Search Results (303)

Background and Aims: Type 2 diabetes mellitus is a recognized risk factor for hepatocellular carcinoma (HCC), particularly in the setting of metabolic dysfunction-associated steatotic liver disease (MASLD), chronic viral hepatitis, advanced fibrosis, and cirrhosis. Beyond hyperglycemia and insulin resistance, diabetic hepatocarcinogenesis is shaped by metabolic inflammation, lipotoxicity, oxidative stress, fibrogenic remodeling, and the cirrhosis-dysplasia-HCC continuum. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) may influence several hepatometabolic pathways, but the epidemiologic evidence linking SGLT2i use to HCC risk remains heterogeneous. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating SGLT2i exposure and incident HCC in adults with type 2 diabetes. PubMed, Embase, and the Cochrane Library were searched up to 15 March 2026. Adjusted time-to-event estimates were pooled using a restricted maximum likelihood (REML) random-effects model. The certainty of evidence was assessed using the GRADE framework and judged to be very low. Results: Six observational studies including 526,446 participants were included. SGLT2i exposure was associated with a lower observed risk of incident HCC (pooled HR 0.59, 95% CI 0.45–0.77), but between-study heterogeneity was substantial (I² = 75.2%, τ² = 0.074). The association remained directionally similar after exclusion of Huynh et al. (HR 0.61, 95% CI 0.45–0.81) and in a DPP-4 inhibitor-restricted active-comparator analysis (HR 0.60, 95% CI 0.39–0.92). However, the 95% prediction interval crossed the null (0.25–1.37), indicating that future comparable studies may plausibly show no protective association. Conclusions: SGLT2i exposure was associated with a lower observed risk of incident HCC across available observational studies. However, the certainty of evidence was judged to be very low, and substantial heterogeneity, comparator variation, mixed time-to-event estimands, residual confounding, and a prediction interval crossing the null preclude causal interpretation. These findings should be considered hypothesis-generating rather than practice-changing evidence and support further hepatology-oriented validation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as key drivers of hepatocellular carcinoma (HCC). Unlike HCC caused by viral infections or alcohol, MASLD/MASH-related liver cancer develops within a chronic immunometabolic environment characterized by lipotoxicity, sterile inflammation, fibrogenesis, and remodeling of the microenvironment. In this setting, interleukin-10 (IL-10) has attracted growing attention due to its complex, context-dependent roles in immune regulation and tumor immune tolerance. This review explores IL-10 biology and its connection to MASLD/MASH-associated HCC, emphasizing the paradox that IL-10 may diminish harmful inflammation in early stages while promoting immunosuppressive conditions in advanced disease. To supplement existing research, we performed an exploratory reanalysis of publicly available bulk liver RNA-seq data from a mouse model that progresses from MASLD/MASH to HCC. The reanalysis revealed a receptor- and effector-specific rewiring of the IL-10 pathway: while the expression of canonical signaling genes (Stat3, Jak1, Jak2, Tyk2, Socs3) showed minimal changes across stages, receptor subunits (Il10ra, Il10rb) and IL-10-responsive effectors (such as Scd2, related to lipid metabolism, and Ddit4, involved in mTOR and glycolysis regulation) displayed strong stage-dependent induction. This was accompanied by a decrease in hepatocyte signature profiles and an increase in stromal and immune signatures. These results generate new hypotheses and raise key questions—particularly whether a large portion of IL-10 modulation originates from peripheral or non-parenchymal sources, and whether the transcriptional patterns observed reflect protein-level changes—that will require stage-specific, cell-focused human studies incorporating proteomic and cytokine measurements. Full article

