{"product_id":"how-a-chemical-tag-called-lactylation-makes-liver-cancer-resist-treatment-and-the-new-strategies-scientists-are-testing-to-stop-it","title":"How a Chemical \"Tag\" Called Lactylation Makes Liver Cancer Resist Treatment — and the New Strategies Scientists Are Testing to Stop It","description":"\u003cp\u003eHepatocellular carcinoma (HCC), the most common type of liver cancer, often becomes resistant to the drugs used to treat it. This review article explains how a newly discovered cellular process called \u003cstrong\u003elactylation\u003c\/strong\u003e — a chemical tag that lactate (a byproduct of sugar metabolism) attaches to proteins — drives that resistance. The authors systematically describe the molecular pathways involved and highlight promising strategies to reverse resistance, such as the drugs 2-DG and AZD3965, and activators of the enzyme SIRT3. For patients, this research points toward a future where doctors can predict which treatments will work and restore drug sensitivity in advanced liver cancer.\u003c\/p\u003e\n\n\u003ch1\u003eHow a Chemical \"Tag\" Called Lactylation Makes Liver Cancer Resist Treatment — and the New Strategies Scientists Are Testing to Stop It\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why Liver Cancer Treatment Resistance Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#warburg\"\u003eThe Warburg Effect: Why Cancer Cells Produce 10 Times More Lactate\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#what-is-lactylation\"\u003eWhat Is Lactylation? A New Type of Protein Modification\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#sites\"\u003eSpecific Lactylation \"Tags\" Found in Liver Cancer\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#metabolic-interplay\"\u003eHow Lactylation and Metabolism Fuel Each Other\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#immune\"\u003eLactylation and the Immune Microenvironment\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#resistance\"\u003eHow Lactylation Causes Treatment Resistance: Key Findings\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#lactate-pathways\"\u003eKey Pathways in Lactate Production: PI3K\/Akt\/mTOR and HIF-1α\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#immunotherapy\"\u003eImmunotherapy Resistance and the MOESIN Discovery\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eClinical Implications: What This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of This Research\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eLactylation is a newly discovered protein modification where lactate attaches to proteins, and it is elevated in hepatocellular carcinoma compared to normal liver tissue.\u003c\/li\u003e\n\u003cli\u003eIn laboratory models, lactylation drives resistance to drugs like lenvatinib, sorafenib, oxaliplatin, and 5-fluorouracil through specific molecular pathways.\u003c\/li\u003e\n\u003cli\u003eLactylation also impairs immune cells and promotes an immunosuppressive environment, which can weaken immunotherapy responses.\u003c\/li\u003e\n\u003cli\u003ePotential strategies to reverse resistance include 2-DG, AZD3965, SIRT3 activators, and LDHA inhibitors, but these are still in preclinical or early clinical testing.\u003c\/li\u003e\n\u003cli\u003eMost findings come from cell lines and animal models; clinical trials are needed to confirm whether targeting lactylation is safe and effective in patients.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why Liver Cancer Treatment Resistance Matters\u003c\/h2\u003e\n\n\u003cp\u003eHepatocellular carcinoma (HCC) — the most common form of primary liver cancer — is one of the cancers with the highest rates of diagnosis and death worldwide. It remains a major global public health challenge.\u003c\/p\u003e\n\n\u003cp\u003eChronic infection with hepatitis B virus and long-term excessive alcohol consumption are currently recognized as the main causes of HCC. However, HCC usually produces no symptoms in its early stages. By the time obvious symptoms appear, the diagnosis is often delayed.\u003c\/p\u003e\n\n\u003cp\u003eFor advanced liver cancer — defined as cancer that has invaded blood vessels or spread outside the liver, and\/or causes mild cancer-related symptoms — the first-line treatment involves \u003cstrong\u003esystemic therapies\u003c\/strong\u003e (drugs that travel through the whole body). These include:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eChemotherapy\u003c\/strong\u003e (drugs that kill rapidly dividing cells)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTargeted therapy\u003c\/strong\u003e (drugs that attack specific molecules that help cancer grow)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eImmunotherapy\u003c\/strong\u003e (drugs that help the immune system fight cancer)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eSurgical resection (removing the tumor), local embolization (blocking blood flow to the tumor), and interventional ablation (destroying the tumor with heat or cold) are often ineffective in advanced-stage cancer.