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Review Open Access

Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review)

  • Authors:
    • Yuanyuan Xiao
    • Niansong Wang
    • Dingkun Gui
    • Youhua Xu
  • View Affiliations / Copyright

    Affiliations: Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, P.R. China, Department of Nephrology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, P.R. China
    Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 143
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    Published online on: March 27, 2026
       https://doi.org/10.3892/ijmm.2026.5814
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Abstract

Emerging insights into lactate‑mediated protein lactylation illuminate novel regulatory axes in the pathogenesis of diabetic nephropathy (DN). While histone lactylation has established epigenetic associations with metabolic memory, expanding proteomic evidence reveals dynamic lactylation landscapes across extracellular matrix components, inflammatory mediators and redox regulators in renal compartments. The present review systematically catalogues DN‑relevant histones and non‑histone substrates undergoing functional lactylation, while mechanistically dissecting how hyperglycemia‑fueled lactate flux drives DN through lactate‑mediated protein modification landscapes. The present review further delineates the progress of research on the potential regulatory mechanisms involved in DN and delve into the possible functions and related mechanisms. This mechanistic reappraisal establishes lactylation topology mapping as a prerequisite for developing precision modulation approaches in DN management.
View Figures

Figure 1

The lactate absorption and
accumulation of lactate in the kidney. Filtered lactate is
predominantly reabsorbed in the renal tubules via MCTs and SMCTs.
Lactate also acts as a signaling molecule by activating the GPR81
receptor, triggering context-dependent downstream effects. MCT,
proton-coupled monocarboxylate transporters; SMCTs, sodium-coupled
MCTs; GLUT, glucose transporters; GRP81, G protein-coupled receptor
81; TECs, tubular epithelial cells. Figure created in Biorender.com.

Figure 2

Overview of lactate metabolism and
mechanisms of histone or non-histone lactylation in diabetic
nephropathy. Intracellular lactate, mainly coming from glucose,
directly generates lactate via pyruvate through glycolysis.
Intracellular lactate undergoes rapid transport by SMCTs/MCTs.
Lactate in the microenvironment partially enters the circulation
and undergoes gluconeogenic metabolism in the kidney for
regenerating glucose. Lactate in the microenvironment may also be
involved in signaling pathways via GPR81 to regulate gene
expression. Lactate undergoes conversion into lactyl-CoA, which
transfers lactyl groups onto lysine moieties on histones and
non-histone proteins for lactylation, a process controlled by
epigenetic writers, readers and erasers, impacting gene expression
in cells epigenetically. MCTs, proton-coupled monocarboxylate
transporters; SMCTs, sodium-coupled monocarboxylate transporters;
LDHA, lactate dehydrogenase A; LDHB, lactate dehydrogenase B; PDH,
pyruvate dehydrogenase; La, lactylation residue. Figure created in
Biorender.com.

Figure 3

Regulatory mechanisms of
enzyme-dependent lactylation. In enzyme-dependent Kla, the 'writer'
(modifying enzymes) uses endogenous or exogenous l-lactic acid as a
substrate to transfer lactyl groups from lactyl-CoA to lysine
residues on histones or non-histones, the 'reader'
(modification-binding enzymes) recognizes Kla changes, influencing
downstream signaling pathways and triggering biological events.
When signal transduction ends, 'erasers' (demodifying enzymes)
remove lactyl groups from target proteins, halting the Kla cycle
and mitigating the lasting effects of lysine Kla. Figure created in
Biorender.com.

Figure 4

Lactylation facilitates disease
development and progression in diabetic nephropathy. Current
research on lactylation regulation in diabetic nephropathy has
shown that ACSF2, H3K14 and HMGB1 undergo lactylation in diabetic
nephropathy, which enhanced epithelial-mesenchymal transition,
mitochondrial damage and inflammation, thus exacerbating DN
progression. PKM2, pyruvate kinase M2; LDHA, lactate dehydrogenase
A; GLUT, glucose transporters; La, lactylation residue; ACSF2, acyl
CoA synthetase family member 2; HMGB1, High Mobility Group Box-1;
KLF5, Krüppel-like Factor 5; EMT, epithelial-mesenchymal
transition. Figure created in Biorender.com.

Figure 5

Possible mechanism of lactylation in
diabetic nephropathy pathogenesis. The diagram illustrates the
categorization of lactylated proteins based on their primary
pathological impact in DN. Metabolic Reprogramming: Lactylation of
ACSF2, PFKP, HIF-1α, Snail, AMPKα, Fis1, YY1, TFEB and PKM2.
Inflammation: Lactylation of HMGB1, Mecp2, YY1, TFEB, PKM2, NEDD4
and Ezrin. Fibrosis and EMT: Lactylation of H3K14, P53, SOX9,
NEDD4, Ezrin, HIF-1α, Snail and AMPKα. ACSF2, Acyl-CoA synthetase
family member 2; PKM2, pyruvate kinase M2; HMGB1, high-mobility
group box 1; YY1, yin yang 1; Fis1, fission 1; HIF-1α,
hypoxia-inducible factor-1α; PFKP, platelet isoform of
phosphofructokinase 1; Sox9, sex determining region Y (SRY)-related
HMG-box gene 9; Mecp2, methylated CpG-binding protein 2; NEDD4,
neuronally expressed developmentally downregulated 4; TFEB,
transcription factor EB; AMPKα, adenosine monophosphate-activated
protein kinase α; DN, diabetic nephropathy; ROS, reactive oxygen
species; EMT, epithelial-mesenchymal transition. Figure created in
Biorender.com.
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Copy and paste a formatted citation
Spandidos Publications style
Xiao Y, Wang N, Gui D and Xu Y: Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review). Int J Mol Med 57: 143, 2026.
APA
Xiao, Y., Wang, N., Gui, D., & Xu, Y. (2026). Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review). International Journal of Molecular Medicine, 57, 143. https://doi.org/10.3892/ijmm.2026.5814
MLA
Xiao, Y., Wang, N., Gui, D., Xu, Y."Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review)". International Journal of Molecular Medicine 57.6 (2026): 143.
Chicago
Xiao, Y., Wang, N., Gui, D., Xu, Y."Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review)". International Journal of Molecular Medicine 57, no. 6 (2026): 143. https://doi.org/10.3892/ijmm.2026.5814
Copy and paste a formatted citation
x
Spandidos Publications style
Xiao Y, Wang N, Gui D and Xu Y: Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review). Int J Mol Med 57: 143, 2026.
APA
Xiao, Y., Wang, N., Gui, D., & Xu, Y. (2026). Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review). International Journal of Molecular Medicine, 57, 143. https://doi.org/10.3892/ijmm.2026.5814
MLA
Xiao, Y., Wang, N., Gui, D., Xu, Y."Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review)". International Journal of Molecular Medicine 57.6 (2026): 143.
Chicago
Xiao, Y., Wang, N., Gui, D., Xu, Y."Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review)". International Journal of Molecular Medicine 57, no. 6 (2026): 143. https://doi.org/10.3892/ijmm.2026.5814
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