At the heart of the study is G9a, an enzyme more formally known as euchromatic histone lysine N-methyltransferase 2, or EHMT2. G9a is a writer of one of the most studied epigenetic marks in biology, the dimethylation of histone H3 at lysine 9, generally abbreviated H3K9me2. By depositing this mark, G9a silences genes without altering their underlying DNA sequence, and the enzyme has previously been implicated in processes as diverse as embryonic development, immune cell differentiation and tumor progression. What makes the new work striking is the context in which G9a appears: the authors found that chronic alcohol exposure robustly increases the expression and activity of G9a in hepatocytes, the metabolic workhorses of the liver. This elevation was observed in liver tissue from mouse models of alcohol-related liver disease and, importantly, was corroborated in liver samples and cellular systems exposed to ethanol, establishing the enzyme as a consistent feature of the alcoholic liver environment rather than an incidental observation.

The researchers next asked what genes G9a silences in this setting, and the answer connected two of the most vibrant areas in modern cell biology: cholesterol metabolism and copper-dependent cell death. Using transcriptomic and chromatin analyses, the team showed that G9a-mediated H3K9 dimethylation represses key regulators of cholesterol homeostasis inside hepatocytes. When these constraints are lifted, or more precisely, when G9a’s enzymatic activity was blocked experimentally, the cells regained control over their cholesterol balance. Conversely, in alcohol-exposed livers, the epigenetic brake imposed by G9a produced a distinctive distortion of sterol metabolism, leading to the abnormal accumulation of free cholesterol and cholesterol intermediates within cellular membranes and organelles. The authors demonstrated that this lipid perturbation was not a passive byproduct of alcoholic injury but a necessary intermediate: mice and cells in which cholesterol accumulation was prevented were substantially protected from liver damage, even in the continued presence of alcohol.

The link to cuproptosis, a form of cell death first described in 2022, is where the study acquires much of its novelty and its viral appeal. Cuproptosis occurs when excess intracellular copper binds directly to lipid-acylated components of the mitochondrial tricarboxylic acid cycle, particularly lipoylated proteins that cluster in the mitochondrial respiratory machinery. This binding causes the lipoylated proteins to aggregate, destabilizes iron-sulfur cluster proteins, triggers proteotoxic stress and ultimately kills the cell in a manner that is distinct from apoptosis, necroptosis, ferroptosis and pyroptosis. Because the pathway depends on mitochondrial respiration and on lipoylation, cells with high mitochondrial activity, such as hepatocytes, are theoretically vulnerable. The new study provides the first coherent explanation of how an alcohol-damaged liver might become primed for this copper-dependent demise.

According to the authors, the bridge is built by the cholesterol that accumulates under G9a’s watch. Elevated free cholesterol disrupts mitochondrial membrane composition and function, impairing oxidative phosphorylation and altering the landscape of the electron transport chain. In their experimental systems, alcohol plus G9a-driven cholesterol loading increased the cells’ susceptibility to copper-induced lipoylated protein aggregation, a biochemical signature of cuproptosis. When copper levels were reduced, either genetically or pharmacologically, the aggregation and the downstream liver injury diminished. Conversely, supplementing the system with copper amplified the damage. These results place cuproptosis downstream of the epigenetic-metabolic axis, rather than as a parallel phenomenon, and provide a causal chain: alcohol elevates G9a, G9a silences cholesterol regulators, cholesterol accumulates, mitochondrial stress rises, and copper then converts that stress into lethal protein aggregation.

To confirm causality in living animals, the researchers employed well-established mouse models of chronic ethanol feeding and manipulated G9a levels both ways. Loss-of-function approaches, including genetic knockdown of G9a specifically in the liver and the use of small-molecule G9a inhibitors, markedly reduced hepatic cholesterol accumulation, decreased markers of cuproptosis, and attenuated steatosis, inflammation and fibrosis. Gain-of-function experiments did the opposite: forcing G9a expression in the liver recreated the metabolic distortion and worsened alcohol-induced pathology, effects that could again be blunted by interventions targeting cholesterol or copper. Rescue experiments were particularly convincing. When G9a-overexpressing mice were treated with agents that either block cholesterol synthesis or chelate intracellular copper, the amplified liver injury receded, demonstrating that cholesterol and copper act in the same linear pathway rather than in independent branches.

The clinical resonance of the work lies in the convergence of several druggable nodes. Statins and other cholesterol-lowering drugs are already among the most widely used medications in the world, and copper chelators such as D-penicillamine and tetrathiomolybdate are established therapies for Wilson disease, a genetic disorder of copper overload. G9a inhibitors, while still largely confined to preclinical and early clinical development, have been optimized for pharmacological use in oncology. The study therefore suggests a menu of intervention points along a defined pathway, each of which could in principle interrupt the cascade that converts alcohol exposure into hepatocyte death. The authors caution, as responsible investigators do, that animal models of alcoholic liver disease imperfectly reproduce the human condition and that systemic copper depletion carries risks, including effects on the nervous system and immune function. Any translational strategy would need to target the liver selectively and to identify which patients, if any, show evidence of copper-primed hepatocyte death in their own biopsies.