\u003c\/p\u003e\n\n\u003cp\u003eUnfortunately, most advanced HCC patients do not experience long-term benefits because of \u003cstrong\u003eprimary drug resistance\u003c\/strong\u003e (the cancer never responds) or \u003cstrong\u003eacquired drug resistance\u003c\/strong\u003e (the cancer initially responds, then stops responding). The rising incidence of HCC makes this problem even more urgent. There is a critical need for new therapeutic approaches.\u003c\/p\u003e\n\n\u003cp\u003eThis review article — published in \u003cem\u003eGastroenterology Report\u003c\/em\u003e in 2026 by researchers at China Medical University — focuses specifically on how lactylation modification drives drug resistance in HCC.\u003c\/p\u003e\n\n\u003ch2 id=\"warburg\"\u003eThe Warburg Effect: Why Cancer Cells Produce 10 Times More Lactate\u003c\/h2\u003e\n\n\u003cp\u003eMore than 60 years ago, scientist Otto Warburg made a famous observation: cancer cells take up and break down sugar (glucose) at an unusually high rate even when oxygen is available. This phenomenon, now called the \u003cstrong\u003eWarburg effect\u003c\/strong\u003e, was not widely recognized as important until researchers understood that lactate — long dismissed as cellular waste — actually plays an active role in cancer progression.\u003c\/p\u003e\n\n\u003cp\u003eThe numbers are striking. The Warburg effect enables tumor cells to generate lactate at a rate \u003cstrong\u003e10 times higher than normal tissues\u003c\/strong\u003e, even in aerobic (oxygen-rich) environments. Lactate then serves as an energy source for the tumor. In fact, the authors report that higher lactate levels predict poorer outcomes in HCC patients, making the lactate pathway highly significant in liver cancer metabolism.\u003c\/p\u003e\n\n\u003cp\u003eDespite this knowledge, treatments that target the Warburg effect remain immature. Preclinical and clinical trials have not yet been widely carried out or translated into everyday clinical practice.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is-lactylation\"\u003eWhat Is Lactylation? A New Type of Protein Modification\u003c\/h2\u003e\n\n\u003cp\u003eHere is the key concept of this article. \u003cstrong\u003eLactylation\u003c\/strong\u003e is a newly discovered type of \u003cstrong\u003epost-translational modification (PTM)\u003c\/strong\u003e — a change made to a protein \u003cem\u003eafter\u003c\/em\u003e the protein has already been built. In lactylation, lactate attaches (conjugates) covalently to the lysine residues of proteins — lysine being one of the building blocks, or amino acids, of proteins.\u003c\/p\u003e\n\n\u003cp\u003eA useful way to picture this: imagine your DNA is a book and the proteins around it are librarians. Lactylation puts a sticky note on a librarian, changing how she does her job — which genes get read, which proteins get made.\u003c\/p\u003e\n\n\u003cp\u003eLactylation comes in two flavors:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHistone lactylation\u003c\/strong\u003e — tags on histones, the spool-like proteins that DNA wraps around. This changes how tightly DNA is packaged, turning genes on or off (epigenetic regulation).\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNon-histone lactylation\u003c\/strong\u003e — tags on other proteins, including metabolic enzymes, which can speed them up, slow them down, or change their function.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe modification is dynamic — it can be added and removed. Its balance is controlled in two directions: \u003cstrong\u003elactate dehydrogenases (LDHA\/LDHB)\u003c\/strong\u003e add lactylation, and \u003cstrong\u003edelactylases\u003c\/strong\u003e such as \u003cstrong\u003eSIRT3\u003c\/strong\u003e remove it.\u003c\/p\u003e\n\n\u003cp\u003eStudies have shown that lactylation levels in HCC tissues are \u003cstrong\u003esignificantly higher than in normal liver tissues\u003c\/strong\u003e, and these levels correlate with tumor cell proliferation, migration, and remodeling of the immune environment. In general, higher lactylation means worse tumor grade and worse patient prognosis.\u003c\/p\u003e\n\n\u003ch2 id=\"sites\"\u003eSpecific Lactylation \"Tags\" Found in Liver Cancer\u003c\/h2\u003e\n\n\u003cp\u003eThe authors systematically cataloged the specific lactylation sites found in HCC — essentially the ZIP codes on proteins where lactate attaches. These sites are divided into histones and non-histones, and each is regulated by its own set of microRNA pathways.\u003c\/p\u003e\n\n\u003cp\u003eUsing mass spectrometry (a tool that measures protein modifications) and antibody-specific detection, researchers have identified two key \u003cstrong\u003eupregulated histone lactylation sites in HCC tissues\u003c\/strong\u003e:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eH3K9la\u003c\/strong\u003e (lactylation on histone H3 at position 9)\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eH3K56la\u003c\/strong\u003e (lactylation on histone H3 at position 56)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese tags loosen the chromatin (the packaged DNA), activating oncogenes (cancer-promoting genes) and driving tumor cell proliferation and metastasis.