Objective: This review examines the evolution of obesity evaluation methods, from traditional anthropometric indices to advanced imaging techniques, focusing on their clinical utility, limitations, and potential for personalized assessment of visceral adiposity and associated metabolic risks.

Methods: A comprehensive analysis of existing literature was conducted, encompassing anthropometric indices (BMI, WC, WHR, WHtR, NC), lipid-related metrics (LAP, VAI, CVAI, mBMI), and imaging technologies (3D scanning, BIA, ultrasound, DXA, CT, MRI). The study highlights the biological roles of white, brown, and beige adipocytes, emphasizing visceral adipose tissue (VAT) as a critical mediator of metabolic diseases.

Conclusion: Although BMI and other anthropometric measurements are still included in the guidelines, indicators that incorporate lipid metabolism information can more accurately reflect the relationship between metabolic diseases and visceral obesity. At the same time, the use of more modern medical equipment, such as ultrasound, X-rays, and CT scans, allows for a more intuitive assessment of the extent of visceral obesity.

Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival benefits. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modifications, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modifications. Additionally, it is useful to consider etiology-specific epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-specific epigenetic patterns and the integration of epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies.

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) progresses from hepatic steatosis to hepatocellular carcinoma (HCC) as a result of systemic immunometabolic dysfunction. This review summarizes the key roles of the innate and adaptive immune mechanisms driving hepatic injury, fibrogenesis, and carcinogenesis in MASLD. Methods: A comprehensive literature review was performed using PubMed to identify relevant published studies. Eligible articles included original research and clinical studies addressing immunological and metabolic mechanisms in MASLD, as well as emerging therapeutic strategies. Results: We highlight the roles of cytokine networks, the gut-liver axis, and immune cell reprogramming. Emerging therapeutic strategies, including cytokine inhibitors, anti-fibrotic agents, metabolic modulators, and nutraceuticals, offer several indications for attenuating MASLD progression and reducing the prevalence of extrahepatic manifestations. Conclusions: Given the heterogeneity of MASLD, personalized combination-based approaches targeting both inflammation and metabolic stress are essential for effective disease management and the prevention of systemic complications.

Metabolic dysfunction associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), is a progressive form of steatotic liver disease (SLD). It is an emerging healthcare threat due its high prevalence, accelerated and non-linear progression, and final culmination as decompensated liver failure and/or hepatocellular carcinoma (HCC). The pathogenesis of NASH is complex with strong ethnic influences and genetic predispositions, underscoring the need for preclinical models that utilize patient-derived cells to enhance our understanding of the disease. Current models face three major limitations: (i) reliance on primary cells with limited reproducibility, high cost, short culture duration and ethical considerations, (ii) failure to recapitulate all key features of NASH, and (iii) inadequate drug testing data and/or data did not correlate with clinical responses. Therefore, there is a pressing need for robust and relevant preclinical models that faithfully recapitulate human NASH, allow generation of patient-specific models and provide quantitative responses for mechanistic studies and drug testing. We have developed a functional liver tissue-on-a-chip by co-culturing human adult liver stem cell (haLSC)-derived hepatobiliary organoids, induced pluripotent stem cell (iPSC)-derived Kupffer cells (iKCs) and iPSC-derived hepatic stellate cells (iHSCs). We simulated the metabolic microenvironment of hyper nutrition and leaky gut by treating the cells with a concoction of free fatty acids (FFAs), fructose, gut-derived lipopolysaccharides (LPS) and a gut-derived metabolite, phenyl acetic acid (PAA). Through optimization of co-culture media and induction regimens, we were able to stably induce steatosis, hepatocellular ballooning, inflammation, and activation of iHSC and fibrosis-all key hallmarks of NASH. Our LEADS (liver-on-a-chip for NASH drug testing) model also recapitulated the pathological types of steatosis and allowed for quantification of the key features via microscopic evaluation and secretome profiling to score for disease severity. Notably, treatment with saroglitazar, pioglitazone, cenicriviroc (CVC), obeticholic acid (OCA) and resmetirom produced responses similar to those observed in clinical trials. Taken together, our LEADS model is the first model developed using patient-derived hepatic stem cells which recapitulated all key features used for comprehensive drug testing, with results matching to clinical responses.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors of the digestive system, and its prevalence is currently increasing. The current study aims to elucidate the mechanism by which membrane-associated RING-CH8 (MARCH8) impedes the progression of HCC. MARCH8 was identified as a distinct prognostic marker for recurrence-free survival (RFS) and overall survival (OS) in patients with HCC. This study shows that MARCH8 hinders lipid deposition by suppressing the expression of key enzymes for the de novo synthesis of fatty acids (FAs) via RNA sequencing, untargeted metabolomics, and a series of in vivo and in vitro experiments. Further experimental validation demonstrated that MARCH8 was a novel E3 ligase of sterol regulatory element binding protein 1 (SREBP1). And, it primarily promoted the degradation of SREBP1, thereby suppressing the expression of key enzymes involved in the de novo synthesis of FAs. In conclusion, this study has identified MARCH8 as a key "switch" that can be targeted to prevent de novo FA synthesis in HCC cells. This finding may have substantial implications for discovering innovative therapeutic strategies for HCC.

