Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.

Metabolic dysfunction-associated steatohepatitis (MASH) is a growing cause of hepatocellular carcinoma (HCC) worldwide. The complex microenvironment of these tumors, characterized by metabolic dysfunction, hypoxia, steatosis, and fibrosis, limits the effectiveness of standard-of-care therapies, such as the multi-tyrosine kinase inhibitor lenvatinib (LEN). Salsalate (SAL), is a rheumatoid arthritis therapy that enhances fatty acid oxidation and reduces de novo lipogenesis, fibrosis and cell proliferation pathways. We hypothesize that addition of SAL could improve the efficacy of LEN in MASH-HCC.

We assessed the efficacy of combination therapy using clinically relevant concentrations of LEN and SAL in human HCC cell models, orthotopic xenograft and MASH-HCC mouse models. In addition, assays assessing fatty acid oxidation and lipogenesis, protein immunoblotting and RNA-sequencing were used to understand mechanisms involved.

LEN + SAL synergistically suppressed the proliferation and clonogenic survival of cells (p ≤0.0001), prolonged survival in an orthotopic xenograft model (p = 0.02), and reduced angiogenesis, fibrosis, and steatosis (p ≤0.05) in a MASH-HCC model. These effects were associated with activation of AMPK and inhibition of the mTOR-HIF1α and Erk1/2 signaling pathways. RNA-sequencing analysis in both Hep3B cells and livers of the MASH-HCC mouse model revealed that SAL enhanced fatty acid oxidation and suppressed fibrosis and cell cycle progression, while LEN reduced angiogenesis with regulatory network analysis, suggesting a potential role for activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS-1).

These data indicate that combining LEN and SAL, which exert distinct effects leading to improvements in the liver microenvironment (steatosis, angiogenesis, and fibrosis) and inhibition of tumor proliferation, may have therapeutic potential for MASH-driven HCC.

Although rates of MASH-HCC are on the rise globally, standard-of-care multi-tyrosine kinase inhibitors and immunotherapy have limited efficacy in this HCC etiology. Metabolic targeting with SAL inhibits cancer growth kinetics while also alleviating drivers of MASH by increasing fatty acid oxidation and reducing de novo lipogenesis and fibrosis. Combined LEN and SAL improved survival and MASH-HCC pathology in mouse models without adverse effects. Given that SAL is a safe, economical, and approved medication, this concept holds great translational potential that could provide a new treatment avenue for patients with unresected MASH-HCC.

Because the liver plays a vital role in the clearance of exogenous chemical compounds, it is susceptible to chemical-induced toxicity. Animal-based testing is routinely used to assess the hepatotoxic potential of chemicals. Although large-scale high-throughput sequencing data can indicate the genes affected by chemical exposures, we need system-level approaches to interpret these changes. To this end, we developed an updated rat genome-scale metabolic model to integrate large-scale transcriptomics data and utilized a chemical structure similarity-based ToxProfiler tool to identify chemicals that bind to specific toxicity targets to understand the mechanisms of toxicity. We used high-throughput transcriptomics data from a 5-day in vivo study where rats were exposed to different non-toxic and hepatotoxic chemicals at increasing concentrations and investigated how liver metabolism was differentially altered between the non-toxic and hepatotoxic chemical exposures. Our analysis indicated that the genes identified via toxicity target analysis and those mapped to the metabolic model showed a distinct gene expression pattern, with the majority showing upregulation for hepatotoxicants compared with non-toxic chemicals. Similarly, when we mapped the metabolic genes at the pathway level, we identified several pathways in carbohydrate, amino acid, and lipid metabolism that were significantly upregulated for hepatotoxic chemicals. Furthermore, using our system-level integration of gene expression data with the rat metabolic model, we could differentiate metabolites in these pathways that were systematically elevated or suppressed due to hepatotoxic versus non-toxic chemicals. Thus, using our combined approach, we were able to identify a set of potential gene signatures that clearly differentiated liver toxic responses from non-toxic chemicals, which helped us identify potential metabolic pathways and metabolites that are systematically associated with the toxicant exposure.