Beyond the therapeutic angle, the study contributes conceptually to a growing recognition that regulated cell death pathways form a layered network rather than a collection of isolated switches. In alcoholic liver disease, hepatocytes are subjected to apoptosis driven by death receptors and endoplasmic reticulum stress, necroptosis and pyroptosis fueled by inflammatory signaling, and ferroptosis linked to iron and lipid peroxidation. The addition of cuproptosis to this landscape, positioned specifically downstream of an epigenetic enzyme and a metabolic perturbation, suggests that different forms of cell death may dominate at different stages of disease or in different metabolic contexts. It also reframes cholesterol accumulation in the alcoholic liver, traditionally viewed through the lens of lipotoxicity and membrane rigidity, as an active sensitizer for a copper-dependent death program, giving an old observation a new mechanistic identity.

The epigenetic component of the findings deserves particular attention. Alcohol is known to perturb the methyl donor economy of the liver, affecting S-adenosylmethionine and S-adenosylhomocysteine levels, and chronic drinking is associated with widespread changes in histone methylation and acetylation. The new work shows that a specific histone methyltransferase acts as a signal-responsive valve on a metabolic gene network, translating environmental exposure into durable transcriptional change. This raises the possibility that some of the enduring, and often persistent, features of alcoholic liver disease reflect epigenetic memory rather than ongoing toxicity alone. If alcohol-driven G9a activity can lock hepatocytes into a cholesterol-vulnerable state, then even periods of abstinence might not fully restore normal metabolic control until the epigenetic mark is actively reversed, a hypothesis the authors suggest deserves direct testing.

Looking forward, the research group and others in the field will need to answer several open questions. How large is the copper contribution in human alcoholic hepatitis relative to other death pathways, and can reliable biomarkers of hepatocyte cuproptosis, such as circulating lipoylated protein fragments or copper-metabolism signatures, be developed? Which specific cholesterol species, whether free cholesterol, oxysterols or biosynthetic intermediates, are the critical sensitizers for mitochondrial lipoylation disruption? And could dietary or pharmacological modulation of copper availability offer a low-risk adjunct to existing care in patients with early-stage disease? The answers will determine how quickly the laboratory findings move toward clinical trials.

For now, the study stands as a vivid example of modern biomedical science’s integrative power, weaving together epigenetics, lipid biology, trace-metal chemistry and cell death research into a single causal narrative for a major human disease. It explains, at the molecular level, how alcohol can commandeer a cell’s own regulatory machinery and turn its energy-producing organelles into the site of its destruction. In doing so, it offers both a cautionary tale about the depth of alcohol’s biological reach and a concrete, pathway-oriented map toward new treatments for millions of patients whose livers bear the accumulating cost of chronic drinking.

EZH2, short for enhancer of zeste homolog 2, is best known as a catalytic component of the Polycomb Repressive Complex 2, or PRC2. In that classical role, EZH2 adds methyl groups to histone H3 at lysine 27, a chemical modification commonly designated H3K27me3. Histones are proteins around which DNA is wrapped, and chemical marks on them can influence whether nearby genes are accessible for transcription. EZH2 is often overexpressed or abnormally activated in cancers, where it has generally been associated with the repression of genes that restrain cell proliferation or promote differentiation. Patients whose tumours contain high levels of EZH2 frequently have poorer clinical outcomes. Yet the exact ways in which excess EZH2 strengthens tumour-forming ability have not been fully explained. The new work expands that picture by showing that EZH2 can participate in a noncanonical, or nontraditional, function: rather than acting only as a chromatin-modifying repressor, it helps stimulate a gene-expression programme connected to lipid metabolism.

The key partner in this process is SREBP2, or sterol regulatory element-binding protein 2. SREBP2 is a transcription factor that monitors and controls cellular cholesterol production. When cells require more cholesterol, SREBP2 can become activated and move into the nucleus, where it binds regulatory DNA sequences near genes involved in cholesterol uptake and synthesis. Among its major targets are genes in the mevalonate pathway, a series of enzymatic reactions that converts acetyl-CoA into cholesterol and other sterol-related products. Cholesterol is not merely a structural component of cell membranes. It also contributes to membrane organization, intracellular signalling and the production of steroid-related molecules. Rapidly dividing cancer cells can place unusually high demands on these systems as they build new membranes and adapt to stressful environments. The study indicates that EZH2 and SREBP2 cooperate to drive high expression of mevalonate-pathway genes, effectively linking an epigenetic cancer-associated protein to a metabolic switch that can increase the supply of cholesterol.