Metabolic dysfunction-associated steatohepatitis (MASH) is becoming increasingly prevalent. Regulated cell death (RCD) has emerged as a significant disease phenotype and may act as a marker for liver fibrosis. The present study aimed to investigate the regulation of RCD-related genes in MASH to elucidate the role of RCD in the progression of MASH.

The gene expression profiles from the GSE130970 and GSE49541 datasets were retrieved from the Gene Expression Omnibus (GEO) database for analysis. A total of 101 combinations of 10 machine learning algorithms were employed to screen for characteristic RCD-related differentially expressed genes (DEGs) that reflect the progression of MASH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the enrichment pathways and functions of the feature genes. we performed cell classification analysis to investigate immune cell infiltration. Consensus cluster analysis was performed to identify MASH subtypes associated with RCD. The GSE89632 dataset was utilized to analyze the correlation of characteristic genes with clinical features of MASH. The DGIdb database was employed to screen for potential therapeutic drugs and compounds targeting the feature genes. In addition, we established mouse liver fibrosis models induced by methionine-choline-deficient (MCD) diet or CCl4 treatment, and further validated the expression of characteristic genes through quantitative real-time PCR (q-PCR). Lastly, we knocked down EPHA3 in LX2 cells to explore its effect on TGFb-induced activation of LX2 cells.

This study discovered a total of 11 RCD-associated DEGs, which predicted the progression of MASH. Advanced MASH has higher levels of immune cell infiltration and is significantly correlated with the RCD-related DEGs expression. MASH can be classified into two subtypes, cluster 1 and cluster 2, based on these feature genes. Compared with cluster 1, cluster 2 has highly expressed RCD-related DEGs, shows an increase in the degree of fibrosis. Furthermore, We discovered that the expression levels of feature genes were positively correlated with AST and ALT levels. Subsequently, We also evaluated the expression of these 11 feature genes in the liver tissues of mice with fibrosis induced by MCD or CCl4, and the results suggested that these genes may be involved in the development of fibrosis. WB results showed that the protein level of EPHA3 significantly increased in both mouse models of liver fibrosis. In vitro, we observed that knocking down EPHA3 in LX2 cells significantly inhibited the activation of the TGF-β/Smad3 signaling pathway.

Our study sheds light on the fact that RCD contribute to the progression of MASH, high lighting potential therapeutic targets for treating this disease.

Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic condition with an incompletely understood pathogenesis. In this study, five candidate genes-RAG1, CKAP2, CENPK, TYMS, and BUB1-were identified as being associated with NAFLD progression through integrative bioinformatics analyses. A predictive model incorporating these genes demonstrated strong robustness and diagnostic accuracy. Single-nucleus RNA sequencing analysis further revealed that RAG1 plays a potential role in hepatocytes of NAFLD patients. Functional experiments using RNA interference to suppress RAG1 expression in HepG2 cells treated with oleic and palmitic acids showed reduced total glyceride and cholesterol levels, mitigated lipid accumulation, and alterations in pathways related to lipid metabolism, inflammation, and fibrosis. Furthermore, adeno-associated virus-specific knockdown of RAG1 in hepatocytes attenuated hepatic steatosis in high-fat diet-fed mice. These findings suggest that investigating the molecular mechanisms of hub genes like RAG1 may advance our understanding of NAFLD pathogenesis and inform therapeutic development.

HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.

The present research was performed to examine the possible capability of allopurinol to prevent developing hepatocellular carcinoma (HCC) and to explore the fundamental mechanisms that control the hepatoprotective effect considering the enormous impact of HCC on patients' quality of life. Male Sprague Dawely rats were given i.p. injection of thioacetamide (TAA) (200 mg/kg) twice a week for 16 weeks in order to induce HCC. The histological analysis and assessment of the serum levels of liver function indicators verified the development of HCC. Two regimens of allopurinol (100 mg/kg, p.o.) were used; the first involved giving it concurrently with TAA from week 13 to week 16, and the second regimen started from week 9 to week 16. Chronic TAA damage was associated with considerable overexpression of the profibrogenic cytokine TGF-β, degradation and nuclear translocation of NF-κB, which released a number of inflammatory mediators, and upregulation of the NLRP3/caspase1 pathway. Administration of allopurinol demonstrated considerable enhancements in liver function and oxidative balance. Moreover, pathological characteristics like cirrhosis, dysplastic changes, and HCC nodules were greatly diminished. Allopurinol via suppressing TGF-β expression, inhibiting NF-κB nuclear translocation, and restricting inflammatory NLRP3/caspase1/IL-1β pathway was able to protect against TAA-induced liver damage, and it could be a promising therapy for HCC.