\u003c\/p\u003e\n\n\u003cp\u003eA protein called \u003cstrong\u003eendothelial cell-specific molecule 1 (ESM1)\u003c\/strong\u003e mediates this process. Importantly, when researchers used a drug called \u003cstrong\u003e2-deoxy-d-glucose (2-DG)\u003c\/strong\u003e to block glycolysis, histone lactylation products dropped, reversing a process called \u003cstrong\u003eepithelial–mesenchymal transition (EMT)\u003c\/strong\u003e — the process by which cancer cells become more mobile and invasive.\u003c\/p\u003e\n\n\u003cp\u003eOther specific sites with identified roles include:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eCENPA at lysine 124 (K124):\u003c\/strong\u003e This lactylation works with a protein called YY1 through the CENPA-YY1-CCND1\/NRP2 axis to promote HCC development.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHistone H2B at K58:\u003c\/strong\u003e Lactylated by LDHA, this promotes HCC metastasis by inhibiting cellular senescence (the natural \"aging\" process that stops cells from dividing uncontrollably).\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eABCF1 at K430:\u003c\/strong\u003e Drives glycolytic reprogramming in HCC through activation of the KDM3A–H3K9me2–HIF1A axis.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAK2 (adenylate kinase 2) at K28:\u003c\/strong\u003e Lactylation here inhibits AK2's enzyme activity, enhancing metabolic adaptability and invasive capacity of HCC cells. This worsens metabolic disorders in the cancer.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eALDOA at K230\/322:\u003c\/strong\u003e Lactylation of these sites promotes self-renewal and drug resistance of liver cancer stem cells (LCSCs) by regulating a protein called DDX17. Liver cancer stem cells are a small population of cells thought to drive tumor growth and resistance.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe authors also note that hypoxia (low oxygen) — common in tumors — increases the expression of glypican-3 (GPC3) in HCC cells, which in turn enhances lactylation of c-myc, a well-known cancer-driving protein.\u003c\/p\u003e\n\n\u003ch2 id=\"metabolic-interplay\"\u003eHow Lactylation and Metabolism Fuel Each Other\u003c\/h2\u003e\n\n\u003cp\u003eLactylation and metabolism form a vicious cycle in HCC. The cancer's metabolic hallmarks — high sugar breakdown (glycolysis) and suppressed mitochondrial energy production (oxidative phosphorylation) — are epigenetically regulated by lactylation. But the elevated glycolysis also produces the lactate that feeds more lactylation. This creates a self-reinforcing loop.\u003c\/p\u003e\n\n\u003cp\u003eSeveral specific mechanisms stand out:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePDHX acetylation\u003c\/strong\u003e disrupts the assembly of the pyruvate dehydrogenase complex (PDC) and activates lactylation at the histone H3K56 site, driving HCC progression.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eH3K18 lactylation\u003c\/strong\u003e upregulates \u003cstrong\u003eglucose transporter 1 (GLUT1)\u003c\/strong\u003e expression, driving metabolic reprogramming via a protein called DLAT and increasing metastasis. This shows that H3K18 is another vital site in HCC, beyond H3K56.\u003c\/li\u003e\n  \u003cli\u003eThe \u003cstrong\u003eHIF-1α signaling pathway\u003c\/strong\u003e enhances glycolysis and lactate production. Additional genes — \u003cstrong\u003eLYRM2, TRPM7, and C1R\u003c\/strong\u003e — further promote HCC progression by amplifying HIF-1α-dependent metabolic reprogramming.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eIn the hypoxic (low-oxygen) tumor microenvironment of HCC, cancer cells ramp up the Warburg effect to produce large quantities of lactate. This lactate accumulates inside cells, providing the raw material (substrate) for lactylation. Beyond changing metabolism, this also changes chromatin structure and gene expression — playing a significant role in HCC cell proliferation, invasion, and metastasis.\u003c\/p\u003e\n\n\u003ch2 id=\"immune\"\u003eLactylation and the Immune Microenvironment\u003c\/h2\u003e\n\n\u003cp\u003eThe immune microenvironment — the collection of immune cells surrounding a tumor — plays a deciding role in whether cancer grows or is eliminated. Lactate accumulation drives tumor progression by impairing immune cell function and recruiting immunosuppressive cells.