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and accounts for over 800,000 deaths worldwide, making it a major global health concern. Unfortunately, despite major advances in systemic treatments, such as the introduction of atezolizumab and bevacizumab, patient objective response rates fall below 30%. HCC most commonly develops against a background of chronic liver disease and cirrhosis, although single gene mutations can also drive HCC development, progression, and metastasis. Around 25% of HCC patient tumours carry mutations in TP53, the gene encoding the tumour-suppressor protein p53. p53 is a central regulator of genomic stability, cell-cycle arrest, apoptosis, senescence, and metabolic homeostasis, and its dysfunction is a frequent event in hepatocarcinogenesis. Accumulating evidence highlights the critical role of p53 in liver fibrosis, inflammation, and shaping of the HCC tumour microenvironment (TME). This review summarizes the role of p53 and its negative regulators Mdm2 and MdmX in HCC development and progression, with an emphasis on how p53 shapes the TME in favour of tumour progression. We also evaluate current and emerging p53-targeted therapeutic strategies, including Mdm2/MdmX inhibitors, mutant p53 reactivators, and rational combinations with immunotherapies. Finally, we discuss major challenges in translating p53-based therapies to the clinic, such as tumour heterogeneity, underlying liver dysfunction, and the development of therapeutic resistance. A deeper understanding of p53 biology in chronic liver disease may unlock new avenues for effective HCC prevention and treatment. Full article

Hepatocellular carcinoma (HCC) represents a major global health challenge and the third leading cause of cancer-related mortality worldwide. Its epidemiological burden is rapidly increasing, largely driven by the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now recognized as the most common chronic liver disease globally. Notably, MASLD frequently coexists with type 2 diabetes mellitus (T2DM), sharing several features, including the interplay of common genetic, metabolic, and environmental factors, thus contributing to a complex multifactorial pathogenesis. Relevantly, patients affected by both conditions represent a subgroup at particularly high risk of liver disease progression and hepatocarcinogenesis. In this population, metabolic and inflammatory disturbances act synergistically to create a pro-tumorigenic hepatic environment where insulin resistance (IR) plays a crucial role, by driving hepatic lipotoxicity, mitochondrial dysfunction, and inflammatory signaling with oxidative stress, thereby establishing a permissive environment for worsening steatosis and malignant transformation. Increasing evidence supports the concept of MASLD as a multisystem disorder reflecting the systemic nature of metabolic dysfunction. Within this framework, beyond IR, extrahepatic factors have also emerged as important contributors to steatosis progression, worsening of T2DM, and modulation of HCC risk. In particular, the gut–liver axis has gained recognition as a key regulator of hepatic homeostasis, integrating signals from the intestinal microbiota, immune responses, and metabolic pathways. Dysregulation of this crosstalk promotes systemic inflammation and metabolic imbalance, exacerbating IR and fostering a pro-oncogenic hepatic environment. This review examines the interconnected metabolic and immune mechanisms linking IR and gut–liver axis dysfunction to HCC development in patients with MASLD and T2DM, highlighting their implications for risk stratification and precision-based therapeutic strategies. Full article

Liver diseases, ranging from chronic hepatitis and metabolic dysfunction to cirrhosis and hepatocellular carcinoma, represent a major global public health burden. As an immune-privileged organ, the liver harbors a unique and intricate immune microenvironment, which plays a dual role in pathogen clearance and chronicity. Kupffer cells (KCs), the primary resident macrophages in the liver, constitute the first line of defense in liver innate immunity and play complex and important roles in pathogen recognition, phagocytosis, and the regulation of liver inflammation and immune responses. The complement receptor of the immunoglobulin superfamily (CRIg) is a membrane receptor that is specifically expressed on KCs. It serves not only as a sentinel for the liver against pathogen invasion but also as a sophisticated regulator for maintaining immune homeostasis. As a key component of the liver’s immune system, CRIg can efficiently mediate the clearance of complement-opsonized particles, thereby playing multidimensional roles in pathogen clearance, antigen cross-presentation, and the establishment of immune tolerance, functioning as both a “pathogen catcher” and an “immune brake.” This review focuses on the CRIg molecule, detailing its mechanisms in the recognition and phagocytic clearance by KCs, and its subsequent impact on hepatic immune responses. Furthermore, we explored the potential involvement of CRIg in the pathological progression of diverse liver diseases, including persistent inflammation, fibrosis, and hepatocarcinogenesis. This synthesis provides novel insights into the immunopathology of liver diseases and establishes a theoretical foundation for developing CRIg-targeted therapeutic strategies. Full article