We aimed to recognize the burden of NAFLD and support public health policy development for its prevention and management.

A cross-sectional analysis of GBD 2021 results was conducted.

We collected incidence data on NAFLD from 1990 to 2021 using Global Burden of Disease Study in 2021. Estimated annual percentage changes (EAPCs) in NAFLD age standardized incidence rate (ASR) were calculated to quantify the temporal trends in NAFLD ASR. Bayesian age-period-cohort models were constructed to project NAFLD incidence rates and cases up to 2050. Additionally, we assessed the percentage of cirrhosis and liver cancer attributable to NAFLD.

Globally, the newly-occurred cases of NAFLD increased by 94.49 % from 24, 856, 159 in 1990 to 48, 353, 272 in 2021. The case number will further increase to 78,602,984 in 2050, and ASR will increase from 5.93 per 1000 in 2021 to 7.26 per 1000 in 2050. The most pronounced increases were observed in young people and men. In 2021, NAFLD accounted for 82.7 % of cirrhosis and other chronic liver diseases and 8.0 % of liver cancer cases.

From 1990 to 2021, the incidence of NAFLD has been continuously increasing and is expected to continue rising until 2050. The increases in young people and men highlight their priority in future schedules. The rising proportions of cirrhosis and liver cancer caused by NAFLD further underscore the serious health risks.

Early recognition of steatosis (fatty liver) and fibrosis in liver health is crucial for effectively managing and preventing the possibility of liver dysfunction. Detecting steatosis helps identify individuals at risk of liver-related diseases, such as inflammation (Non-Alcoholic SteatoHepatitis, NASH) and fibrosis. Fibrosis involves the formation of scar tissue in the liver due to chronic inflammation and injury. Early recognition of fibrosis helps categorize patients based on their risk of progression to advanced liver disease. Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) leads to many outcomes, including Metabolic dysfunction-Associated Steatohepatitis (MASH), fibrosis, and cirrhosis. We aim to show that routine clinical tests supported by machine learning offer sufficient information to predict these endpoints.

The research focused on applying various operational research methods such as Linear Regression, Support Vector Machine, K-Nearest Neighbors, Decision Tree, Multi-Layer Perceptron, and Naive Bayes.

The proposed method - FibrAIm - allows the identification of patients at risk of complications related to the conditions analyzed based on inconclusive test results. It can also identify the risk of fibrosis in those whose results appear correct.

Given the results obtained during the trials, FibrAIm could become a valuable tool for diagnosing patients at risk of liver early steatosis and fibrosis by identifying cases based on standardized screening tests.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.

Accumulating evidence indicates that antioxidants promote tumor growth and metastasis after tumor onset in several cancer types. However, whether antioxidants prevent or accelerate hepatic tumorigenesis during steatosis remains unknown. Therefore, we investigated the effects of resveratrol (RES) and N-acetylcysteine (NAC) on hepatocellular carcinoma (HCC) development using two fatty liver mouse models.

High-fat diet (HFD) plus diethylnitrosamine (DEN)- and AKT/Ras-induced primary HCC mouse models were used. The weight, liver weight ratio and the number of HCC tumors were calculated and histological features of mouse HCC tissues were analyzed using immumohistochemical staining such as hematoxylin and eosin staining. Proteomic analysis was used to screen for differences in liver cancer progression between antioxidant-treated HCC and models. Protein inhibitor recovery experiments in mice and in vitro cells validate the targets screened by proteomic analysis. The expression of GST-pi, p-JNK and p-p38 signaling molecules in HCC were investigated using Western blotting.

RES and NAC enhance HCC formation in both DEN/HFD and AKT/Ras mice. RES and NAC alleviate hepatosteatosis, and reduce ROS and DNA damage in mice. Proteomic analysis and protein inhibitor recovery assay demonstrated that GST-pi is a therapeutic target for antioxidant-induced hepatocellular carcinoma growth. Mechanistically, RES and NAC decreased p-JNK and p-p38, the two major mitogen-activated protein kinases, in HCC cells. Blockade of GST-pi abrogated the reduction in p-JNK and p-p38 levels and increased apoptosis of HCC cells.

Antioxidants may increase the incidence of HCC in a population with fatty liver, despite reduction in ROS production, by inhibiting GST-pi-MAPK axis.

