# How a Chemical "Tag" Called Lactylation Makes Liver Cancer Resist Treatment — and the New Strategies Scientists Are Testing to Stop It

Hepatocellular 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 **lactylation** — 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.

# How a Chemical "Tag" Called Lactylation Makes Liver Cancer Resist Treatment — and the New Strategies Scientists Are Testing to Stop It

## Table of Contents

- Key Points
- Background: Why Liver Cancer Treatment Resistance Matters
- The Warburg Effect: Why Cancer Cells Produce 10 Times More Lactate
- What Is Lactylation? A New Type of Protein Modification
- Specific Lactylation "Tags" Found in Liver Cancer
- How Lactylation and Metabolism Fuel Each Other
- Lactylation and the Immune Microenvironment
- How Lactylation Causes Treatment Resistance: Key Findings
- Key Pathways in Lactate Production: PI3K/Akt/mTOR and HIF-1α
- Immunotherapy Resistance and the MOESIN Discovery
- Clinical Implications: What This Means for Patients
- Limitations of This Research
- Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Lactylation is a newly discovered protein modification where lactate attaches to proteins, and it is elevated in hepatocellular carcinoma compared to normal liver tissue.
- In laboratory models, lactylation drives resistance to drugs like lenvatinib, sorafenib, oxaliplatin, and 5-fluorouracil through specific molecular pathways.
- Lactylation also impairs immune cells and promotes an immunosuppressive environment, which can weaken immunotherapy responses.
- Potential strategies to reverse resistance include 2-DG, AZD3965, SIRT3 activators, and LDHA inhibitors, but these are still in preclinical or early clinical testing.
- Most findings come from cell lines and animal models; clinical trials are needed to confirm whether targeting lactylation is safe and effective in patients.

## Background: Why Liver Cancer Treatment Resistance Matters

Hepatocellular 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.

Chronic 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.

For 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 **systemic therapies** (drugs that travel through the whole body). These include:

-
**Chemotherapy** (drugs that kill rapidly dividing cells)
-
**Targeted therapy** (drugs that attack specific molecules that help cancer grow)
-
**Immunotherapy** (drugs that help the immune system fight cancer)

Surgical 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.

Unfortunately, most advanced HCC patients do not experience long-term benefits because of **primary drug resistance** (the cancer never responds) or **acquired drug resistance** (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.

This review article — published in *Gastroenterology Report* in 2026 by researchers at China Medical University — focuses specifically on how lactylation modification drives drug resistance in HCC.

## The Warburg Effect: Why Cancer Cells Produce 10 Times More Lactate

More 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 **Warburg effect**, was not widely recognized as important until researchers understood that lactate — long dismissed as cellular waste — actually plays an active role in cancer progression.

The numbers are striking. The Warburg effect enables tumor cells to generate lactate at a rate **10 times higher than normal tissues**, 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.

Despite 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.

## What Is Lactylation? A New Type of Protein Modification

Here is the key concept of this article. **Lactylation** is a newly discovered type of **post-translational modification (PTM)** — a change made to a protein *after* 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.

A 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.

Lactylation comes in two flavors:

-
**Histone lactylation** — 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).
-
**Non-histone lactylation** — tags on other proteins, including metabolic enzymes, which can speed them up, slow them down, or change their function.

The modification is dynamic — it can be added and removed. Its balance is controlled in two directions: **lactate dehydrogenases (LDHA/LDHB)** add lactylation, and **delactylases** such as **SIRT3** remove it.

Studies have shown that lactylation levels in HCC tissues are **significantly higher than in normal liver tissues**, 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.

## Specific Lactylation "Tags" Found in Liver Cancer

The 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.

Using mass spectrometry (a tool that measures protein modifications) and antibody-specific detection, researchers have identified two key **upregulated histone lactylation sites in HCC tissues**:

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**H3K9la** (lactylation on histone H3 at position 9)
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**H3K56la** (lactylation on histone H3 at position 56)

These tags loosen the chromatin (the packaged DNA), activating oncogenes (cancer-promoting genes) and driving tumor cell proliferation and metastasis.

A protein called **endothelial cell-specific molecule 1 (ESM1)** mediates this process. Importantly, when researchers used a drug called **2-deoxy-d-glucose (2-DG)** to block glycolysis, histone lactylation products dropped, reversing a process called **epithelial–mesenchymal transition (EMT)** — the process by which cancer cells become more mobile and invasive.

Other specific sites with identified roles include:

-
**CENPA at lysine 124 (K124):** This lactylation works with a protein called YY1 through the CENPA-YY1-CCND1/NRP2 axis to promote HCC development.
-
**Histone H2B at K58:** Lactylated by LDHA, this promotes HCC metastasis by inhibiting cellular senescence (the natural "aging" process that stops cells from dividing uncontrollably).
-
**ABCF1 at K430:** Drives glycolytic reprogramming in HCC through activation of the KDM3A–H3K9me2–HIF1A axis.
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**AK2 (adenylate kinase 2) at K28:** Lactylation here inhibits AK2's enzyme activity, enhancing metabolic adaptability and invasive capacity of HCC cells. This worsens metabolic disorders in the cancer.
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**ALDOA at K230/322:** 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.