The researchers describe a direct molecular connection between the two proteins and the transcriptional machinery that activates cancer-related genes. According to the study, transcriptional activation domains within EZH2 and SREBP2 bind directly to p300, a well-known coactivator that helps turn genes on. p300 can modify histones and other proteins through acetylation, a process that often promotes a more transcriptionally permissive chromatin environment. In this model, the EZH2–SREBP2 partnership is not simply bringing two regulatory proteins into proximity; it is also recruiting a coactivator capable of strengthening gene activation. The result is a functional complex that supports expression of genes in the mevalonate pathway and activates proto-oncogene programmes. Proto-oncogenes normally contribute to controlled growth and survival, but when inappropriately activated they can promote malignant transformation. This mechanism provides a possible explanation for how high EZH2 levels can support cancer even when its tumour-promoting activity does not fit the classic PRC2-mediated model of gene repression.

The implications are especially striking because cholesterol metabolism has often been viewed as a supporting feature of cancer biology rather than as a central output of EZH2 activity. Tumours rewire metabolism to obtain energy, construct cellular components and survive conditions such as nutrient limitation or low oxygen. Increased cholesterol synthesis may help supply the membrane material required for proliferation, while mevalonate-pathway intermediates can influence signalling and protein modification. The study’s findings place EZH2 near the top of that metabolic control system, where it may help SREBP2 maintain the expression of multiple biosynthetic genes at once. This is different from blocking a single enzyme downstream in the pathway. A regulatory partnership that controls a broad gene set could, in principle, produce a larger effect on tumour biology—but it could also create challenges, because cholesterol production is essential to normal cells. The research therefore points to a vulnerability, not yet a finished treatment strategy, and further work would be needed to determine how selectively the pathway can be disrupted in cancer.

To test whether this noncanonical function could be targeted, the researchers used proteolysis-targeting chimeras, widely known as PROTACs. These are engineered molecules designed to bring a target protein into contact with an E3 ubiquitin ligase, part of the cell’s protein-disposal system. Once recruited, the target can be tagged with ubiquitin and sent to the proteasome, a large molecular machine that breaks down proteins. Unlike conventional inhibitors, which generally occupy a functional pocket and block activity, PROTACs can remove a protein from the cell and may continue acting catalytically as long as the degradation machinery remains available. In the study, independent EZH2-targeting PROTACs degraded EZH2 and, notably, also reduced SREBP2. This dual effect suppressed SREBP2-associated gene-expression programmes, including those linked to cholesterol biosynthesis, and inhibited tumour growth. The result suggests that eliminating EZH2 may dismantle the regulatory partnership more effectively than simply blocking one of its biochemical activities.

The observation that EZH2-targeting PROTACs affect both proteins is central to the study’s therapeutic significance. If EZH2 supports tumour growth through several distinct functions, an agent that removes the protein could potentially block more than a single catalytic activity. Degradation of EZH2 may weaken its association with SREBP2, reduce the availability of the coactivator p300 at relevant genes and collapse the transcriptional programme that sustains the mevalonate pathway. The accompanying loss of SREBP2 would further limit the cell’s ability to activate cholesterol-biosynthesis genes. Together, these effects could explain why the PROTAC strategy inhibited tumour growth in the researchers’ experiments. However, the findings do not establish that such compounds are ready for clinical use, nor do they show that every cancer with high EZH2 depends on the same mechanism. Tumours are genetically and metabolically diverse, and cholesterol production is also vital in healthy tissues. The future challenge will be identifying cancers most reliant on the EZH2–SREBP2 axis while minimizing damage to normal metabolism.

The work ultimately shifts the way scientists may think about EZH2 in cancer. Rather than treating the protein solely as an epigenetic repressor that silences protective genes, the study presents it as a versatile regulator capable of joining a transcriptional complex that actively promotes metabolic and oncogenic programmes. Its partnership with SREBP2 creates a bridge between chromatin biology, gene activation and lipid metabolism, revealing how a cancer-associated protein can influence the supply of molecules needed for tumour expansion. The findings also illustrate why protein degradation strategies are attracting attention: destroying a regulatory protein can expose vulnerabilities created by its interactions, not just those associated with its best-known enzymatic function. By identifying cholesterol biosynthesis as a downstream output of EZH2–SREBP2 cooperation, the researchers offer a new framework for understanding tumour metabolism and a potential route for therapeutic development. The axis is not yet a proven universal weakness, but it may represent a molecular Achilles’ heel in cancers that depend on elevated EZH2 activity and SREBP2-driven cholesterol production.

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

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02705-4