The incidence of nonalcoholic steatohepatitis (NASH) is increasing annually, posing a significant threat to human health. NASH is typified by hepatic steatosis, inflammation, and hepatocellular injury, frequently culminating in fibrosis and cirrhosis. Yet, the precise pathogenesis of NASH remains to be fully elucidated. The hepatic sinusoid, which serves as the fundamental structural and functional unit of the liver, is intricately composed of endothelial cells, Kupffer cells, and hepatic stellate cells. Consequently, the homeostasis of the hepatic sinusoidal microenvironment may exert a pivotal influence on the progression and prognosis of NASH. However, the limitations of current NASH animal models have significantly impeded advancements in understanding the disease's pathogenesis and the development of effective therapeutic interventions. In light of these challenges, this review endeavors to delve deeper into the critical role of hepatic sinusoidal microenvironment homeostasis in the pathogenesis of NASH, critically analyze the commonly employed animal models, and comprehensively summarize the most recent and promising developments in drug research and development. It is anticipated that these efforts will collectively expedite the advancement of the field of NASH research and therapeutic innovation.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in the world, and its incidence and mortality have increased year by year. HCC research has increasingly focused on understanding its pathogenesis and developing treatments.The Wnt signaling pathway, a complex and evolutionarily conserved signal transduction system, has been extensively studied in the genesis and treatment of several malignant tumors. Recent investigations suggest that the pathogenesis of HCC may be significantly influenced by dysregulated Wnt/β-catenin signaling. This article aimed to examine the pathway that controls Wnt signaling in HCC and its mechanisms. In addition, we highlighted the role of this pathway in HCC etiology and targeted treatment.

Hepatocellular carcinoma (HCC) represents the third deadliest cancer worldwide with limited treatment options. Immune checkpoint inhibitors (ICIs) have revolutionized HCC therapy, but immune suppression within the tumor microenvironment remains a major challenge. Therefore, in this study, we aimed to define novel ICI molecules arising on T cells during aggressive HCC development.

Using autochthonous HCC models, we performed microarray analyses followed by in vivo RNA interference screen and identified several new ICI molecules on CD4 and CD8 T lymphocytes in HCC-bearing mice. Short hairpin RNA (shRNA)-mediated knockdown of the ICI molecules was performed to validate their functional role in T cell activity and survival of HCC-bearing mice. Finally, we searched for the presence of the defined ICI molecules in HCC patients.

We identified neutrophilic granule protein (Ngp), hemoglobin subunit alpha-1 (Hba-a1), and S100 calcium-binding protein a8 (S100a8) as novel inhibitory molecules of T cells in HCC. The specific shRNA-based knockdown of these inhibitory targets was safe, led to a downregulation of classical ICI molecules (PD-1, PD-L1, 4-1BBL, CD160), and kept liver parameters under control in murine HCC. Besides, we detected upregulation of S100A8 and S100A9 in blood and liver tissues in HCC patients, supporting their clinical relevance.

The obtained results pave the way for the use of the newly defined ICI molecules Ngp, Hba-a1, and S100a8 as novel immunotherapeutic targets in further preclinical and clinical studies in HCC patients.

The relationship between sodium intake and the incidence and mortality of non-alcoholic fatty liver disease (NAFLD) is underexplored in nutritional epidemiology, highlighting the need for further research.

This longitudinal cohort study analyzed data from 13,853 Participants aged 20 and older from the National Health and Nutrition Examination Survey (NHANES) (2003-2018), including 4,465 participants with NAFLD. We collected comprehensive data on mortality, dietary sodium intake, and relevant covariates. Logistic regression assessed the relationship between sodium consumption and NAFLD incidence, while Cox regression and smooth curve fitting explored sodium intake's link to all-cause mortality among Participants with NAFLD.

After adjusting for confounders, logistic regression revealed a positive association between higher sodium intake and NAFLD incidence (OR = 1.16, 95% CI = 1.11, 1.21). Adjusted odds ratios for the second (Q2), third (Q3), and fourth (Q4) quartiles of sodium intake were 0.91, 1.23, and 1.52, respectively. Smooth curve fitting and threshold analysis revealed a non-linear association between sodium intake and NAFLD risk, with an inflection point at 2.49 g/d, above which NAFLD risk significantly increased. In Cox regression, sodium intake was inversely correlated with all-cause mortality in Participants with NAFLD (HR = 0.87, 95% CI = 0.80, 0.96), with adjusted hazard ratios for Q2, Q3, and Q4 being 0.79, 0.66, and 0.63, respectively. A nonlinear model indicated a threshold effect, revealing a correlation between dietary sodium intake and mortality risk (p = 0.001). We identified a threshold intake of 3.5 grams per day (equivalent to 8.9 grams of sodium chloride): below this, each unit increase in sodium intake was associated with a 16% reduction in mortality risk (HR = 0.84, 95% CI = 0.80, 0.90). For intakes above this threshold, no significant relationship with mortality risk was observed (HR = 0.99, 95% CI = 0.90, 1.08).

This study suggests that higher sodium intake in individuals with NAFLD is associated with increased disease incidence but decreased all-cause mortality. The dose-response relationship between sodium intake and mortality risk exhibited a nonlinear pattern, with a critical inflection point around 3.5 grams per day.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule.