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.

Current guidelines recommend contrast-enhanced CT/MRI as confirmatory imaging tests for diagnosing hepatocellular carcinoma (HCC). However, these modalities are not always able to differentiate HCC from benign/dysplastic nodules that are commonly observed in cirrhotic livers. Consequently, many lesions require either pathological confirmation via invasive biopsy or surveillance imaging after 3-6 months, which results in delayed diagnosis and treatment. We aimed to develop noninvasive imaging biomarkers of liver cell size and cellularity, using magnetic resonance imaging (MRI), and to assess their utility in identifying HCC.

MR cytometry combines measurements of water diffusion rates over different times corresponding to probing cellular microstructure at different spatial scales. Maps of microstructural properties, such as cell size and cellularity, are derived by fitting voxel values in multiple diffusion-weighted images to a three-compartment (blood, intra-, and extracellular water) model of the MRI signal. This method was validated in two phases: (1) histology-driven simulations, utilizing segmented histological images of different liver pathologies, and (2) ex vivo MR cytometry performed on fixed human liver specimens.

Both simulations and ex vivo MR cytometry of fixed human liver specimens demonstrated that HCC exhibits significantly smaller cell sizes and higher cellularities compared to normal liver and cirrhotic regenerative nodules.

This study highlights the potential of MR cytometry to differentiate HCC from non-HCC lesions by quantifying cell size and cellularity in liver tissues. Our findings provide a strong foundation for further research into the role of MR cytometry in the noninvasive early diagnosis of HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by metabolic dysfunction and inflammation burden, involving a significant enhancement of cellular glycolytic activity. Here, we elucidate how a positive feedback loop in liver macrophages drives MASLD pathogenesis and demonstrate that disrupting this cycle mitigates metabolic stress and macrophage M1 activation during MASLD. We detect elevated expression of hexokinase 2 (HK2) and H3K18la in liver macrophages from patients with MASLD and MASLD mice. This lactate-dependent histone lactylation promotes glycolysis and liver macrophage M1 polarization by enriching the promoters of glycolytic genes and activating transcription. Ultimately, the HK2/glycolysis/H3K18la positive feedback loop exacerbates the vicious cycle of enhancing metabolic dysregulation and histone lactylation and the inflammatory phenotype of liver macrophages. Myeloid-specific deletion of Hk2 or pharmacological inhibition of the transcription factor HIF-1α significantly disrupts this deleterious cycle. Therefore, our study illustrates that targeting this amplified pathogenic loop may offer a promising therapeutic strategy for MASLD.

Metabolic liver disease is the fastest-rising cause of hepatocellular carcinoma (HCC), but the underlying molecular processes that drive HCC development in the setting of metabolic perturbations are unclear. We investigated the role of aberrant DNA methylation in metabolic HCC development in a multicenter international study.

We used a case-control design, frequency-matched on age, sex, and study site. Genome-wide profiling of peripheral blood leukocyte DNA was performed using the 850k EPIC array. The study sample was split 80% and 20% for training and validation. Cell type proportions were estimated from the methylation data. Differential methylation analysis was performed adjusting for cell type, generating area under the receiver-operating characteristic curves (AUC-ROC).

We enrolled 272 metabolic HCC patients and 316 control patients with metabolic liver disease from 6 sites. Fifty-five differentially methylated CpGs were identified; 33 hypermethylated and 22 hypomethylated in cases vs controls. The panel of 55 CpGs discriminated between the cases and controls with AUC = 0.79 (95% confidence interval [CI] = 0.71-0.87), sensitivity = 0.77 (95% CI = 0.66-0.89), and specificity = 0.74 (95% CI = 0.64-0.85). The 55-CpG classifier panel performed better than a base model that comprised age, sex, race, and diabetes mellitus (AUC = 0.65, 95% CI = 0.55-0.75; sensitivity = 0.62, 95% CI = 0.49-0.75; and specificity = 0.64, 95% CI = 0.52-0.75). A multifactorial model that combined the 55 CpGs with age, sex, race, and diabetes yielded AUC = 0.78 (95% CI = 0.70-0.86), sensitivity = 0.81 (95% CI = 0.71-0.92), and specificity = 0.67 (95% CI = 0.55-0.78).

