Construction and Validation of a Prognostic Model for Low-Grade Glioma Based on Lactylation-Related Genes

ZHU Tianai; WEN Yi; ZHANG Doudou; ZHANG Yong; PENG Xiaoning

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Journal of Hunan Normal University(Medical Science) ›› 2026, Vol. 23 ›› Issue (1) : 25-34.

Basic Medicine

Construction and Validation of a Prognostic Model for Low-Grade Glioma Based on Lactylation-Related Genes

ZHU Tianai, WEN Yi, ZHANG Doudou, ZHANG Yong, PENG Xiaoning

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Abstract

Objective Low-grade glioma (LGG) is a malignant tumor with significant molecular heterogeneity. Lactylation, a lactate-driven post-translational modification, regulates tumor progression by remodeling the tumor microenvironment. This study aims to establish a prognostic prediction model for LGG based on lactylation-related genes (LRGs) and explore their relevant molecular targets. Methods LRGs were retrieved from the MSigDB database. By integrating data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), LRGs that were differentially expressed and prognosis-related in LGG were screened. Patients were stratified into subtypes using non-negative matrix factorization (NMF) clustering. A Lactylation-Related Risk Score (LRRS) was constructed using differentially expressed genes and multiple machine learning algorithms, and the relationship between LRRS and LGG prognosis was evaluated. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression differences of PDPN (a prognosis-related gene in LGG) in human glioma cells and normal human astrocytes. Small interfering RNA was employed to knock down PDPN expression in the human glioma cell line HS683. Cell Counting Kit-8 assay, wound healing assay, and Transwell assay were respectively used to verify the effects of PDPN knockdown on the proliferation, invasion, and migration abilities of HS683 cells. Results NMF clustering classified LGG into two molecular subtypes with significantly different pathway enrichments. The constructed LRRS model contained 2 key genes associated with LGG prognosis, and patients in the high-risk group exhibited significantly shortened overall survival. Experimental validation demonstrated that PDPN was abnormally highly expressed in glioma cells, and knockdown of PDPN significantly inhibited the proliferation, migration, and invasion abilities of the HS683 cells. Conclusion The constructed lactylation-related prognostic model can effectively predict the survival outcomes of LGG patients. PDPN, a modeling-related gene for LGG, may serve as a candidate worth further in vivo validation.

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low-grade glioma / lactylation / prognostic model / podoplanin

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ZHU Tianai, WEN Yi, ZHANG Doudou, ZHANG Yong, PENG Xiaoning. Construction and Validation of a Prognostic Model for Low-Grade Glioma Based on Lactylation-Related Genes[J]. Journal of Hunan Normal University(Medical Science). 2026, 23(1): 25-34