A growing number of steatotic grafts have been used in liver transplantation (LT), including hepatocellular carcinoma (HCC) patients. However, the impact of steatotic grafts on the prognosis of HCC recipients remains unclear. This study aims to evaluate the impact of steatotic graft in long-term prognosis for HCC recipients and development an algorithm for minimizing the risk of these grafts.

The clinicopathologic data of HCC patients undergoing LT from 2003 to 2022 in the United Network for Organ Sharing database was analyzed. The disease-free survival (DFS) and overall survival (OS) of recipients were compared between non-steatotic (macrosteatosis <30 %) and steatotic (macrosteatosis ≥30 %) graft groups after propensity score matching (PSM). Interaction analysis was conducted to identify factors that amplified the negative impact of steatotic grafts on DFS.

A total of 8345 eligible HCC patients were included. Three factors exhibited significant interaction effect with steatotic grafts: cold ischemia time ≥6h (HR = 1.447; P = 0.023), donor body mass index ≥40 (HR = 1.771; P = 0.018) and recipient with non-alcoholic fatty liver disease (HR = 1.632; P = 0.032). Hazard Associated with Macrosteatotic Liver (HAML) score was created based on these three factors. In HAML ≥1 cohort, the DFS and OS of steatotic graft group were significantly reduced compared to non-steatotic graft group. But in HAML = 0 cohort, no significant differences in DFS and OS were observed between the two groups.

The risk of steatotic grafts in LT for HCC could be minimized through evaluating HAML score.

Both Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and sarcopenia are associated with numerous chronic diseases, and the link between the two broad-spectrum phenotypes has been extensively researched. We focused on the relationship between the hepatic steatosis index (HSI) and hand grip strength (HGS). The Korean National Health and Nutrition Examination Surveys (2014-2019) were utilized to identify the association between estimated MASLD (eMASLD) and muscle strength. HSI determined eMASLD status, and HGS evaluated muscle strength. The HSI demonstrated a positive correlation with HGS. The alanine transaminase (ALT)/aspartate aminotransferase (AST) ratio and diabetes among the five components of HSI exhibited significant relationships with HGS in men and women. The robust linearity between HSI and HGS was observed in multivariate models and stratified analyses, particularly in older non-diabetic men with a higher body mass index (BMI) and young women without diabetes. However, younger men and older women exhibited nonlinear associations influenced by the ALT/AST ratio, BMI, and diabetes. After adjusting HGS with BMI, a significant negative association between HSI and muscle strength was observed, particularly in women. The disruption in linearity was influenced by the ALT/AST ratio, particularly in men with diabetes. Our findings highlight the complex interplay between HSI and HGS. The relationship between the two broad-range phenotypes was observed, and liver profiles influenced the linearity.

Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related deaths worldwide. We recently showed that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of HCC. Synthetic LXRα agonists induce the production of toxic saturated fatty acids in tumor cells. When combined with DFG-out Raf inhibitors, which block fatty acid desaturation by inducing proteasomal degradation of stearoyl-CoA desaturase (SCD1), LXRα activation can trigger lipotoxicity-induced cancer cell death. However, the clinical translation of this therapeutic strategy is limited by the lack of specific LXRα agonists for clinical use. Here, we have developed a series of promising maleimide LXR agonists with increased potency for LXRα and enhanced specificity. Our agonist frontrunner 40 shows high selectivity for LXRα and strong therapeutic efficacy in HCC organoids, therefore illustrating a strong potential for advancing this lipotoxic treatment strategy to clinical application.

Hepatocellular carcinoma (HCC) is the main phenotype of liver cancer with a poor prognosis. Copper is vital in liver function, and HCC cells rely on it for growth and metastasis, leading to cuproplasia. Excessive copper can induce cell death, termed cuproptosis. Tumor microenvironment (TME) is pivotal in HCC, especially in immunotherapy, and copper is closely related to the TME pathogenesis. However, how these two mechanisms contribute to the TME is intriguing.

We conducted the latest progress literature on cuproplasia and cuproptosis in HCC, and summarized their specific roles in TME and treatment strategies. The mechanisms of cuproplasia and cuproptosis and their relationship and role in TME have been deeply summarized. Cuproplasia fosters TME formation, angiogenesis, and metastasis, whereas cuproptosis may alleviate mitochondrial dysfunction and hypoxic conditions in the TME. Inhibiting cuproplasia and enhancing cuproptosis in HCC are essential for achieving therapeutic efficacy in HCC.

An in-depth analysis of cuproplasia and cuproptosis mechanisms within the TME of HCC unveils their opposing nature and their impact on copper regulation. Grasping the equilibrium between these two factors is crucial for a deeper understanding of HCC mechanisms to shed light on novel directions in treating HCC.