\u003c\/p\u003e\n\n\u003cp\u003eHistone lactylation affects nearly every major immune cell type involved in the fight against cancer. The authors summarize these effects in a detailed table, and the key findings are preserved here:\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCD4+ T cells (helper T cells):\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eLactate directly inhibits T cell-mediated immune responses and cytotoxic function\u003c\/li\u003e\n  \u003cli\u003eIt inhibits T cell receptor (TCR) activation and reduces induction of T cell apoptosis\u003c\/li\u003e\n  \u003cli\u003eSignaling proteins p38 and JNK\/cJun are inhibited, blocking T cell proliferation\u003c\/li\u003e\n  \u003cli\u003eThe PD-1\/PD-L1 pathway is enhanced, reducing anti-tumor immunity\u003c\/li\u003e\n  \u003cli\u003eLactate promotes Th17 cell differentiation, shifting the balance of the immune response\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eCD8+ T cells (killer T cells):\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eLactate directly suppresses their cancer-killing function\u003c\/li\u003e\n  \u003cli\u003eIt reduces NAD utilization and cellular motility\u003c\/li\u003e\n  \u003cli\u003eThe JAK-JUN pathway is inhibited, reducing production of cytotoxic cytokines — the chemical weapons T cells use against cancer\u003c\/li\u003e\n  \u003cli\u003eAcidic pH (caused by lactate) induces cytotoxic T lymphocyte (CTL) inactivation\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eMacrophages:\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eLactate reduces NF-κB activation and secretion of cytotoxic cytokines\u003c\/li\u003e\n  \u003cli\u003eIt enhances the ERK-STAT3, GPR132, and Notch pathways\u003c\/li\u003e\n  \u003cli\u003eHIF-1α stabilization is enhanced, which drives \u003cstrong\u003eM2 polarization\u003c\/strong\u003e — pushing tumor-associated macrophages (TAMs) into their tumor-promoting, not tumor-fighting, state\u003c\/li\u003e\n  \u003cli\u003eThe anti-tumor Th1 response is suppressed\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eDendritic cells (the immune system's \"teachers\"):\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eLactate inhibits the differentiation of monocytes into dendritic cells\u003c\/li\u003e\n  \u003cli\u003eIt transforms cells into a drug-resistant phenotype and reduces IFN-γ production\u003c\/li\u003e\n  \u003cli\u003eGPR81 signaling is enhanced while TLR signaling is reduced\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eNatural killer (NK) cells:\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eLactate impairs NK cell activation and metabolic function, including their tumor-infiltrating ability (regulated through chemokines such as CCL5)\u003c\/li\u003e\n  \u003cli\u003eIt prevents activation of nuclear factor of activated T cells (NFAT), reducing NKp46 activity\u003c\/li\u003e\n  \u003cli\u003eThe mTOR signaling pathway is inhibited, and the number of immunosuppressive myeloid-derived suppressor cells (MDSCs) increases\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eMyeloid-derived suppressor cells (MDSCs):\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eLactate enhances their secretion of G-CSF and GM-CSF, promoting their growth and strengthening their immunosuppressive effects\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eRegulatory T cells (Tregs):\u003c\/strong\u003e\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eLactate upregulates FoxP3 protein expression, driving Treg differentiation and proliferation\u003c\/li\u003e\n  \u003cli\u003eMCT1-mediated lactate influx (lactate entering the cell) supports Treg metabolism and function\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe bottom line: lactylation tips the immune system away from attacking the tumor and toward protecting it.\u003c\/p\u003e\n\n\u003ch2 id=\"resistance\"\u003eHow Lactylation Causes Treatment Resistance: Key Findings\u003c\/h2\u003e\n\n\u003cp\u003eThis is the heart of the review. The authors detail multiple specific mechanisms by which lactylation makes HCC resistant to specific drugs. Each numbered mechanism below represents a distinct resistance pathway discovered in laboratory models.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e1. Lenvatinib resistance: the IGF2BP3-PCK2-SAM-m6A loop.\u003c\/strong\u003e A glycolysis-lactylation positive feedback loop has been identified in lenvatinib-resistant HCC models. Lenvatinib is a targeted therapy commonly used for advanced HCC. In this loop:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003eCancer cells increase glycolysis, producing more lactate.\u003c\/li\u003e\n  \u003cli\u003eLactate promotes lactylation of the protein IGF2BP3.\u003c\/li\u003e\n  \u003cli\u003eLactylated IGF2BP3 binds to m6A-modified sites on PCK2 mRNA, stabilizing it.\u003c\/li\u003e\n  \u003cli\u003eThis activates the PCK2-NRF2 antioxidant pathway, which counteracts the oxidative stress that lenvatinib is designed to cause.\u003c\/li\u003e\n\u003c\/ol\u003e\n\u003cp\u003eThe result is that cancer cells survive treatment that should kill them.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e2. Chemoresistance from cancer stem cells.\u003c\/strong\u003e Lactylation of ALDOA at K230\/322 dissociates the DDX17 complex. This enhances the self-renewal capacity of liver cancer stem cells (LCSCs) — the cells that can regenerate a tumor — and contributes to chemotherapy resistance.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e3. Sorafenib resistance and SIRT3.