Exploring the Epidemiologic Burden, Pathogenetic Features, and Clinical Outcomes of Primary Liver Cancer in Patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Scoping Review
Abstract
1. Background
1.1. Primary Liver Cancer in the Era of MASLD: Epidemiological Changes Guide the Etiological Shift
1.2. Primary Liver Cancer in MASLD: Impact of T2DM on Relative Occurrence Risk and Prognosis
1.3. Status of the Art and Aims of the Research
2. Methods
3. Results
3.1. Type 2 Diabetes Mellitus, MASLD, and Hepatic Cancer: From “Classic” to Novel Pathogenesis
3.1.1. Role of Insulin Resistance in Influencing Hepatobiliary Cancerogenesis
3.1.2. Insulin Resistance-Related Inflammation Influences Hepatobiliary Cancerogenesis
3.1.3. MASLD-T2DM-Associated Gut Dysbiosis in the Pathogenesis of Primary Liver Cancer
3.1.4. Glucose-Related Metabolic Reprogramming Contributes to Cancer Immunoescape: The Emerging Frontiers of PLC Pathogenesis
3.2. Identifying Pathogenetic Targets to Design Tailored Strategies in the Management of MASLD-TD2M Associated PLC: State of the Art
3.2.1. Targeting Insulin Resistance
Metformin
SGLT2-Is
DPP4-Is
GLP-1 RAs
3.2.2. Modulating Gut-Biliary Liver Axis: A Promising and Still Embryonal Strategy
3.2.3. Modulating Immunometabolic Responses: The Novel Therapeutic Frontier
4. Discussion and Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AFP | Alpha-fetoprotein |
AUD | Alcohol Use Disorder |
BA | Bile Acid |
BCG | Bacillus Calmette–Guérin |
CCA | Cholangiocarcinoma |
CMRF | Cardiometabolic Risk Factor |
COX-2 | Cyclooxygenase-2 |
DCA | Deoxycholic Acid |
DM | Diabetes Mellitus |
FABP4 | Fatty Acid Binding Protein 4 |
FFAs | Free Fatty Acids |
FLR | Future Liver Remnant |
GLP-1 | Glucagon-Like Peptide-1 Receptor Agonists |
HBV | Hepatitis B Virus |
HCC | Hepatocellular Carcinoma |
HCV | Hepatitis C Virus |
HFD | High-Fat Diet |
HGF | Hepatocyte Growth Factor |
HR | Hazard Ratio |
ICC | Intrahepatic Cholangiocarcinoma |
ICIs | Immune Checkpoint Inhibitors |
IGF-1 | Insulin-like Growth Factor 1 |
IGF1-R | Insulin-like Growth Factor 1 Receptor |
IGFBPs | Insulin-like Growth Factor-Binding Proteins |
IL | Interleukin |
IR | Insulin Resistance |
JNK | c-Jun N-terminal Kinase |
LD | Linear Dichroism |
LPS | Lipopolysaccharide |
LSECs | Liver Sinusoidal Endothelial Cells |
MASLD | Metabolic Dysfunction-Associated Steatotic Liver Disease |
MASH | Metabolic Dysfunction-Associated Steatohepatitis |
MD | Metabolic Dysfunction |
Met | MNNG HOS Transforming Gene |
NAFLD | Non-Alcoholic Fatty Liver Disease |
PDHC | Pyruvate Dehydrogenase Complex |
PLC | Primary Liver Cancer |
ROS s | Reactive Oxygen Species |
SGLT2-Is | Sodium-Glucose Cotransporter-2 Inhibitors |
SCFAs | Short-Chain Fatty Acids |
STAT3 | STAT3—Signal Transducer and Activator of Transcription 3 |
T2DM | T2DM—Type 2 Diabetes Mellitus |
TCR | TCR—T-Cell Receptor |
TGF-β | Transforming Growth Factor Beta |
TI | Trained Immunity |
TLR4 | Toll-like Receptor 4 |
TNF-alpha | Tumor Necrosis Factor Alpha |
TKI | Tyrosine Kinase Inhibitor |
VEGF | Vascular Endothelial Growth Factor |
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Bacterial Species | Key Characteristics | Role in HCC Pathogenesis | References |
---|---|---|---|
Escherichia coli | Gram-negative; enriched in MD-related gut dysbiosis | Activates TLR4 signaling via LPS; promotes chronic hepatic inflammation and oxidative stress | [107] |
Klebsiella pneumoniae | Gram-negative; enriched in MD-related gut dysbiosis | Promoting bacterial translocation; activates Kupffer cells and hepatic immune response via LPS | [113] |
Bacteroides fragilis | Commensal; enriched in MD-related gut dysbiosis contributing to the deterioration of glucose metabolism | Activates TLR4 signaling via LPS; induction of senescence-associated secretory phenotypes in hepatic stellate cells; promotion of chronic hepatic inflammation | [112] |
Fusobacterium nucleatum | Anaerobic opportunist; associated with T2DM and various GI malignancies | Promotes inflammation and may activate TLR4-dependent oncogenic pathways in tumor-prone environments. | [110] |