Liver stiffness (LS) predicts liver complication occurrence in patients with hepatitis C virus (HCV) infection after sustained virological response (SVR). The FibroScan-AST (FAST) score, which includes aspartate aminotransferase (AST) and controlled attenuation parameter (CAP; measured by FibroScan), may improve the prediction ability of isolated LS. Our aim was to compare the predictive capacity of LS vs FAST in this setting.

Multicenter cohort study including individuals with HIV/HCV coinfection or HCV monoinfection from Spain if they had (1) LS ≥9.5 kPa pretreatment, (2) SVR with a direct-acting antiviral (DAA)-based regimen, and (3) LS and CAP measurement at SVR. Fatty liver disease (FLD) was defined as CAP ≥248 dB/m. The primary outcome was the occurrence of a liver complication (decompensation or hepatocellular carcinoma [HCC]) after SVR.

Three hundred patients were included; 213 (71%) had HIV. At SVR, 131 (44%) had FLD. The FAST score was <0.35 in 182 (61%), 0.35-0.67 in 79 (27%), and >0.67 in 34 (12%) patients. After a median (Q1-Q3) follow-up of 73 (53-83) months, 36 (12%) liver complications (15 [5%] HCC) occurred. LS was independently associated with an increased risk of developing liver complications (sub-hazard ratio [sHR], 1.06; 95% CI, 1.04-1.08; P < .001). In a separate model, FAST ≥0.35 was also independently associated with greater risk of liver complications (sHR, 8.12; 95% CI, 3.11-21.17; P < .001). The area under the receiver operating characteristics curve of the model based on LS was 0.83 (95% CI, 0.76-0.91), and that of the model based on FAST was 0.80 (95% CI, 0.72-0.88; P = .158).

The FAST score predicts the development of liver events after SVR but does not improve the predictive capacity of LS alone at this time point.

Existing hepatocellular carcinoma (HCC) prediction models for the general population without traditional risk factors for chronic liver disease are limited. This study aimed to develop an HCC prediction model for individuals lacking these traditional risk factors.

The total of 138 452 adult participants without chronic viral hepatitis or significant alcohol intake who underwent regular health checkup at a tertiary hospital in South Korea were followed up for the development of HCC. Risk factors for HCC development were analyzed using Cox regression analysis, and prediction model was developed using the risk factors.

Significant predictors of HCC development included older age, male sex, higher body mass index, presence of diabetes mellitus, and levels of aspartate aminotransferase, total cholesterol, and platelet count. A new HCC prediction model using these variables was developed. Harrell's concordance index and Heagerty's integrated area under the receiver operating characteristics (AUROC) curve of the model were 0.88 (95% confidence interval [CI] 0.85-0.91) and 0.89 (95% CI 0.86-0.91), respectively. The 5- and 10-year AUROC were 0.89 (95% CI 0.88-0.89) and 0.87 (95% CI 0.87-0.88), respectively. This model significantly outperformed the FIB-4 scoring model in predicting HCC and effectively stratified individuals into low-, intermediate-, and high-risk groups with significantly different cumulative incidences of HCC.

The new model, based on clinical parameters, provides a valuable tool for clinicians to stratify HCC risk in the general population without risk factors for chronic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects > 25% of the global population, potentially leading to severe hepatic and extrahepatic complications, including metabolic dysfunction-associated steatohepatitis. Given that the pathophysiology of MASLD is incompletely understood, identifying therapeutic targets and optimizing treatment strategies are crucial for addressing this severe condition.

Mendelian randomization (MR) analysis was conducted using two genome-wide association study datasets: a European meta-analysis (8,434 cases; 770,180 controls) and an additional study (3,954 cases; 355,942 controls), identifying therapeutic targets for MASLD. Of 4302 drug-target genes, 2,664 genetic instrument variables were derived from cis-expression quantitative trait loci (cis-eQTLs). Colocalization analyses assessed shared causal variants between MASLD-associated single nucleotide polymorphisms and eQTLs. Using the drug target gene cis-eQTL of liver tissue from the genotype-tissue expression project, we performed MR and summary MR to validate the significance of the gene results of the blood eQTL MR. RNA-sequencing data from liver biopsies were validated using immunohistochemistry and quantitative polymerase chain reaction (qPCR) tests to confirm gene expression findings.

MR analysis across both datasets identified significant MR associations between MASLD and two drug targets-milk fat globule-EGF factor 8 (MFGE8) (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.85-0.94; P = 2.15 × 10-6) and cluster of differentiation 33 (CD33) (OR 1.17, 95% CI 1.10-1.25; P = 1.39 × 10-6). Both targets exhibited strong colocalization with MASLD. Genetic manipulation indicating MFGE8 activation and CD33 inhibition did not increase the risk for other metabolic disorders. RNA-sequencing, qPCR, and immunohistochemistry validation demonstrated consistent differential expressions of MFGE8 and CD33 in MASLD.