The 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.

## How Lactylation and Metabolism Fuel Each Other

Lactylation 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.

Several specific mechanisms stand out:

-
**PDHX acetylation** disrupts the assembly of the pyruvate dehydrogenase complex (PDC) and activates lactylation at the histone H3K56 site, driving HCC progression.
-
**H3K18 lactylation** upregulates **glucose transporter 1 (GLUT1)** expression, driving metabolic reprogramming via a protein called DLAT and increasing metastasis. This shows that H3K18 is another vital site in HCC, beyond H3K56.
- The **HIF-1α signaling pathway** enhances glycolysis and lactate production. Additional genes — **LYRM2, TRPM7, and C1R** — further promote HCC progression by amplifying HIF-1α-dependent metabolic reprogramming.

In 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.

## Lactylation and the Immune Microenvironment

The 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.

Histone 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:

**CD4+ T cells (helper T cells):**

- Lactate directly inhibits T cell-mediated immune responses and cytotoxic function
- It inhibits T cell receptor (TCR) activation and reduces induction of T cell apoptosis
- Signaling proteins p38 and JNK/cJun are inhibited, blocking T cell proliferation
- The PD-1/PD-L1 pathway is enhanced, reducing anti-tumor immunity
- Lactate promotes Th17 cell differentiation, shifting the balance of the immune response

**CD8+ T cells (killer T cells):**

- Lactate directly suppresses their cancer-killing function
- It reduces NAD utilization and cellular motility
- The JAK-JUN pathway is inhibited, reducing production of cytotoxic cytokines — the chemical weapons T cells use against cancer
- Acidic pH (caused by lactate) induces cytotoxic T lymphocyte (CTL) inactivation

**Macrophages:**

- Lactate reduces NF-κB activation and secretion of cytotoxic cytokines
- It enhances the ERK-STAT3, GPR132, and Notch pathways
- HIF-1α stabilization is enhanced, which drives **M2 polarization** — pushing tumor-associated macrophages (TAMs) into their tumor-promoting, not tumor-fighting, state
- The anti-tumor Th1 response is suppressed

**Dendritic cells (the immune system's "teachers"):**

- Lactate inhibits the differentiation of monocytes into dendritic cells
- It transforms cells into a drug-resistant phenotype and reduces IFN-γ production
- GPR81 signaling is enhanced while TLR signaling is reduced

**Natural killer (NK) cells:**

- Lactate impairs NK cell activation and metabolic function, including their tumor-infiltrating ability (regulated through chemokines such as CCL5)
- It prevents activation of nuclear factor of activated T cells (NFAT), reducing NKp46 activity
- The mTOR signaling pathway is inhibited, and the number of immunosuppressive myeloid-derived suppressor cells (MDSCs) increases

**Myeloid-derived suppressor cells (MDSCs):**

- Lactate enhances their secretion of G-CSF and GM-CSF, promoting their growth and strengthening their immunosuppressive effects

**Regulatory T cells (Tregs):**

- Lactate upregulates FoxP3 protein expression, driving Treg differentiation and proliferation
- MCT1-mediated lactate influx (lactate entering the cell) supports Treg metabolism and function

The bottom line: lactylation tips the immune system away from attacking the tumor and toward protecting it.

## How Lactylation Causes Treatment Resistance: Key Findings

This 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.

**1. Lenvatinib resistance: the IGF2BP3-PCK2-SAM-m6A loop.** 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:

1. Cancer cells increase glycolysis, producing more lactate.
1. Lactate promotes lactylation of the protein IGF2BP3.
1. Lactylated IGF2BP3 binds to m6A-modified sites on PCK2 mRNA, stabilizing it.
1. This activates the PCK2-NRF2 antioxidant pathway, which counteracts the oxidative stress that lenvatinib is designed to cause.

The result is that cancer cells survive treatment that should kill them.

**2. Chemoresistance from cancer stem cells.** 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.

**3. Sorafenib resistance and SIRT3.** 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.

**4. Oxaliplatin (OXA) and 5-fluorouracil (5-Fu) resistance.** 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.

**5. Pro-survival gene activation.** 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.

**6. Sorafenib resistance via H3K18la.** PYCR1-mediated H3K18 lactylation promotes sorafenib resistance by activating the IRS1/PI3K signaling pathway.

**7. The HTR1D contribution.** The 5-hydroxytryptamine receptor 1D (HTR1D) also contributes to resistance to treatments like sorafenib through the PI3K/Akt pathway.

**8. Non-coding RNA stabilization.** 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).

**9. Mitochondrial dysfunction and energy stress.** 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.

Collectively, these lactylation-mediated mechanisms significantly limit the clinical effectiveness of molecularly targeted drugs and chemotherapy regimens in HCC.

