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Review Open Access

Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review)

  • Authors:
    • Zhengjun Lin
    • Yugang Zou
    • Songzhu Zou
    • Kunming Wen
  • View Affiliations / Copyright

    Affiliations: Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China, Department of Gastrointestinal Surgery, The First People's Hospital of Zunyi, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
    Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 42
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    Published online on: December 8, 2025
       https://doi.org/10.3892/ijmm.2025.5713
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Abstract

Lysine lactylation (Kla), an emerging post‑translational modification, bidirectionally regulates cell fate decisions through epigenetic reprogramming and the direct modification of key ferroptosis proteins. It drives disease progression or mediates therapeutic resistance in inflammation, neurodegenerative diseases, cancer and ischemia‑reperfusion injury, with its regulatory direction being disease‑type‑dependent. The present review discusses the functions of the Kla‑ferroptosis regulatory network, unraveling the role of Kla‑ferroptosis in diseases and its therapeutic implications. The present review aimed to provide novel perspectives for the treatment of human diseases.
View Figures

Figure 1

Histone lactylation regulates
cellular ferroptosis by affecting transcription of target genes.
Glycolysis leads to lactate accumulation, promoting histone
lactylation modification under the action of writer enzymes. This
acts on promoter regions to regulate target gene transcription,
thereby mediating ferroptosis. AARS2, alanyl-tRNA synthetase 2;
AIM2, absent in melanoma 2; CBP, CREB-binding protein; GCLC,
glutamate-cysteine ligase catalytic subunit; H3K13la, histone H3
lysine 13 lactylation; HDAC1, histone deacetylase 1; HIF1A,
hypoxia-inducible factor 1 subunit alpha; HMGB1, high mobility
group box 1; HMOX1, heme oxygenase 1; LDHA, lactate dehydrogenase
A; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3;
PMCH2, pro-melanin-concentrating hormone 2; SLC40A1, solute carrier
family 40 member 1 (Ferroportin); STAT5B, signal transducer and
activator of transcription 5B; TFRC, transferrin receptor; UCHL1,
ubiquitin C-terminal hydrolase L1; USP49, ubiquitin specific
peptidase 49; ZFP64, zinc finger protein 64.

Figure 2

Non-histone lactylation regulates
cell fate by modifying key ferroptosis effector molecules.
Glycolysis leads to lactate accumulation. Under the action of
writer enzymes, it regulates ferroptosis through pathways including
direct targeting of key ferroptosis effectors, remodeling cellular
metabolic pathways and reprogramming the epigenetic landscape.
ACAT2, acetyl-CoA acetyltransferase 2; AKT, AKT serine/threonine
kinase; ALKBH5, AlkB homolog 5; FTH1, ferritin heavy chain 1; FSP1,
ferroptosis suppressor protein 1; FTO, fat mass and
obesity-associated protein; FosL1, FOS like 1, AP-1 transcription
factor subunit; GCLC, glutamate-cysteine ligase catalytic subunit;
GCLM, GCL modifier subunit; GPX4, glutathione peroxidase 4; HDAC1,
histone deacetylase 1; H3K27ac, histone H3 lysine 27 acetylation;
IREB2, iron-responsive element-binding protein 2; KRAS, KRAS
proto-oncogene, GTPase; LDHA, lactate dehydrogenase A; LSD1,
lysine-specific demethylase 1; METTL3, methyltransferase-like 3;
mtFAS, mitochondrial fatty acid synthesis; NAA10,
N-alpha-acetyltransferase 10; NCOA4, nuclear receptor coactivator
4; NR3C1, nuclear receptor subfamily 3 group C member 1; NRF2,
nuclear factor erythroid 2-related factor 2; NSUN2, NOP2/Sun RNA
methyltransferase 2; OXPHOS, oxidative phosphorylation; OXSM,
mitochondrial 3-oxoacyl-ACP synthase; P38, p38 mitogen-activated
protein kinase; P300, E1A binding protein p300; PCK1,
phosphoenolpyruvate carboxykinase 1; PCK2, p PDK4, pyruvate
dehydrogenase kinase 4; PRDX1, peroxiredoxin 1; PRMT5, protein
arginine methyltransferase 5; SLC7A11, solute carrier family 7
member 11; SPRING, SREBP pathway regulator in Golgi; TCA,
tricarboxylic acid; TFRC, transferrin receptor; TRIM65, tripartite
motif-containing protein 65; YAP1, Yes-associated protein 1;
ZNF207, zinc finger protein 207.
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Copy and paste a formatted citation
Spandidos Publications style
Lin Z, Zou Y, Zou S and Wen K: Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review). Int J Mol Med 57: 42, 2026.
APA
Lin, Z., Zou, Y., Zou, S., & Wen, K. (2026). Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review). International Journal of Molecular Medicine, 57, 42. https://doi.org/10.3892/ijmm.2025.5713
MLA
Lin, Z., Zou, Y., Zou, S., Wen, K."Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review)". International Journal of Molecular Medicine 57.2 (2026): 42.
Chicago
Lin, Z., Zou, Y., Zou, S., Wen, K."Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 42. https://doi.org/10.3892/ijmm.2025.5713
Copy and paste a formatted citation
x
Spandidos Publications style
Lin Z, Zou Y, Zou S and Wen K: Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review). Int J Mol Med 57: 42, 2026.
APA
Lin, Z., Zou, Y., Zou, S., & Wen, K. (2026). Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review). International Journal of Molecular Medicine, 57, 42. https://doi.org/10.3892/ijmm.2025.5713
MLA
Lin, Z., Zou, Y., Zou, S., Wen, K."Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review)". International Journal of Molecular Medicine 57.2 (2026): 42.
Chicago
Lin, Z., Zou, Y., Zou, S., Wen, K."Lactylation‑mediated ferroptosis: A novel mechanism and therapeutic prospects in human diseases (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 42. https://doi.org/10.3892/ijmm.2025.5713
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