A panel of 55 blood leukocyte DNA methylation markers differentiates patients with metabolic HCC from control patients with benign metabolic liver disease, with a slightly higher sensitivity when combined with demographic and clinical information.

Liver fibrosis predisposes patients to liver failure and hepatocellular carcinoma. Various markers, which can be calculated easily from serum parameters, have been reported to predict liver fibrosis accurately. This study investigated the prognostic factors, including blood-based markers for liver fibrosis of patients with hepatocellular carcinoma following initial curative hepatectomy.

This retrospective study included 407 patients with hepatocellular carcinoma who underwent initial curative hepatectomy between April 2010 and December 2017. We investigated prognosis-associated variables in these patients.

Among the blood-based markers for liver fibrosis examined in this study, the steatosis-associated fibrosis estimator score demonstrated the best predictive capabilities. This score was revealed as a poor prognostic factor for both overall survival and recurrence-free survival in patients with hepatocellular carcinoma following initial curative hepatectomy. A high steatosis-associated fibrosis estimator score was independently associated with poor overall survival and recurrence-free survival. After propensity score-matching to minimize bias between high- and low-steatosis-associated fibrosis estimator score groups, the high steatosis-associated fibrosis estimator score remained associated with poor overall survival and recurrence-free survival.

The steatosis-associated fibrosis estimator score is an independent predictor of long-term prognosis in patients with hepatocellular carcinoma following initial curative hepatectomy.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most prevalent liver disease worldwide. It is associated with an increased risk of developing hepatocellular carcinoma (HCC) in the background of cirrhosis or without cirrhosis. The prevalence of NAFLD-related HCC is increasing all over the globe, and HCC surveillance in NAFLD cases is not that common. In the present review, we attempt to summarize promising treatments and clinical trials focused on NAFLD, nonalcoholic steatohepatitis (NASH), and HCC in the past five to seven years. We categorized the trials based on the type of intervention. Most of the trials are still running, with only a few completed and with conclusive results. In clinical trial NCT03942822, 25 mg/day of milled chia seeds improved NAFLD condition. Completed trial NCT03524365 concluded that Rouxen-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) results in histological resolution of NASH without worsening of fibrosis, while NCT04677101 validated sensitivity/accuracy of blood biomarkers in predicting NASH and fibrosis stage. Moreover, trials with empagliflozin (NCT05694923), curcuvail (NCT06256926), and obeticholic acid (NCT03439254) were completed but did not provide conclusive results. However, trial NCT03900429 reported effective improvement in fibrosis by at least one stage, without worsening of NAFLD activity score (NAS), as well as improvement in lipid profile of the NASH patients by 80 or 100 mg MGL-3196 (resmetirom). Funded by Madrigal Pharmaceuticals, Rezdiffra (resmetirom), used in the clinical trial NCT03900429, is the first FDA-approved drug for the treatment of NAFLD/NASH.

Integrating biomarkers into a comprehensive strategy is crucial for precise patient management, especially considering the significant healthcare costs associated with diseases. Current studies emphasize the urgent need for a paradigm shift in conceptualizing nonalcoholic fatty liver disease (NAFLD), now renamed metabolic dysfunction-associated steatotic liver disease (MASLD). Biomarkers are emerging as indispensable tools for accurate diagnosis, risk stratification, and monitoring disease progression. This review classifies biomarkers into conventional and novel categories, such as lipids, insulin resistance, hepatic function, and cutting-edge imaging/omics, and evaluates their potential to transform the approach to MASLD among individuals with type 2 diabetes mellitus (T2D). It focuses on the critical role of biomarkers in early MASLD detection, enhancing predictive accuracy, and discerning responses to interventions (pharmacological or lifestyle modifications). Amid this discussion, the complexities of the relationship between T2D and MASLD are explored, considering factors like age, gender, genetics, ethnicity, and socioeconomic background. Biomarkers enhance the effectiveness of interventions and support global initiatives to reduce the burden of MASLD, thereby improving public health outcomes. This review recognizes the promising potential of biomarkers for diagnostic precision while candidly addressing the challenges in implementing these advancements in clinical practice. The transformative role of biomarkers emerges as a central theme, promising to reshape our understanding of disease trajectories, prognosis, and the customization of personalized therapeutic strategies for improved patient outcomes. From a future perspective, identifying early-stage biomarkers, understanding environmental impact through exposomes, and applying a multiomics approach may reveal additional insight into MASLD development.