\u003c\/strong\u003e Reduced expression of the mitochondrial enzyme SIRT3 leads to accumulated lactylation — and this correlates with resistance to sorafenib, another first-line targeted drug for HCC. SIRT3 normally acts as a delactylase (removing lactylation tags), so when it is low, tags pile up.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e4. Oxaliplatin (OXA) and 5-fluorouracil (5-Fu) resistance.\u003c\/strong\u003e In chemotherapy resistance models, histone lactylation upregulates a protein called NEDD4. NEDD4 promotes ubiquitination and degradation of PTEN — a critical tumor suppressor gene. This activates the PI3K\/AKT pathway and ultimately inhibits chemotherapy-induced apoptosis (programmed cell death). In simpler terms: the chemotherapy tells the cancer cell to die, but the lactylation-driven pathway blocks the message.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e5. Pro-survival gene activation.\u003c\/strong\u003e In HCC drug-resistant cells, elevated levels of H3K9la and H3K56la promote the expression of pro-survival genes GP73 and NDRG1 by relaxing chromatin structure.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e6. Sorafenib resistance via H3K18la.\u003c\/strong\u003e PYCR1-mediated H3K18 lactylation promotes sorafenib resistance by activating the IRS1\/PI3K signaling pathway.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e7. The HTR1D contribution.\u003c\/strong\u003e The 5-hydroxytryptamine receptor 1D (HTR1D) also contributes to resistance to treatments like sorafenib through the PI3K\/Akt pathway.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e8. Non-coding RNA stabilization.\u003c\/strong\u003e Lactylated IGF2BP3 enhances the invasive capacity of HCC cells by stabilizing MALAT1, a long non-coding RNA (lncRNA). This process promotes EMT (the process by which cancer cells become invasive). IGF2BP3, which is upregulated under low-oxygen conditions, also promotes EMT and augments the production of circular RNAs (circRNAs).\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e9. Mitochondrial dysfunction and energy stress.\u003c\/strong\u003e Lactylation of AK2 at K28 inhibits its enzymatic activity, leading to impaired ATP (energy) synthesis. This energy imbalance activates the AMPK\/mTOR pathway, which in turn promotes HCC cell proliferation and metastasis.\u003c\/p\u003e\n\n\u003cp\u003eCollectively, these lactylation-mediated mechanisms significantly limit the clinical effectiveness of molecularly targeted drugs and chemotherapy regimens in HCC.\u003c\/p\u003e\n\n\u003ch2 id=\"lactate-pathways\"\u003eKey Pathways in Lactate Production: PI3K\/Akt\/mTOR and HIF-1α\u003c\/h2\u003e\n\n\u003cp\u003eTo understand how lactylation builds up, we must understand the pathways that produce its raw material, lactate. The review describes these in detail.\u003c\/p\u003e\n\n\u003cp\u003eThe \u003cstrong\u003ePI3K\/Akt signaling pathway\u003c\/strong\u003e is widely recognized for promoting digestive system tumors. The PI3K enzyme family has three subtypes with distinct jobs:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eClass I PI3K\u003c\/strong\u003e generates PIP3, regulating cell growth and metabolism.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eClass II PI3K\u003c\/strong\u003e activates AKT signaling through PIP2 synthesis.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eClass II and Class III PI3K together\u003c\/strong\u003e produce PI3P, involved in membrane trafficking and autophagy (cellular recycling).\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eActivation of the PI3K\/AKT\/HIF-1α pathway is closely tied to enhanced tumor invasiveness. Research by Wei and colleagues in endometrial cancer showed how histone lactylation regulates tumors through this pathway: it upregulates USP39, and USP39 then interacts with PGK1 to accelerate PI3K\/AKT\/HIF-1α activation. PGK1, a key glycolytic enzyme, has a hidden second job — it acts as a protein kinase that stabilizes HIF-1α through phosphorylation, helping tumor cells survive in low-oxygen environments.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003emTOR\u003c\/strong\u003e is a key regulator in the PI3K\/Akt\/mTOR pathway, controlling it through positive and negative feedback. After mTOR activates, a downstream protein called S6K can reduce PI3K activity, weakening the whole pathway and inhibiting tumor activity — a built-in brake.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAMPK\u003c\/strong\u003e (adenosine monophosphate-activated protein kinase) plays a counterbalancing role. Researchers have found that elevated lactic acid in HCC can inactivate AMPK, accelerating tumor invasion. On the flip side, high lactate accumulation may reduce mTORC1 activity by activating AMPK, indirectly weakening the PI3K\/Akt\/mTOR pathway.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eHIF-1α\u003c\/strong\u003e is one of the core mechanisms by which tumors adapt to their environment — and it is a key downstream effector of PI3K\/AKT. Hypoxia (low oxygen) in the tumor microenvironment is a major trigger for HIF-1α activation:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003eHypoxia prevents the hydroxylation of proline on HIF-1α.