Bacterial Species | Key Characteristics | Role in CCA Pathogenesis | References |
---|---|---|---|
Escherichia coli | Gram-negative facultative anaerobe; enriched in MD-related gut dysbiosis | Promotes chronic inflammation and oxidative stress in biliary epithelium via LPS | [119] |
Clostridium spp. | Anaerobic Firmicutes; capable of 7α-dehydroxylation of primary bile acids; enriched in MD-related gut dysbiosis | Production of secondary bile acids (e.g., deoxycholic acid, DCA) with pro-carcinogenic properties | [112,120] |
Helicobacter spp. | Bile-resistant; colonizes biliary tract; includes H. hepaticus and H. bilis; enriched in MD-related gut dysbiosis | Chronic inflammation and DNA damage; potential carcinogenic role | [121,122] |
Bacteroides spp. | Dominant gut anaerobes; key in bile acid and carbohydrate metabolism; enriched in MD-related gut dysbiosis | Reduced abundance disrupts bile acid homeostasis and favors dysbiosis | [123,124] |
Veillonella spp. | Gram-negative anaerobes; lactate fermenters; enriched in MD-related gut dysbiosis | Promoting local inflammation via LPS/TLR4-dependent pathways | [125] |
Drug Class | Mechanisms of Action in Hepatic Cancerogenesis | Potential Therapeutic Implications (Type of Supporting Evidence) | Ref. |
---|---|---|---|
Metformin | Improving IR and IR-related effects; modulation of gut-liver axis (regulates BAs metabolism) | HCC: reduction of HCC risk and mortality in T2DM patients (metanalysis) CCA: reduction of malignant cells proliferation and invasion potential (preclinical models) | [143] [36] |
SGLT2-Is | Blocking renal glucose reabsorption thus reducing glucose levels and relative pro-cancerogenic effects; activates NAD+ salvage pathways. | HCC: combination with metformin reduces incidence (retrospective in human evidence) CCA: high doses suppress CCA cell viability (dose-dependent effects in vitro). | [148] [150] |
DPP4-Is | Inhibition of DPP4/CD26-regulated pathways; modulation of immune response and oxidative stress | HCC: Promotion of apoptosis in HCC cells via suppressing of p62/Keap1/Nrf2 axis (in vitro); reduction of HCC incidence in T2DM-Hepatitis C Virus (HCV) infected patients (in human) CCA: lack of solid evidence | [155] [156] |
GLP-1 RAs | Enhancing insulin secretion and reducing glucagon levels; promotion of anti-inflammatory effects | HCC: Reduction of HCC incidence in T2DM patients (emerging in vivo evidence) CCA: Limited role in tumor suppression (in vitro & in vivo evidence) | [161] [36] |
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Romeo, M.; Di Nardo, F.; Napolitano, C.; Basile, C.; Palma, C.; Vaia, P.; Dallio, M.; Federico, A. Exploring the Epidemiologic Burden, Pathogenetic Features, and Clinical Outcomes of Primary Liver Cancer in Patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Scoping Review. Diabetology 2025, 6, 79. https://doi.org/10.3390/diabetology6080079
Romeo M, Di Nardo F, Napolitano C, Basile C, Palma C, Vaia P, Dallio M, Federico A. Exploring the Epidemiologic Burden, Pathogenetic Features, and Clinical Outcomes of Primary Liver Cancer in Patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Scoping Review. Diabetology. 2025; 6(8):79. https://doi.org/10.3390/diabetology6080079
Chicago/Turabian StyleRomeo, Mario, Fiammetta Di Nardo, Carmine Napolitano, Claudio Basile, Carlo Palma, Paolo Vaia, Marcello Dallio, and Alessandro Federico. 2025. "Exploring the Epidemiologic Burden, Pathogenetic Features, and Clinical Outcomes of Primary Liver Cancer in Patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Scoping Review" Diabetology 6, no. 8: 79. https://doi.org/10.3390/diabetology6080079
APA StyleRomeo, M., Di Nardo, F., Napolitano, C., Basile, C., Palma, C., Vaia, P., Dallio, M., & Federico, A. (2025). Exploring the Epidemiologic Burden, Pathogenetic Features, and Clinical Outcomes of Primary Liver Cancer in Patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Scoping Review. Diabetology, 6(8), 79. https://doi.org/10.3390/diabetology6080079