Metabolic liver disease is the fastest rising cause of hepatocellular carcinoma (HCC) worldwide, but the underlying molecular processes that drive HCC development in the setting of metabolic perturbations are unclear. We investigated the role of aberrant DNA methylation in metabolic HCC development in a multicenter international study.

We used a case-control design, frequency-matched on age, sex, and study site. Genome-wide profiling of peripheral blood leukocyte DNA was performed using the 850k EPIC array. Cell type proportions were estimated from the methylation data. The study samples were split 80% and 20% for training and validation. Differential methylation analysis was performed with adjustment for cell type, and we generated area under the receiver-operating curves (ROC-AUC).

We enrolled 272 metabolic HCC patients and 316 control patients with metabolic liver disease from six sites. Fifty-five differentially methylated CpGs were identified; 33 hypermethylated and 22 hypomethylated in cases versus controls. The panel of 55 CpGs discriminated between cases and controls with AUC=0.79 (95%CI=0.71-0.87), sensitivity=0.77 (95%CI=0.66-0.89), and specificity=0.74 (95%CI=0.64-0.85). The 55-CpG classifier panel performed better than a base model that comprised age, sex, race, and diabetes mellitus (AUC=0.65, 95%CI=0.55-0.75, sensitivity=0.62 (95%CI=0.49-0.75) and specificity=0.64 (95%CI=0.52-0.75). A multifactorial model that combined the 55 CpGs with age, sex, race, and diabetes, yielded AUC=0.78 (95%CI=0.70-0.86), sensitivity=0.81 (95%CI=0.71-0.92), and specificity=0.67 (95%CI=0.55-0.78).

A panel of 55 blood leukocyte DNA methylation markers differentiates patients with metabolic HCC from control patients with benign metabolic liver disease, with a slightly higher sensitivity when combined with demographic and clinical information.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a growing health concern worldwide, affecting more than 1 billion adults. It may progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and ultimately hepatocellular carcinoma (HCC). Emerging evidence has demonstrated the role in this transition of microRNAs (miRNAs), which regulate the expression of genes associated with lipid metabolism, inflammation, fibrosis, and cell proliferation. Specific miRNAs have been identified to exacerbate or mitigate fibrotic and carcinogenic processes in hepatic cells. The modulation of these miRNAs through synthetic mimics or inhibitors represents a promising therapeutic strategy. Preclinical models have demonstrated that miRNA-based therapies can attenuate liver inflammation, reduce fibrosis, and inhibit tumorigenesis, thus delaying or preventing the onset of HCC. However, challenges such as delivery mechanisms, off-target effects, and long-term safety remain to be addressed. This review, focusing on recently published preclinical and clinical studies, explores the pharmacological potential of miRNA-based interventions to prevent MASLD/MASH and progression toward HCC.

