In recent years, the biochemical landscape of cellular metabolism has revealed fascinating layers of complexity, particularly with the discovery of novel post-translational modifications. Among these, protein lactylation has emerged as a critical modulator, intricately linked with lipid metabolism and a diverse array of lipid-associated diseases. Lactylation, the covalent attachment of lactyl groups to lysine residues on proteins, functions as a double-edged sword within the biological system, influencing disease onset and progression in surprising and sometimes contradictory ways.
At the molecular level, the significance of lactylation pivots around its capacity to regulate both histone and non-histone proteins, thereby altering gene expression patterns and enzymatic activities relevant to lipid metabolism pathways. This modification essentially bridges the gap between metabolic status and epigenetic regulation. Novel detection and characterization methods, pioneered through advances in genetic code expansion and probe-targeted workflows, have propelled our understanding of lactylation’s biological roles forward, illuminating its nuanced involvement in metabolic diseases.
In hepatic conditions, especially non-alcoholic fatty liver disease (NAFLD), lactylation occupies a paradoxical position. On one hand, lactylation of fatty acid synthase (FASN) acts to inhibit de novo lipogenesis (DNL), effectively reducing lipid overaccumulation in hepatocytes and attenuating disease progression. Conversely, histone lactylation at specific residues such as H3K18la drives increased synthesis of triglycerides and cholesterol by upregulating genes associated with fatty acid synthesis, accelerating NAFLD’s advancement. This dual role extends to the interplay between lactylation and other epigenetic modifications such as m^6A methylation, underscoring the complexity of epigenetic crosstalk in disease etiology.
Ischemia-reperfusion injury (IRI) following liver transplantation further unravels the pathological implications of lactylation. Recent studies highlight lactylation of phosphoenolpyruvate carboxykinase 2 (PCK2) as a contributing factor to hepatocyte ferroptosis—a form of oxidative, iron-mediated cell death—which exacerbates IRI. The involvement of mitochondrial fatty acid synthesis (mtFAS) pathways in this process presents new therapeutic avenues, although clinical inhibitors remain to be developed. Targeting lactylation-modulated enzymes like PCK2 offers hope for minimizing damage during liver transplantation and potentially broadening donor organ usability.
The landscape of cancer biology has been profoundly shaped by metabolic reprogramming, with lipid metabolism at the core of tumorigenic processes. Lactylation has surfaced as a key post-translational modification maneuvering the lipid metabolic rewiring known to fuel tumor growth, invasion, and resistance to therapies. Elevated lactylation levels, both in histones and other proteins, have been implicated in malignancies such as hepatocellular carcinoma, pancreatic cancer, and pancreatic ductal adenocarcinoma. Intriguingly, specific lactylation at histone H3 lysine 18 (H3K18la) appears particularly influential in gene regulation related to oncogenesis and drug resistance, positioning it as a promising biomarker and therapeutic target.
Furthermore, resistance to chemotherapy and immunotherapy, perennial challenges in oncology, may be driven in part by lactylation-induced alterations in tumor lipid metabolism. For instance, antibodies aimed at neutralizing lactylated apolipoprotein C2 (APOC2) have shown suppressive effects on tumor progression in non-small cell lung cancer models, suggesting that targeting lactylated proteins extracellularly could complement existing treatments. Meanwhile, simvastatin’s ability to interfere with lactylation involved in the mevalonate (MVA) pathway exemplifies the potential for repurposing lipid-lowering agents to enhance cancer therapy efficacy by disrupting tumor metabolic circuits.
Vascular diseases such as atherosclerosis also display a compelling connection to lactylation-driven lipid metabolic dysregulation. The progression of atherosclerotic plaques is influenced by the lactylation state of various proteins, which in turn modulate foam cell formation, endothelial dysfunction, and inflammatory responses. Fascinatingly, lactylation has been shown to have both pro-atherogenic and protective roles depending on the cellular context and specific protein targets. For example, lactylation of MeCP2 attenuates lesion development after aerobic exercise by dampening inflammatory signaling, whereas histone lactylation mediated by the acetyltransferase P300 fosters endothelial-to-mesenchymal transition, exacerbating disease pathology. These dualistic effects imply that tailored modulation of lactylation pathways could revolutionize atherosclerosis treatment paradigms.
Metabolic disorders broadly, including obesity, diabetes, and their complications, also bear the imprint of lactylation-driven lipid reprogramming. Within the hypothalamic circuitry, histone lactylation influences neuronal pathways controlling appetite and energy expenditure, with specific marks like H4K12la linked to reduced adiposity and improved insulin sensitivity. On the other hand, lactylation of metabolic enzymes such as ACSF2 in kidneys aggravates mitochondrial dysfunction, contributing to diabetic nephropathy progression. These multi-tissue and systemic effects underscore lactylation’s role as a pivotal node in metabolic homeostasis and pathology.