Chronic hepatitis B (CHB) and Type 2 diabetes (T2DM) are major independent risk factors for Hepatocellular carcinoma (HCC). The bidirectional promotion between T2DM and CHB forms the biological basis for their synergistic carcinogenic effect. T2DM mainly accelerates the progression of CHB through mechanisms such as metabolic disorders, oxidative stress, chronic inflammation, and immunosuppression; CHB promotes the development of T2DM mainly through liver damage leading to dysfunction of the central glucose metabolism, HBx-driven gluconeogenesis, inhibition of the insulin signaling pathway, and potential β-cell damage. In comorbid conditions, these mechanisms intertwine to form a vicious cycle across four key aspects: metabolic and lipid disorders, activation of carcinogenic pathways, oxidative stress, and amplification of chronic inflammation, significantly accelerating the hepatocarcinogenesis. Regarding management strategies, we adopt the concept of three-level prevention, integrate various management plans and combine emerging drug therapies. We thus propose the establishment of a management strategy centered on “liver and glucose co-management” with multi-faceted joint control. This review aims to summarize the latest evidence on the mechanisms and management strategies by which the comorbidity of T2DM and CHB promotes the development of HCC, providing a theoretical basis for research on the mechanisms of this comorbidity and population-level HCC prevention strategies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading driver of hepatocellular carcinoma (HCC) worldwide. A substantial proportion of MASLD-related HCC arises in the noncirrhotic liver, highlighting critical gaps in current surveillance strategies that rely primarily on fibrosis stage to define risk. Although the annual incidence of HCC in noncirrhotic MASLD is low and does not justify universal surveillance, the extraordinary global prevalence of MASLD translates into a considerable absolute burden of cancer. Accumulating evidence demonstrates that HCC risk in MASLD is modulated not only by histologic severity but also by metabolic comorbidities, particularly type 2 diabetes mellitus, which can significantly amplify cancer risk even in pre-cirrhotic stages. From both clinical and health economic perspectives, these observations underscore the need for more complex and targeted surveillance approaches. This review synthesizes current epidemiologic data, metabolic and histologic modifiers of HCC risk, emerging biomarkers, and predictive models in MASLD, with a focus on noncirrhotic disease. We discuss how integrated, precision-based risk assessment may identify high-risk MASLD subgroups and enable targeted, cost-effective surveillance strategies to mitigate the growing burden of MASLD-associated HCC. Full article

Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major global health burden, ranking as the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The rising incidence of HCC is closely linked to metabolic comorbidities, including non-alcoholic fatty liver disease (NAFLD), underscoring the need for improved diagnostic and therapeutic strategies. NAFLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by inflammation and fibrosis, which markedly increases HCC risk, especially in individuals with obesity and type 2 diabetes (T2D). NAFLD has recently been redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) to better reflect its metabolic basis. However, robust experimental models to study the progression from MASLD to MASH and ultimately HCC remain limited. This proof-of-concept study investigates sex-specific effects of metabolic dysregulation using the STAM (STelic Animal Model; streptozotocin and high-fat diet) mouse model, which recapitulates key features of human MASH and HCC. Neonatal C57BL/6J mice received streptozotocin to induce T2D-like symptoms followed by a high-fat diet. Streptozotocin (STZ) treated mice showed reduced body fat, lower insulin levels, impaired glucose tolerance, and increased expression of genes linked to inflammation, lipid metabolism, and apoptosis. These findings support the STAM model’s utility for MASLD research and highlight the importance of sex-specific strategies to limit HCC progression. Full article