Metformin is known for its antioxidant properties and ability to ameliorate metabolic dysfunction-associated fatty liver disease (MAFLD) and is the focus of this study. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is linked to MAFLD risk. This study investigated the effects of metformin on ferroptosis in free fatty acid (FFA)-treated Huh7 hepatoma cells and its association with MAFLD risk. Using Western blot, immunofluorescence, and ELISA, this study revealed that FFA treatment led to increased intracellular fat and iron accumulation, heightened Lp-PLA2 expression, reduced levels of the cysteine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), altered glutathione (GSH)/oxidized glutathione (GSSG) ratios, generation of reactive oxygen species (ROS), and initiation of lipid peroxidation, which ultimately resulted in cell ferroptosis. Importantly, metformin reversed FFA-induced iron accumulation, and this effect was attenuated by ferrostatin-1 but enhanced by erastin, RSL3, and si-GPX4. Additionally, metformin activated antioxidant and antiapoptotic mechanisms, which reduced lipid peroxidation and suppressed Lp-PLA2 expression in FFA-treated Huh7 cells. In conclusion, our findings indicate that metformin may protect against MAFLD by inhibiting iron accumulation and Lp-PLA2 expression through the ROS, ferroptosis, and apoptosis signaling pathways. This study highlights potential therapeutic strategies for managing MAFLD-related risks and emphasizes the diverse roles of metformin in maintaining hepatocyte balance.

Cancer represents a major global public health burden, with new cases estimated to increase from 14 million in 2012 to 24 million by 2035. Primary prevention is an effective strategy to reduce the costs associated with cancer burden. For example, measures to ban tobacco consumption have dramatically decreased lung cancer incidence and vaccination against human papillomavirus can prevent cervical cancer development. Unfortunately, the etiological factors of many cancer types are not completely clear or are difficult to actively control; therefore, the primary prevention of such cancers is not practical. In this review, we update the progress on precision therapy by targeting the whole carcinogenesis process, especially for three high-risk groups: (1) those with chronic inflammation, (2) those with inherited germline mutations, and (3) those with precancerous lesions like polyps, gastritis, actinic keratosis or dysplasia. We believe that attenuating chronic inflammation, treating precancerous lesions, and removing high-risk tissues harboring germline mutations are precision methods for cancer prevention.

Type 2 diabetes mellitus (DM) is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). With the increasing prevalence of type 2 DM and MASLD due to lifestyle changes, understanding their impact on liver health is crucial. However, the hepatocellular damage caused by glucose alone is unknown. This study investigates the effect of excess glucose on hepatocytes, focusing on oxidative stress, endoplasmic reticulum stress (ER stress), apoptosis, autophagy, and cell proliferation. We treated an immortalized-human hepatocyte cell line with excess glucose and analyzed. Excess glucose induced oxidative stress and ER stress in a time- and concentration-dependent manner, leading to apoptosis. Oxidative stress and ER stress were independently induced by excess glucose. Proteasome inhibitors and palmitic acid exacerbated glucose-induced stress, leading to the formation of Mallory-Denk body-like inclusion bodies. Despite these stresses, autophagic flux was not altered. Excess glucose also caused DNA damage but did not affect cell proliferation. This suggests that glucose itself can contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH) and carcinogenesis of HCC in patients with type 2 DM. Managing blood glucose levels is crucial to prevent hepatocyte damage and associated complications.

Nonalcoholic steatohepatitis (NASH) has been an increasingly significant contributor to hepatocellular carcinoma (HCC). Understanding the progression from NASH to HCC is critical to early diagnosis and elucidating the underlying mechanisms.

5 significant prognostic genes related to NASH-HCC transformation were identified through algorithm selection, which were ME1, TP53I3, SOCS2, GADD45G and CYP7A1. A diagnostic model for NASH prediction was established (AUC=0.988). TP53I3 and SOCS2 were selected as potential critical genes in the progression of NASH-HCC by external dataset validation and in vitro experiments on NASH and HCC cell lines. Immune infiltration analysis illustrated the correlation between 5 significant prognostic genes and immune cells. Single-cell analysis identified hepatocytes related to NASH-HCC transformation markers, revealing their promoting role in the transformation from NASH to HCC.

With bulk-seq analysis and single-cell analysis, 5 significant prognostic genes related to NASH-HCC transformation were identified and validated at both dataset and in vitro experiment level. Among them, TP53I3 and SOCS2 might be potential critical genes in NASH-HCC progression. Single-cell analysis identified and revealed the critical role that NASH-HCC related hepatocytes play in NASH-HCC tansformation. Our research may introduce a new perspective to the diagnosis, treatment of NASH-related HCC.

Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression.

We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo.

Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice.

KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.

Despite superior outcomes with liver transplantation, cirrhotic patients with HCC may turn to other forms of definitive treatment. To understand perioperative outcomes, we examined perioperative mortality and major morbidity after hepatectomy for HCC among cirrhotic and non-cirrhotic patients.

ology: The American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database was queried for liver resection for HCC. Multivariable logistic regression was performed to determine the association between liver texture and risk of major non-infectious morbidity, post-hepatectomy liver failure (PHLF) and 30-day mortality.

From 2014 to 2018, 2203 patients underwent hepatectomy: 58.6 % cirrhotic, 12.8 % fatty and 28.6 % normal texture. Overall 30 day-mortality was 2.1 % (n = 46), although higher among fatty liver (2.8 %) and cirrhotic (2.6 %; p = 0.025) patients. The incidence of PHLF was 6.9 %, with hepatectomy type, cirrhosis, and platelet count as major risk factors. Age, resection type, and platelet count were associated with major complications. Trisegmentectomy and right hepatectomy (OR = 3.60, OR = 3.46, respectively) conferred a greater risk of major noninfectious morbidity compared to partial hepatectomy. Among cirrhotics alone, hepatectomy type, platelet count, preoperative sepsis and ASA class were associated with major morbidity.

Hepatic parenchymal disease/texture and function, presence of portal hypertension, and the extent of the liver resection are critical determinants of perioperative risk among HCC patients.

Cancer stem cells (CSCs) are a type of stem cell that possesses not only the intrinsic abilities of stem cells but also the properties of cancer cells. Therefore, CSCs are known to have self-renewal and outstanding proliferation capacity, along with the potential to differentiate into specific types of tumor cells. Cancers typically originate from CSCs, making them a significant target for tumor treatment. Among the related cascades of the CSCs, mammalian target of rapamycin (mTOR) pathway is regarded as one of the most important signaling pathways because of its association with significant upstream signaling: phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) pathway and mitogen‑activated protein kinase (MAPK) cascade, which influence various activities of stem cells, including CSCs. Recent studies have shown that the mTOR pathway not only affects generation of CSCs but also the maintenance of their pluripotency. Furthermore, the maintenance of pluripotency or differentiation into specific types of cancer cells depends on the regulation of the mTOR signal in CSCs. Consequently, the clinical potential and importance of mTOR in effective cancer therapy are increasing. In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug development aimed at overcoming existing drawbacks, such as drug resistance, by targeting CSCs through mTOR inhibition.

Young Korean men are obligated to serve in the military for 18 to 21 months. We investigated the effects of military service on steatotic liver disease (SLD) and other metabolic parameters.

Pre-enlistment health check-up performed from 2019 to 2022 and in-service health check-up performed from 2020 to 2022 were merged as paired data. SLD was defined as a hepatic steatosis index of 36 or higher. Hypertension (HTN) and hypertriglyceridemia were also included in the analysis.

A total of 503,136 paired cases were included in the analysis. Comparing pre-enlistment and in-service health check-ups, the prevalence of SLD (22.2% vs 17.6%, p<0.001), HTN (7.6% vs 4.3%, p<0.001), and hypertriglyceridemia (8.1% vs 2.9%, p<0.001) decreased during military service. In terms of body mass index, the proportion of underweight (8.2% vs 1.4%, p<0.001) and severely obese (6.1% vs 4.9%, p<0.001) individuals decreased over time. Regarding factors associated with SLD development and resolution, age was positively associated with SLD development (odds ratio, 1.146; p<0.001) and a health check-up interval of <450 days was a protective factor for SLD development (odds ratio, 0.746; p<0.001). Those serving in the marines were less likely to develop SLD, whereas those serving in the navy were more likely to develop SLD. Serving in the army or the navy was negatively associated with SLD resolution, whereas serving in the air force was positively associated with SLD resolution.