CD33 inhibition can reduce MASLD risk, while MFGE8 activation may offer therapeutic benefits for MASLD treatment.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a clinical-pathological syndrome primarily characterized by excessive accumulation of fat in hepatocytes, independent of alcohol consumption and other well-established hepatotoxic agents. Mitochondrial dysfunction is widely acknowledged as a pivotal factor in the pathogenesis of various diseases, including cardiovascular diseases, cancer, neurodegenerative disorders, and metabolic diseases such as obesity and obesity-associated MAFLD. Mitochondria are dynamic cellular organelles capable of modifying their functions and structures to accommodate the metabolic demands of cells. In the context of MAFLD, the excess production of reactive oxygen species induces oxidative stress, leading to mitochondrial dysfunction, which subsequently promotes metabolic disorders, fat accumulation, and the infiltration of inflammatory cells in liver and adipose tissue. This review aims to systematically analyze the role of mitochondria-targeted therapies in MAFLD, evaluate current therapeutic strategies, and explore future directions in this rapidly evolving field. We specifically focus on the molecular mechanisms underlying mitochondrial dysfunction, emerging therapeutic approaches, and their clinical implications. This is of significant importance for the development of new therapeutic approaches for these metabolic disorders.

This study aimed to evaluate the effects of antihypertensives, lipid-lowering agents, and antiplatelet medications on hepatocellular carcinoma (HCC) risk in patients with fatty liver disease (FLD) and type 2 diabetes (T2D).

Using data from Korea Health Insurance Review and Assessment Service, 212,443 FLD-T2D patients were analyzed through Cox regression, propensity score matching (PSM), and Kaplan-Meier analysis. The analysis considered medication use and its relation to HCC development. Cohort admission day was set as the date of the first oral hypoglycemic prescription.

The multivariate Cox regression analysis revealed that old age, male sex, chronic viral hepatitis, alcoholic liver disease, liver cirrhosis, using a combination of insulin and oral hypoglycemic agents for antidiabetic treatment, and calcium channel blocker (CCB) use were significantly correlated with higher HCC development risk, whereas dyslipidemia and statin, ezetimibe, and fibrate use was correlated with lower HCC risk, in the study cohort of 212,443 patients. Patients who used statins (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.42-0.80, P = 0.001) and fibrates (HR = 0.46, 95% CI = 0.22-0.93, P = 0.031) showed a significantly lower risk of HCC development even after PSM. In contrast, CCB use was linked to an elevated HCC risk (HR = 1.35, 95% CI = 1.05-1.72, P = 0.019), highlighting the differential impact of various medications on HCC incidence.

The use of specific medications, such as statins and fibrates, may offer protective effects against HCC in patients with FLD-T2D, whereas that of CCB may increase the risk. This underscores the importance of tailored medication strategies for the management of chronic conditions.

Adipose tissue and the liver are known to regulate lipid metabolism through the storage, synthesis, and breakdown of lipids. However, the shared molecular factors affecting lipid metabolism in both tissues remain unclear. Plant Homeodomain Finger 2 (PHF2), one of the histone lysine demethylase7 family, serves as an epigenetic regulator in adipose tissue and E3 ubiquitin ligase in liver cancer. This study uses bioinformatics to analyze the role of PHF2 in lipid metabolism, focusing on its functions in adipose tissue and the liver. We utilized cDNA-chip microarrays, public clinical data, and in vitro three-dimensional cell culture models, validating our bioinformatics findings. Consequently, our analyses showed that PHF2 is positively involved in histone demethylase activity and adipogenesis in patients with obesity and moderate liver disease. However, PHF2 suppressed de novo lipogenesis and tumor progression in patients with liver cancer, enhancing immune cell infiltration in liver cancer. Furthermore, it was experimentally confirmed that PHF2 increases lipid accumulation in adipocytes but acts as a tumor suppressor in liver cancer cells. Overall, this study provides a comprehensive overview of PHF2, highlighting its biological importance.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with limited treatment options. This review explores the role of post-translational modifications (PTMs) in MASLD pathogenesis, highlighting their potential as therapeutic targets. We discuss the impact of PTMs, including their phosphorylation, ubiquitylation, acetylation, and glycosylation, on key proteins involved in MASLD, drawing on studies that use both human subjects and animal models. These modifications influence various cellular processes, such as lipid metabolism, inflammation, and fibrosis, contributing to disease progression. Understanding the intricate PTM network in MASLD offers the potential for developing novel therapeutic strategies that target specific PTMs to modulate protein function and alleviate disease pathology. Further research is needed to fully elucidate the complexity of PTMs in MASLD and translate these findings into effective clinical applications.

Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.