Hepatocellular carcinoma (HCC) remains a leading cause of mortality in patients with advanced chronic liver disease (ACLD), particularly in those with decompensated cirrhosis, where traditional biomarkers such as alpha-fetoprotein (AFP) often fail to reliably detect malignancy. Interleukin-37 (IL-37), an anti-inflammatory cytokine with reported tumour-suppressive properties, has emerged as a candidate biomarker in hepatocarcinogenesis. This prospective study investigated serum IL-37 concentrations in 221 patients with ACLD (54 with HCC and 167 without HCC). IL-37 was measured at the time of clinical assessment, and routine laboratory parameters, disease severity scores (MELD, Child–Pugh), and tumour staging (BCLC, LI-RADS) were recorded. IL-37 levels were not significantly different in patients with compensated ACLD (cACLD) with or without HCC. In contrast, in decompensated ACLD (dACLD), IL-37 concentrations were significantly lower in patients with HCC, particularly in those with advanced hepatic dysfunction. Stratified analyses revealed an inverse relationship between IL-37 and AFP in cACLD, whereas in dACLD, IL-37 appeared more informative, as AFP levels were affected by systemic inflammation. Patients with prevalent HCC exhibited numerically lower IL-37 compared with those who developed HCC during follow-up, suggesting that IL-37 decline may precede overt tumour manifestation. Kaplan–Meier survival analysis showed a trend toward improved overall survival in patients with higher IL-37 levels, although this did not reach statistical significance. These findings highlight IL-37 as a promising biomarker candidate that might reflect immune regulation and tumour biology in ACLD. In particular, IL-37 may complement AFP for HCC detection in decompensated cirrhosis, where conventional biomarkers often fail. Future studies with larger, longitudinal cohorts are warranted to validate IL-37 as a predictive and prognostic marker in high-risk populations. Full article

Long non-coding RNAs (lncRNAs) are key regulators of gene expression and play critical roles in cancer-related signaling networks. Dysregulation of antagonistic lncRNAs may contribute to hepatocarcinogenesis and disease progression. This study investigated the clinical significance and predictive value of two biologically antagonistic lncRNAs, UFC1 and PTENP1, as circulating biomarkers for hepatocellular carcinoma (HCC) in an Egyptian cohort. Expression levels of these lncRNAs were quantified in 100 HCC patients and 100 age- and sex-matched healthy controls. UFC1 was significantly upregulated (~2.9-fold), while PTENP1 was markedly downregulated (~4-fold) in HCC patients, with a strong inverse correlation (r = −0.609, p < 0.001). Both lncRNAs demonstrated higher diagnostic accuracy compared to alpha-fetoprotein (AFP); combining them with AFP further enhanced overall performance. UFC1 expression was increased progressively with advancing fibrosis grade and Barcelona Clinic Liver Cancer (BCLC) stage, while PTENP1 levels diminished with BCLC stage. Logistic regression confirmed UFC1 as an independent risk factor and PTENP1 as a protective factor for HCC. In conclusion, the blood-based UFC1/PTENP1 panel exhibits promising diagnostic accuracy and is associated with disease severity, surpassing AFP. Their fibrosis-associated dysregulation suggests a role in early hepatocarcinogenesis. This antagonistic lncRNA signature represents a potential, non-invasive tool for HCC detection and risk stratification, meriting further clinical validation. Full article

Cytoglobin (Cygb) was discovered in 2001 as a cytoplasmic globin predominantly expressed in hepatic stellate cells (HSCs). While its initial physiological role remained elusive, subsequent studies using Cygb-deficient mouse models of liver injury have demonstrated that Cygb exerts protective effects against liver fibrosis and inflammation. It achieves this by regulating HSC activation, thereby preserving hepatic homeostasis. Furthermore, accumulating evidence suggests a significant role for Cygb in hepatocarcinogenesis. Analysis of human liver tissues and cell-based models has further confirmed the critical involvement of CYGB in liver pathology. Functionally, Cygb acts as an antioxidant protein that mitigates oxidative stress, a property that appears to modulate transforming growth factor-beta signaling and downstream fibrogenic responses. Based on these findings, therapeutic strategies employing recombinant CYGB for the treatment of human liver cirrhosis are currently being explored, and their potential clinical applications are eagerly anticipated. Full article

Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKKβ^Δhep mice (Tg-IKKβ^Δhep), which combine hepatocyte-specific IKKβ deletion with liver expression of a nuclear, kinase-inactive IKKβ mutant (NLS-IKKβKN). Tg-IKKβ^Δhep mice developed spontaneous chronic hepatitis and progressive fibrosis but were strikingly resistant to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, with markedly reduced tumor multiplicity and total tumor burden. Despite persistent inflammatory injury, DEN-triggered oxidative DNA damage and p53 activation were markedly attenuated, compatible with reduced tumor initiation. Transcriptomic and biochemical analyses revealed broad repression of xenobiotic-metabolizing cytochrome P450 genes, including the pericentral enzyme CYP2E1, accompanied by reduced CYP2E1 protein abundance. This was associated with impaired HNF4α–PXR–CAR transcriptional output and reduced HNF4α occupancy at target promoters. Acute TNFα or IL-1β exposure recapitulated this repression, in part through reduced PGC-1α expression and decreased RNA polymerase II recruitment to target promoters. In parallel, pericentral xenobiotic metabolism was blunted, a change that could plausibly diminish DEN bioactivation and genotoxic stress. Together, these findings support a “metabolic gatekeeping” model in which chronic inflammation can constrain chemical hepatocarcinogenesis by attenuating carcinogen-metabolizing capacity. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC. Full article

The prevalence of hepatocellular carcinoma (HCC) has increased in recent years and resulted in many deaths, which necessitates new therapeutic solutions. The pathogenesis of HCC is associated with uncontrolled metabolic modulation and resistance to therapy. As diabetic carcinogenesis accelerates HCC progression, proper evaluation of anti-diabetic drugs to attenuate HCC is important. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors that suppress renal SGLT2 are beneficial for treating diabetes, chronic kidney diseases, and heart failure, the use of SGLT2 inhibitors for treating HCC remains unclear. In this review article, some oncotargets involved in metabolic reprogramming, including glucose metabolism, Wnt/β-catenin, and hypoxia-inducible factor-1 alpha signaling, and the tumor microenvironment of HCC are briefly highlighted. Moreover, upregulated SGLT2 expression may be associated with hepatocarcinogenesis and therapy resistance, whereas the incorporation of SGLT2 inhibitors into combination therapies effectively attenuates HCC progression, metastasis, and therapy resistance through multiple mechanisms. Notably, how SGLT2 inhibitors modulate immune responses to cancer vaccines against HCC is highly appreciated and requires further evaluation. Thus, the clinical application of SGLT2 inhibitors in HCC and therapy resistance provides a promising direction for therapeutic strategies. Full article

Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related death worldwide. Its high aggressiveness and resistance to therapy arise, in large part, from an immunosuppressive tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are web-like assemblies of chromatin and granular proteins released during NETosis, and they have emerged as major inflammatory drivers within the HCC TME. NETs actively promote tumor progression by physically trapping circulating tumor cells, remodeling the extracellular matrix, stimulating angiogenesis, and facilitating immune evasion. In this review, we systematically dissect the molecular networks that link NETs to HCC. We summarize the signaling pathways that regulate NETs formation, detail the multifaceted roles of NETs in hepatocarcinogenesis, metastasis, and therapy resistance, and assess the translational potential of NETs as diagnostic biomarkers and therapeutic targets. Together, these analyses offer theoretical guidance for developing the next generation of precision-medicine strategies for HCC. Full article