References

[1] BAO Z, WANG Y, WANG Q, et al.Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and evolution[J]. Front Med, 2021, 15(4): 551-561.
[2] HORBINSKI C, BERGER T, PACKER RJ, et al.Clinical implications of the 2021 edition of the WHO classification of central nervous system tumours[J]. Nat Rev Neurol, 2022, 18(9): 515-529.
[3] LI Y, DENG G, QI Y, et al.Downregulation of LUZP2 is correlated with poor prognosis of low‐grade glioma[J]. Biomed Res Int, 2020(1): 9716720.
[4] GUSYATINER O, HEGI M E.Glioma epigenetics: from subclassification to novel treatment options[J]. Semin Cancer Biol, 2018, 51: 50-58.
[5] SMITH J S, CHANG E F, LAMBORN K R, et al.Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas[J]. J Clin Oncol, 2008, 26(8): 1338-1345.
[6] JAKOLA AS, MYRMEL KS, KLOSTER R, et al.Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting inlow-grade gliomas[J]. JAMA, 2012, 308(18): 1881.
[7] VAN DEN BENT M J, AFRA D, DE WITTE O, et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial[J]. Lancet, 2005, 366(9490): 985-990.
[8] HOUILLIER C, WANG X, KALOSHIG, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas[J]. Neurology, 2010, 75(17): 1560-1566.
[9] CAIRNCROSS G, WANG M, SHAW E, et al.Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term Results results of RTOG 9402[J]. J Clin Oncol, 2013, 31(3): 337-343.
[10] VAN DEN BENT MJ, BRANDES AA, Taphoorn MJ, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951[J]. J Clin Oncol, 2013, 31(3): 344-350.
[11] YANG Y, LIU X, CHENG L, et al.Tumor suppressor microRNA-138 suppresses low-grade glioma development and metastasis via regulating IGF2BP2[J]. Onco Targets Ther, 2020, 13: 2247-2260.
[12] APOSTOLOVA P, PEARCE EL.Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment[J]. Trends Immunol, 2022, 43(12): 969-977.
[13] COLLBERT LE, EI ALAM MB, WANG R, et al.Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring[J]. Cancer Cell, 2023, 41(11): 1945-1962.
[14] BYUN JK.Tumor lactic acid: a potential target for cancer therapy[J]. Arch Pharm Res, 2023, 46(2): 90-110.
[15] QU J, LI P, SUN Z.Histone lactylation regulates cancer progression by reshaping the tumor microenvironment[J]. Front Immunol, 2023, 14: 1284344.
[16] VANDER HEIDEN MG, CANTLEY LC, THOMPSON CB.Understanding the Warburg effect: the metabolic requirements of cell proliferation[J]. Science, 2009, 324(5930): 1029-1033.
[17] ZHANG D, TANG Z, HUANG H, et al.Metabolic regulation of gene expression by histone lactylation[J]. Nature, 2019, 574(7779): 575-580.
[18] yIRIZARRY-CARO RA, MCDANIEL MM, OVERCAST GR, et al. TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation[J]. Proc Natl Acad Sci U S A, 2020, 117(48): 30628-30638.
[19] YU J, CHAI P, XIE M, et al.Histone lactylation drives oncogenesis by facilitating m⁶A reader protein YTHDF2 expression in ocular melanoma[J]. Genome Biol, 2021, 22(1): 85.
[20] XIE B, LIN J, CHEN X, et al.CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer[J]. Mol Cancer, 2023, 22(1): 151.
[21] DARLIXA, GOZĖ C, RIGAU V, et al.The etiopathogenesis of diffuse low-grade gliomas[J]. Crit Rev Oncol Hematol, 2017, 109: 51-62.
[22] VENNETI S, HUSE JT.The evolving molecular genetics of low-grade glioma[J]. Adv Anat Pathol, 2015, 22(2): 94-101.
[23] BRONISCER A, BAKER SJ, WEST AN, et al.Clinical and molecular characteristics of malignant transformation of low-grade glioma in children[J]. J Clin Oncol, 2007, 25(6): 682-689.
[24] VENNETI S, HUSE JT.The evolving molecular genetics of low-grade glioma[J]. Adv Anat Pathol, 2015, 22(2): 94-101.
[25] GONDA DD, CHEUNGV J, MULLER K A, et al.The Cancer Genome Atlas expression profiles of low-grade gliomas[J]. Neurosurg Focus, 2014, 36(4): E23.
[26] VAN DER VLIS TA MB, HOEBEN A, BECKERVORDERSANDFORTH JC, et al. Impact of the revised WHO classification of diffuse low-grade glioma on clinical decision making: A case report[J]. Surg Neurol Int, 2017, 8(1): 223.
[27] BARAKAT R, CHATTERJEE J, MU R, et al.Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth[J]. Nat Commun, 2024, 15(1): 10312.
[28] ZHANG X, SUN X, GUO C, LI J, et al.Cancer-associated fibroblast-associated gene IGFBP2 promotes glioma progression through induction of M2 macrophage polarization[J]. Am J Physiol Cell Physiol, 2024, 326(1): C252-C268.
[29] XIONG J, HE J, ZHU J, et al.Lactylation-driven METTL3-mediated RNA m⁶A modification promotes immunosuppression of tumor-infiltrating myeloid cells[J]. Mol Cell, 2022, 82(9): 1660-1677.
[30] YANG Z, YAN C, MA J, et al.Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma[J]. Nat Metab, 2023, 5(1): 61-79.
[31] zBIENIASZ-KRZYWIEC P, MARTIN-PĖREZ R, EHLING M, et al. Podoplanin-expressing macrophages promote lymphangiogenesis and lymphoinvasion in breast cancer[J]. Cell Metab, 2019, 30(5): 917-936.
[32] MAOY, ZHANG J, ZHOU Q, et al.Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation[J]. Cell Res, 2024, 34(1): 13-30.
[33] LIY, MA Z, LI W, et al.PDPN+ CAFs facilitate the motility of OSCC cells by inhibiting ferroptosis via transferring exosomal lncRNAFTX[J]. Cell Death Dis, 2023, 14(11): 759.
[34] SUZUKI H, KANEKO M K, KATO Y.Roles of podoplanin in malignant progression tumor[J]. Cells, 2022, 11(3): 575.
[35] SHARMA B, AGRIANTONIS G, SHAFAEE Z, et al.Role of podoplanin (PDPN) in advancing the progression and metastasis of glioblastoma multiforme[J]. Cancers, 2024, 16(23): 4051.
[36] WU M, SHI Y, LIU Y, et al.Exosome‐transmitted podoplanin promotes tumor-associated macrophage-mediated immune tolerance in glioblastoma[J]. CNS Neurosci Ther, 2024, 30(3): e14643.
[37] HUANG J, LI J, TANG J, et al.ZDHHC22-mediated mTOR palmitoylation restrains breast cancer growth and endocrine therapy resistance[J]. Int J Biol Sci, 2022, 18(7): 2833-2850.
[38] NG TA F, YANG C, LI F, et al.Palmitoyl transferases act as potential regulators of tumor-infiltrating immune cells and glioma progression[J]. Mol Ther Nucleic Acids, 2022, 28: 716-731.