Musculoskeletal degenerative diseases reveal additional dimensions of lactylation’s influence. Tendinopathies have been connected to aberrant lactylation of apolipoproteins within tendon tissues, hinting at metabolic markers for early detection and novel interventions. In intervertebral disc degeneration, the relationship between glycolytic shift, lactate accumulation, and subsequent enhancement of ferroptotic pathways through lactylation uncovers fresh therapeutic targets to slow or reverse disc aging. Similarly, lactylation-mediated modulation of key proteins in osteoarthritis establishes a metabolic link to cartilage degradation, spotlighting epigenetic regulation in musculoskeletal health.
Inflammatory diseases represent another domain where lactylation’s dichotomous nature is evident. Depending on the modification type and cellular milieu, lactylation can tip the balance between pro-inflammatory and anti-inflammatory states. In sepsis-associated acute lung injury (ALI), lactylation of histone H3K18la promotes mitochondrial damage and ferroptosis through upregulation of lipid peroxidation pathways. In parallel, specific enzyme lactylation in myocardium contributes to cardiac dysfunction in septic states. These findings hint at lactylation’s potential as both a biomarker and therapeutic target in inflammatory cascades linked to lipid metabolism.
Reproductive health disorders, including primary ovarian insufficiency (POI) and preeclampsia, have surfaced as emerging fields intersecting with lactylation and lipid metabolism. Lactylation facilitates granulosa cell proliferation and follicular development under hypoxic stress, but excessive lactylation drives premature follicle depletion, implicating it in POI pathogenesis. Furthermore, lipid-related proteins modified by lactylation in preeclampsia elucidate novel epigenetic mechanisms underlying maternal-fetal risk factors, broadening potential diagnostic and therapeutic interventions.
Neurological injury and disease, especially ischemic stroke, display complex interactions with lactylation-driven lipid metabolic regulation. The LDL receptor-related protein 1 (LRP1) modulates lactylation of ARF1 in astrocytes, influencing mitochondrial communication with neurons and affecting stroke outcomes. Additionally, lactylation of phospholipase B domain-containing protein 1 (PLBD1) exacerbates neuronal injury, whereas MeCP2 lactylation mitigates apoptosis, emphasizing the nuanced epigenetic control of neuronal survival post-insult. This bidirectional modulation advocates for therapeutic strategies seeking to harness lactylation’s neuroprotective potential.
Beyond diseases, lactylation has been implicated in specialized physiological processes such as mineralized tissue regeneration. The KDM6B/HADHA lactylation axis regulates fatty acid oxidation essential for cementum formation, with implications for dental health and regenerative medicine. Similarly, protein disulfide-isomerase lactylation emerges as a factor in radiation-induced cardiac damage, highlighting potential targets for limiting collateral tissue injury during cancer radiotherapy.
Collectively, these insights paint lactylation as a critical integrator of metabolic, epigenetic, and pathological signals in lipid-associated diseases. While research is still evolving, the identification of key lactylation sites and their corresponding enzymes opens the floodgates for innovative diagnostics and targeted therapeutics. By manipulating lactylation status, it may be possible to recalibrate disturbed lipid metabolism pathways across a spectrum of diseases—from metabolic syndromes to cancer and cardiovascular disorders—offering hope for precision medicine interventions.
However, challenges remain in fully elucidating the mechanistic intricacies of lactylation, including the identification of specific “writers,” “erasers,” and “readers,” and their tissue-specific roles. The development of selective inhibitors or mimetics, alongside advanced detection technologies, promises to accelerate translational applications. Interdisciplinary efforts blending epigenetics, metabolism, and clinical research are thus essential to unlock the therapeutic potential inherent in lactylation’s regulation of lipid metabolism.
As the field advances, a more comprehensive understanding of lactylation’s dualistic impact on disease progression and resolution will be indispensable. Close examination of its crosstalk with other epigenetic marks and metabolic pathways may reveal synergistic targets, providing novel frameworks to tackle some of the most intractable lipid-associated diseases. Ultimately, lactylation holds promise as both a biomarker for disease state monitoring and a modifiable target to alter disease trajectories across a wide biomedical spectrum.
Subject of Research: Roles of lactylation in lipid metabolism and its involvement in lipid-related diseases such as cancers, metabolic disorders, cardiovascular diseases, and reproductive system disorders.
Article Title: Roles of lactylation in lipid metabolism and related diseases.
Article References:
Zhao, B., Lan, Z., Li, C. et al. Roles of lactylation in lipid metabolism and related diseases. Cell Death Discov. 11, 401 (2025). https://doi.org/10.1038/s41420-025-02705-4
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