMC12964770