\u003c\/li\u003e\n  \u003cli\u003eThis stops the pVHL tumor suppressor from binding to HIF-1α.\u003c\/li\u003e\n  \u003cli\u003eHIF-1α is no longer marked for degradation, so it accumulates.\u003c\/li\u003e\n\u003c\/ol\u003e\n\u003cp\u003eOther stimulators — insulin, insulin-like growth factor 1, epidermal growth factor, and angiotensin II — can also increase HIF-1α levels.\u003c\/p\u003e\n\n\u003cp\u003eOnce activated, HIF-1 affects tumor progression mainly through two routes: upregulating \u003cstrong\u003evascular endothelial growth factor (VEGF)\u003c\/strong\u003e to promote blood vessel growth (angiogenesis), and upregulating \u003cstrong\u003eerythropoietin\u003c\/strong\u003e to stimulate red blood cell production. Both increase oxygen and nutrient supply to the tumor. HIF-1 also directly upregulates glucose transporters and glycolysis-related enzymes — especially hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase — boosting aerobic glycolysis while suppressing oxidative phosphorylation.\u003c\/p\u003e\n\n\u003cp\u003eAnd here is the loop closing: the lactic acid produced by glycolysis acts back on tumor cells through the PI3K\/AKT\/AMPK pathways, forming a \"metabolism–pathway–microenvironment\" regulatory loop.\u003c\/p\u003e\n\n\u003ch2 id=\"immunotherapy\"\u003eImmunotherapy Resistance and the MOESIN Discovery\u003c\/h2\u003e\n\n\u003cp\u003eImmunotherapy — particularly drugs that block the PD-1\/PD-L1 checkpoint — has transformed treatment for many cancers, but it does not work for everyone with HCC. This review reveals a specific lactylation mechanism behind immunotherapy failure.\u003c\/p\u003e\n\n\u003cp\u003eRegulatory T cells (Tregs) are immune cells that normally keep the immune system from overreacting — but in cancer, they protect the tumor from attack. Tregs use flexible metabolic strategies to survive in diverse environments, and they appear to use lactylation as an alternative energy source to carry out their immunosuppressive functions.\u003c\/p\u003e\n\n\u003cp\u003eHere is the key finding: \u003cstrong\u003elactate in the tumor microenvironment enhances Treg suppressive function by inducing lactylation of the MOESIN protein\u003c\/strong\u003e, and this directly weakens the effectiveness of anti-PD-1 therapy.\u003c\/p\u003e\n\n\u003cp\u003eThe clinical data are particularly notable. Researchers compared Tregs from HCC patients who responded to anti-PD-1 therapy with those from patients who were resistant. \u003cstrong\u003eMOESIN lactylation levels in Tregs from responding patients were significantly lower than those from resistant patients.\u003c\/strong\u003e In other words, the lactylation level in a patient's immune cells could theoretically predict whether immunotherapy will work for them.\u003c\/p\u003e\n\n\u003cp\u003eIncreased lactate production drives the activation of PD-1+ Tregs, substantially increasing the likelihood that immunotherapy will fail.\u003c\/p\u003e\n\n\u003cp\u003eTumor-associated macrophages (TAMs) also matter here. TAMs come in two broad flavors: M1 macrophages (tumor-fighting) and M2 macrophages (tumor-promoting). Lactylation promotes M2 polarization of TAMs by activating the HIF1α\/IL-10 axis, which in turn inhibits the anti-tumor activity of CD8+ T cells. The review reports that \u003cstrong\u003eLDHA-targeted inhibitors can reverse this immunosuppressive phenotype and enhance the efficacy of immune checkpoint inhibitors\u003c\/strong\u003e — a strategy already under investigation.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eClinical Implications: What This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe authors outline several emerging therapeutic strategies based on this research. While most are still in preclinical stages, they point toward future treatment options.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e1. Restoring drug sensitivity with metabolic inhibitors.\u003c\/strong\u003e The glycolytic inhibitor \u003cstrong\u003e2-DG\u003c\/strong\u003e reduces intracellular lactate levels and reverses H3K56la-mediated abnormal gene expression, thereby restoring sensitivity to lenvatinib. It has also been shown to reduce lactylation products and reverse the EMT process.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e2. Targeting lactate transport.\u003c\/strong\u003e \u003cstrong\u003eAZD3965\u003c\/strong\u003e, which targets the MCT1 lactate transporter, is mentioned as a therapeutic option — alone or in combination — to restore drug sensitivity by cutting off the lactate supply that feeds lactylation.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e3. Activating SIRT3.\u003c\/strong\u003e Because SIRT3 removes lactylation tags, \u003cstrong\u003eSIRT3 activators\u003c\/strong\u003e can reverse lactylation and restore drug sensitivity, particularly relevant in sorafenib resistance where SIRT3 is reduced.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e4. LDHA-targeted inhibitors.\u003c\/strong\u003e These can reverse the immunosuppressive phenotype driven by M2 macrophages and enhance the efficacy of immune checkpoint inhibitors.