## Key Pathways in Lactate Production: PI3K/Akt/mTOR and HIF-1α

To understand how lactylation builds up, we must understand the pathways that produce its raw material, lactate. The review describes these in detail.

The **PI3K/Akt signaling pathway** is widely recognized for promoting digestive system tumors. The PI3K enzyme family has three subtypes with distinct jobs:

-
**Class I PI3K** generates PIP3, regulating cell growth and metabolism.
-
**Class II PI3K** activates AKT signaling through PIP2 synthesis.
-
**Class II and Class III PI3K together** produce PI3P, involved in membrane trafficking and autophagy (cellular recycling).

Activation 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.

**mTOR** 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.

**AMPK** (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.

**HIF-1α** 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:

1. Hypoxia prevents the hydroxylation of proline on HIF-1α.
1. This stops the pVHL tumor suppressor from binding to HIF-1α.
1. HIF-1α is no longer marked for degradation, so it accumulates.

Other stimulators — insulin, insulin-like growth factor 1, epidermal growth factor, and angiotensin II — can also increase HIF-1α levels.

Once activated, HIF-1 affects tumor progression mainly through two routes: upregulating **vascular endothelial growth factor (VEGF)** to promote blood vessel growth (angiogenesis), and upregulating **erythropoietin** 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.

And 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.

## Immunotherapy Resistance and the MOESIN Discovery

Immunotherapy — 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.

Regulatory 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.

Here is the key finding: **lactate in the tumor microenvironment enhances Treg suppressive function by inducing lactylation of the MOESIN protein**, and this directly weakens the effectiveness of anti-PD-1 therapy.

The 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. **MOESIN lactylation levels in Tregs from responding patients were significantly lower than those from resistant patients.** In other words, the lactylation level in a patient's immune cells could theoretically predict whether immunotherapy will work for them.

Increased lactate production drives the activation of PD-1+ Tregs, substantially increasing the likelihood that immunotherapy will fail.

Tumor-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 **LDHA-targeted inhibitors can reverse this immunosuppressive phenotype and enhance the efficacy of immune checkpoint inhibitors** — a strategy already under investigation.

## Clinical Implications: What This Means for Patients

The authors outline several emerging therapeutic strategies based on this research. While most are still in preclinical stages, they point toward future treatment options.

**1. Restoring drug sensitivity with metabolic inhibitors.** The glycolytic inhibitor **2-DG** 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.

**2. Targeting lactate transport.** **AZD3965**, 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.

**3. Activating SIRT3.** Because SIRT3 removes lactylation tags, **SIRT3 activators** can reverse lactylation and restore drug sensitivity, particularly relevant in sorafenib resistance where SIRT3 is reduced.

**4. LDHA-targeted inhibitors.** These can reverse the immunosuppressive phenotype driven by M2 macrophages and enhance the efficacy of immune checkpoint inhibitors.

**5. Personalized prediction with the LMRG model.** The authors describe a patient stratification model called **LMRG**, built on lactylation modification signatures. This model combines gene expression profiles — including **ACACA and MRPL3** — to predict individualized treatment responses. This represents a step toward precision medicine: using a patient's specific lactylation profile to choose the right treatment.

The 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.

**What this means for patients:** 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.

## Limitations of This Research

The 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.

Specific 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.

Additionally, 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.

## Recommendations for Patients

This 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:

1.
**Discuss lactate-related metabolism with your oncologist.** 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.
1.
**Ask about clinical trials.** 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.
1.
**Understand that drug resistance is not a personal failure.** 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.
1.
**Keep lifestyle factors in view.** 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.
1.
**Know that research is progressing rapidly.** 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.

## Frequently Asked Questions

### What is lactylation and how does it relate to liver cancer?

Lactylation 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.

### Why does liver cancer become resistant to drugs like lenvatinib or sorafenib?

Resistance 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.

### Are there treatments that can reverse lactylation-related resistance?

Several 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.

### Can lactylation levels predict whether immunotherapy will work for me?

Research 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.

### What is the LMRG model and how could it help choose treatment?

The 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.

### What are the limitations of this research on lactylation in liver cancer?

Most 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.

### What can I do now if I have advanced liver cancer and worry about resistance?

Discuss 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.

### When should a patient with advanced hepatocellular carcinoma that has stopped responding to lenvatinib or sorafenib seek a second opinion?

A 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.

## Source Information

**Original article title:** Mechanisms of lactylation modification in hepatocellular carcinoma treatment resistance.

**Authors:** Zhu Y, Wang Z, Xi H, Lu W, Sun M, Lin X.

**Publication:** *Gastroenterology Report*, 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.

**DOI:** https://doi.org/10.1093/gastro/goag003

**Received:** July 13, 2025 | **Revised:** November 16, 2025 | **Accepted:** November 27, 2025

*Note: 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.*


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