Lactylation in health and disease: physiological or pathological?

Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1787 - 1821

Published: Jan. 2, 2025

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles different aspects of energy metabolism signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as novel posttranslational modification (PTM). Research indicates that Kla essential balancing mechanism variety organisms involved many biological processes pathways. closely related to disease development represents potential important new drug target. In line with existing reports, we searched for newly discovered sites on histone nonhistone proteins; reviewed the mechanisms (particularly focusing enzymes directly reversible regulation Kla, including "writers" (modifying enzymes), "readers" (modification-binding "erasers" (demodifying enzymes); summarized crosstalk between PTMs help researchers better understand widespread distribution diverse functions. Furthermore, considering "double-edged sword" role both pathological contexts, this review highlights "beneficial" states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) "detrimental" pathogenic or inducive effects processes, particularly malignant tumors complex nontumor diseases. We also clarify molecular health disease, discuss feasibility therapeutic Finally, describe detection technologies their applications diagnosis clinical settings, aiming provide insights treatment diseases accelerate translation from laboratory research practice.

Language: Английский

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m6A demethylase Fto inhibited macrophage activation and glycolysis in diabetic nephropathy via m6A/Npas2/Hif‐1α axis

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 20, 2025

Abstract Macrophage infiltration and activation is a key factor in the progression of diabetic nephropathy (DN). However, aerobic glycolysis induced by m6A methylation modification plays role M1‐type macrophages, but specific mechanism remains unclear DN. In this study, expression demethylase Fto bone marrow derived macrophages primary kidney from db/db mice. Loss gain‐of‐function analysis were performed to assess Transcriptome MeRIP‐seq association was identified target gene Npas2. we found that exhibits low type 2 DN Npas2 mediated regulates glucose metabolism reprogramming participate process Furthermore, reduces level through Prrc2a‐dependent mechanism, decreasing its stability. This mediates inflammation M1 regulating Hif‐1α signaling pathway. may act as suppressor m6A/Npas2/Hif‐1α axis. findings providing new basis for prevention treatment

Language: Английский

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Lactate metabolism and lactylation in kidney diseases: insights into mechanisms and therapeutic opportunities

Renal Failure, Journal Year: 2025, Volume and Issue: 47(1)

Published: Feb. 26, 2025

The kidney is essential for lactate metabolism. Under normal conditions, the renal cortex mainly absorbs and metabolizes lactate, with minimal amounts excreted in urine. This process part of a glucose-lactate recycling system between medulla. In conditions such as acute injury (AKI) diabetic disease (DKD), kidney's ability to metabolize impaired, leading accumulation exacerbated dysfunction. Novel post-translational modifications, lactylation, are critical pathophysiology by modulating gene transcription, protein function, cellular Lactylation involved inflammatory responses tumor promotion AKI, mitochondrial dysfunction DKD, progression clear cell carcinoma (ccRCC). lactate-lactylation axis central Warburg effect ccRCC, where cells preferentially rely on glycolysis rather than oxidative phosphorylation. Understanding mechanisms metabolism lactylation diseases may offer new therapeutic strategies. review examines role esters, especially diseases, focus their regulatory potential targets.

Language: Английский

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Fufang Zhenzhu Tiaozhi (FTZ) capsule ameliorates diabetic kidney disease in mice via inhibiting the SGLT2/glycolysis pathway

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 335, P. 118698 - 118698

Published: Aug. 14, 2024

Language: Английский

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Unraveling Diabetic Kidney Disease: The Roles of Mitochondrial Dysfunction and Immunometabolism

Kidney International Reports, Journal Year: 2024, Volume and Issue: 9(12), P. 3386 - 3402

Published: Oct. 4, 2024

Language: Английский

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Mitochondrial dysfunction has a central role in diabetic kidney disease

Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Language: Английский

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The PKM2 activator TEPP‐46 suppresses cellular senescence in hydrogen peroxide‐induced proximal tubular cells and kidney fibrosis in CD‐1^db/db mice

Journal of Diabetes Investigation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

ABSTRACT Aim/Introduction Senescence is a key driver of age‐related kidney dysfunction, including diabetic disease. Oxidative stress activates cellular senescence, induces abnormal glycolysis, and associated with pyruvate kinase muscle isoform 2 (PKM2) dysfunction; however, the mechanisms linking PK activation to senescence have not been elucidated. We hypothesized that PKM2 by TEPP‐46 could suppress oxidative stress‐induced renal tubular cell injury senescence. Materials Methods To investigate effects on we conducted β‐galactosidase staining western blot analysis human primary cells (pRPTECs) treated hydrogen peroxide or without TEPP‐46. IL‐6 levels glycolytic flux were measured. Cell viability apoptosis assessed via MTS assay caspase 3 cleavage. For in vivo experiments, utilized CD‐1 db/db mice, fibrotic type diabetes model, which exhibit fibrosis. After 4 weeks intervention, fibrosis expression markers analyzed. Results In pRPTECs, increased number β‐galactosidase‐positive cells, (p16, p21, p53), p38 phosphorylation; co‐incubation suppressed these alterations. Hydrogen reduced viability, induced apoptosis, mesenchymal alterations, lactate production secretion; inhibitor mitigated effects. intervention fibrosis, tended reduce senescence‐associated molecules kidney. Conclusions be molecular target for protection against organ damage,

Language: Английский

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Lactate and Lactylation in AKI‐to‐CKD: Epigenetic Regulation and Therapeutic Opportunities

Cell Proliferation, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

ABSTRACT Lactate is not only a byproduct of glycolysis, but also considered an energy source, gluconeogenic precursor, signalling molecule and protein modifier during the process cellular metabolism. The discovery lactylation reveals multifaceted functions lactate in metabolism opens new avenues for lactate‐related research. Both have been implicated regulating numerous biological processes, including tumour progression, ischemic–hypoxic injury, neurodevelopment immune‐related inflammation. kidney plays crucial role metabolism, influencing levels while being regulated by lactate. Previous studies demonstrated importance pathogenesis acute injury (AKI) chronic disease (CKD). This review explores these diseases, comparing function metabolic mechanisms normal diseased kidneys from perspective lactylation. key regulatory roles different organs, multiple systems, various pathological states underlying AKI‐to‐CKD progression are summarised. Moreover, potential therapeutic targets future research directions across diseases identified.

Language: Английский

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Editorial: Diabetic kidney disease: routes to drug development, pharmacology and underlying molecular mechanisms, volume II

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 25, 2025

Language: Английский

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Reader Response: Prehospital Lactate Levels Obtained in the Ambulance and Prediction of 2-Day In-Hospital Mortality in Patients With Traumatic Brain Injury

Neurology, Journal Year: 2025, Volume and Issue: 104(11)

Published: May 12, 2025

Language: Английский

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