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e5. Personalized prediction with the LMRG model.\u003c\/strong\u003e The authors describe a patient stratification model called \u003cstrong\u003eLMRG\u003c\/strong\u003e, built on lactylation modification signatures. This model combines gene expression profiles — including \u003cstrong\u003eACACA and MRPL3\u003c\/strong\u003e — to predict individualized treatment responses. This represents a step toward precision medicine: using a patient's specific lactylation profile to choose the right treatment.\u003c\/p\u003e\n\n\u003cp\u003eThe review also emphasizes that lactylation-related genes and models can predict how well a patient will respond to therapy, making lactylation a potential predictive biomarker.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eWhat this means for patients:\u003c\/strong\u003e In the future, a doctor might measure lactylation levels or lactylation-related genes in a biopsy sample to predict whether a drug like lenvatinib, sorafenib, or an immunotherapy will work — and if not, add a medication to \"reset\" the lactylation balance and restore the drug's effectiveness.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of This Research\u003c\/h2\u003e\n\n\u003cp\u003eThe authors are careful to note important limitations. Current therapeutic targeting of the Warburg effect remains immature; preclinical and clinical trials have not yet been widely carried out or translated into clinical practice.\u003c\/p\u003e\n\n\u003cp\u003eSpecific detectors for lactylation are still limited, which constrains research. And while many mechanisms have been identified in laboratory models and animal studies, there remains a scarcity of drugs that have successfully made the leap from experimental study to approved clinical use.\u003c\/p\u003e\n\n\u003cp\u003eAdditionally, most of the specific resistance mechanisms described — such as the IGF2BP3-PCK2 loop in lenvatinib resistance or ALDOA lactylation in stem cell self-renewal — have been demonstrated in cell lines and animal models. Translation to human patients will require carefully designed clinical trials to confirm that these pathways behave the same way in people and that targeting them is both safe and effective.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis research is at the laboratory and early clinical stage, so it does not yet translate into immediate changes in everyday cancer care. However, patients with HCC can take meaningful steps based on this knowledge:\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDiscuss lactate-related metabolism with your oncologist.\u003c\/strong\u003e If you are being treated with lenvatinib, sorafenib, oxaliplatin, or anti-PD-1 immunotherapy, ask whether your treatment team monitors markers related to metabolism and resistance. Some cancer centers are beginning to use resistance biomarkers in treatment planning.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk about clinical trials.\u003c\/strong\u003e Because lactylation-targeting therapies (such as 2-DG, AZD3965, SIRT3 activators, and LDHA inhibitors) are in clinical development, inquire whether any relevant trials are available at your treatment center.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eUnderstand that drug resistance is not a personal failure.\u003c\/strong\u003e Resistance in HCC is driven by biological mechanisms — including the lactylation pathways described here — not by anything a patient did or did not do. New research is actively working to solve this problem.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eKeep lifestyle factors in view.\u003c\/strong\u003e The main preventable causes of HCC — chronic hepatitis B infection and excessive alcohol consumption — are well established. If you have hepatitis B, antiviral treatment and regular surveillance are critical. Limiting alcohol protects liver health.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eKnow that research is progressing rapidly.\u003c\/strong\u003e The field of lactylation was only recently discovered and is developing quickly. What is experimental today may become standard care within a few years. Staying informed — with guidance from your care team — is valuable.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is lactylation and how does it relate to liver cancer?\u003c\/h3\u003e\n\u003cp\u003eLactylation is a newly discovered protein modification where lactate attaches to proteins. In hepatocellular carcinoma, lactate is produced at ten times the normal rate. This tag changes how genes are read and can drive tumor growth, spread, and resistance to treatment. Higher lactylation levels are linked to worse tumor grade and prognosis.\u003c\/p\u003e\n\u003ch3\u003eWhy does liver cancer become resistant to drugs like lenvatinib or sorafenib?