Metabolic dysfunction-associated steatotic liver disease (MASLD) can be interpreted as the hepatic expression of metabolic syndrome, which is estimated to affect 30% of the adult population. Obesity, dyslipidaemia, arterial hypertension, and T2DM are considered significant risk factors of MASLD. The relationship is two-way with MASLD found in up to 75% of patients with T2DM. Importantly, MASLD is associated with increased risk of cardiovascular diseases (CVD) such as arrhythmia, atherosclerotic heart disease, heart failure, and CVD-associated mortality. In addition, MASLD patients present with a high prevalence of major adverse cardiac events, which calls for systematic surveillance of CVD in MASLD. This review focuses on the pathophysiology behind development of CVD in MASLD, the types of cardiovascular complications, morbidity and survival, and suggestions for evaluation of patients with MASLD.

Liver cancer is a significant global health issue, with its incidence rising in parallel with the obesity epidemic. The limited therapeutic options available emphasize the need for a better understanding of the molecular pathways involved in its pathogenesis. While much of the previous research has focused on transcriptional changes, this study examines translational alterations, specifically the role of cytoplasmic polyadenylation element binding protein 4 (CPEB4), a key regulator of translation.

We analyzed publicly available patient databases and conducted studies using human and mouse liver cancer cells, xenograft and allograft models, mouse models of high-fat diet-related liver cancer, and CPEB4 knockout and knockdown mice and cell lines.

Patient data analysis (n = 87) showed a strong correlation between low CPEB4 levels and reduced survival rates (p <0.001). In mouse models of diet-induced liver cancer (n = 10-15 per group), both systemic and hepatocyte-specific CPEB4 knockout mice exhibited significantly increased tumor burden compared with wild-type controls (p <0.05). In vitro studies using human and murine liver cancer cells (n = 3 biological replicates) demonstrated reduced sensitivity to ferroptosis upon CPEB4 depletion when induced by erastin or RSL3 (p <0.01). Mechanistically, CPEB4 deficiency suppressed hepcidin expression, leading to elevated ferroportin levels, decreased intracellular iron accumulation, and reduced lipid peroxidation (p <0.05).

This study uncovers a novel CPEB4-dependent mechanism linking translational control to liver cancer progression and ferroptosis regulation. Therapeutic strategies targeting CPEB4-mediated pathways hold promise for advancing treatment options in liver cancer.

This study addresses the pressing need for improved therapies in liver cancer, particularly given its increasing prevalence linked to obesity and metabolic-associated fatty liver disease. By uncovering the role of the RNA-binding protein cytoplasmic polyadenylation element binding protein 4 (CPEB4) in modulating iron regulation and cancer cell sensitivity to ferroptosis, our research highlights a new translational mechanism with potential therapeutic relevance. These findings are particularly significant for clinicians, researchers, and policymakers focused on advancing targeted treatments for hepatocellular carcinoma. If further validated in human clinical studies, targeting CPEB4-mediated pathways could help develop treatments that enhance cancer cell susceptibility to ferroptosis, offering a promising strategy for improving outcomes in patients with advanced liver cancer. Limitations of the study include the need for further clinical validation to confirm these preclinical findings in human disease contexts.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

Metabolic dysfunction-associated steatotic liver (MASLD) progression is driven by chronic inflammation and fibrosis, largely influenced by Kupffer cell (KC) dynamics, particularly replenishment of pro-inflammatory monocyte-derived KCs (MoKCs) due to increased death of embryo-derived KCs. Adenosine A3 receptor (A3AR) plays a key role in regulating metabolism and immune responses, making it a promising therapeutic target. This study aimed to investigate the impact of selective A3AR antagonism for regulation of replenished MoKCs, thereby improving MASLD.

A3AR expression was significantly elevated in KCs from both patients with MASLD and fast-food diet (FFD)-fed mice. A3AR knockout (KO) mice displayed marked improvements in hepatic inflammation and fibrosis along with a reduction in CLEC4F-positive KCs. The spatial transcriptomics of these KCs revealed disrupted mitochondrial integrity, increased oxidative stress, and enhanced cell death due to A3AR deletion. Similarly, in vivo FM101 treatment, a highly potent and selective antagonist of A3AR with a truncated 4'-thioadenosine structure, mitigated FFD-induced MASLD in mice. Mechanistically, FM101 induces β-arrestin2-mediated A3AR degradation, leading to mitochondrial dysfunction-mediated necroptosis in KCs. Consistently, A3AR was highly expressed in monocyte-derived macrophages in MASLD patients, with strong correlations with macrophage activation and monocyte chemoattractant gene sets. Thus, FM101 induced necroptosis in pro-inflammatory MoKCs, facilitating anti-inflammatory effects.

This study demonstrated that inhibiting A3AR via FM101 or genetic deletion alleviates MASLD by inducing mitochondrial dysfunction and subsequent necroptosis in MoKCs, establishing FM101 as a promising therapeutic strategy for MASLD.