\u003c\/h3\u003e\n\u003cp\u003eResistance can occur through lactylation-driven mechanisms. For example, in laboratory models, lactylation of a protein called IGF2BP3 stabilizes PCK2 mRNA, activating an antioxidant pathway that helps cancer cells survive lenvatinib. In sorafenib resistance, reduced levels of the enzyme SIRT3 lead to accumulated lactylation tags. These mechanisms limit the effectiveness of targeted drugs and chemotherapy.\u003c\/p\u003e\n\u003ch3\u003eAre there treatments that can reverse lactylation-related resistance?\u003c\/h3\u003e\n\u003cp\u003eSeveral strategies are being tested in preclinical studies. The glycolytic inhibitor 2-DG reduces lactate and reverses lactylation, restoring lenvatinib sensitivity in laboratory models. AZD3965 targets lactate transport. SIRT3 activators remove lactylation tags. LDHA inhibitors may enhance immunotherapy. These approaches are not yet approved for clinical use and require further trials.\u003c\/p\u003e\n\u003ch3\u003eCan lactylation levels predict whether immunotherapy will work for me?\u003c\/h3\u003e\n\u003cp\u003eResearch suggests that lactylation of the MOESIN protein in regulatory T cells may predict immunotherapy response. In a comparison, patients who responded to anti-PD-1 therapy had significantly lower MOESIN lactylation levels than those who were resistant. This is still experimental, but it points toward using lactylation as a predictive biomarker in the future.\u003c\/p\u003e\n\u003ch3\u003eWhat is the LMRG model and how could it help choose treatment?\u003c\/h3\u003e\n\u003cp\u003eThe LMRG model is a patient stratification tool built on lactylation modification signatures. It combines gene expression profiles, including ACACA and MRPL3, to predict individualized treatment responses. This represents a step toward precision medicine, where a patient's lactylation profile could guide the selection of the most appropriate therapy. It is not yet used in routine care.\u003c\/p\u003e\n\u003ch3\u003eWhat are the limitations of this research on lactylation in liver cancer?\u003c\/h3\u003e\n\u003cp\u003eMost findings come from laboratory models and animal studies, not human trials. Therapeutic targeting of the Warburg effect remains immature, and specific detectors for lactylation are limited. There is a scarcity of drugs that have successfully moved from experimental study to approved clinical use. Clinical trials are needed to confirm safety and effectiveness in patients.\u003c\/p\u003e\n\u003ch3\u003eWhat can I do now if I have advanced liver cancer and worry about resistance?\u003c\/h3\u003e\n\u003cp\u003eDiscuss lactate-related metabolism with your oncologist, especially if you are on lenvatinib, sorafenib, oxaliplatin, or immunotherapy. Ask whether your treatment team monitors resistance markers. Inquire about clinical trials of lactylation-targeting therapies. Understand that resistance is driven by biological mechanisms, not personal failure. Keep hepatitis B and alcohol intake in view, as these are main preventable causes.\u003c\/p\u003e\n\u003ch3\u003eWhen should a patient with advanced hepatocellular carcinoma that has stopped responding to lenvatinib or sorafenib seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eA second opinion is worth considering when advanced hepatocellular carcinoma stops responding to a first-line drug such as lenvatinib or sorafenib, or when resistance is suspected. Resistance can be primary, where the cancer never responds, or acquired, where it responds and then stops. Lactylation-driven pathways, including reduced SIRT3 and the IGF2BP3-PCK2 loop, are among the mechanisms behind this. A second opinion can review whether metabolism-related markers or clinical trials of lactylation-targeting therapies are relevant. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Mechanisms of lactylation modification in hepatocellular carcinoma treatment resistance.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Zhu Y, Wang Z, Xi H, Lu W, Sun M, Lin X.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e \u003cem\u003eGastroenterology Report\u003c\/em\u003e, 2026, Volume 14, Article goag003. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University. Open Access article distributed under the terms of the Creative Commons Attribution License.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e https:\/\/doi.org\/10.1093\/gastro\/goag003\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eReceived:\u003c\/strong\u003e July 13, 2025 | \u003cstrong\u003eRevised:\u003c\/strong\u003e November 16, 2025 | \u003cstrong\u003eAccepted:\u003c\/strong\u003e November 27, 2025\u003c\/p\u003e\n\u003cp\u003e\u003cem\u003eNote: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not constitute medical advice. Patients should consult their care team for guidance specific to their situation. The authors of the original review contributed equally; Yinan Zhu and Ziyue Wang are co-first authors.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47738955694236,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/es\/products\/how-a-chemical-tag-called-lactylation-makes-liver-cancer-resist-treatment-and-the-new-strategies-scientists-are-testing-to-stop-it","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}