The prevalence of SLD, HTN, and hypertriglyceridemia decreased substantially during Korean military service.

Background: The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. Methods: rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. Results: Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., p = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., p = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (β = 0.10, -0.003 to 0.12 95% C.I., p = 0.04) on diabetes, but only in TT genotypes. Conclusions: The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD.

Lipolysis is the hydrolysis of triglycerides (TGs), commonly known as fats. Intracellular lipolysis of TG is associated with adipose triglyceride lipase (ATGL), which provides fatty acids during times of metabolic need. The aim of this study was to determine whether Coix lacryma-jobi L. var. ma-yuen Stapf (Coix) sprouts (CS) can alleviate obesity through lipolysis. Overall, we investigated the potential of CS under in vitro and in vivo conditions and confirmed the underlying mechanisms. Huh7 cells were exposed to free fatty acids (FFAs), and C57BL/6J mice were fed a 60% high-fat diet. When FFA were introduced into Huh7 cells, the intracellular TG levels increased within the Huh7 cells. However, CS treatment significantly reduced intracellular TG levels. Furthermore, CS decreased the expression of Pparγ and Srebp1c mRNA and downregulated the mutant Pnpla3 (I148M) mRNA. Notably, CS significantly upregulated ATGL expression. CS treatment at a dose of 200 mg/kg/day resulted in a significant and dose-dependent decrease in body weight gain and epididymal adipose tissue weight. Specifically, the group treated with CS (200 mg/kg/day) exhibited a significant modulation of serum lipid biomarkers. In addition, CS ameliorated histological alterations in both the liver and adipose tissues. In summary, CS efficiently inhibited lipid accumulation through the activation of the lipolytic enzyme ATGL coupled with the suppression of enzymes involved in TG synthesis. Consequently, CS show promise as a potential anti-obesity agent.

Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems.

Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group.

ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases.

Intravoxel incoherent motion (IVIM) modeling is a widely used double-exponential model for describing diffusion-weighted imaging (DWI) signal, with a slow component related to pure molecular diffusion and a fast component associated with microcirculatory perfusion, which compensates for the limitations of traditional DWI. IVIM is a noninvasive technique for obtaining liver pathological information and characterizing liver lesions, and has potential applications in the initial diagnosis and treatment monitoring of liver diseases. Recent studies have demonstrated that IVIM-derived parameters are useful for evaluating liver lesions, including nonalcoholic fatty liver disease (NAFLD), liver fibrosis and liver tumors. However, the results are not stable. Therefore, it is necessary to summarize the current applications of IVIM in liver disease research, identify existing shortcomings, and point out the future development direction. In this review, we searched for studies related to hepatic IVIM-DWI applications over the past two decades in the PubMed database. We first introduce the fundamental principles and influential factors of IVIM, and then discuss its application in NAFLD, liver fibrosis, and focal hepatic lesions. It has been found that IVIM is still unstable in ensuring the robustness and reproducibility of measurements in the assessment of liver fibrosis grade and liver tumors differentiation, due to inconsistent and substantial overlap in the range of IVIM-derived parameters for different fibrotic stages. In the end, the future direction of IVIM-DWI in the assessment of liver diseases is discussed, emphasizing the need for further research on the stability of IVIM-derived parameters, particularly perfusion-related parameters, in order to promote the clinical practice of IVIM-DWI. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition, characterized by a spectrum that progresses from simple hepatic steatosis to nonalcoholic steatohepatitis, which may eventually lead to cirrhosis and hepatocellular carcinoma. The precise pathogenic mechanisms underlying NAFLD and its related metabolic disturbances remain elusive. Epigenetic modifications, which entail stable transcriptional changes without altering the DNA sequence, are increasingly recognized as pivotal. The principal forms of epigenetic modifications include DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. These alterations participate in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial injury, oxidative stress response, and release of inflammatory cytokines, all of which are associated with the onset and progression of NAFLD. This review discussed recent advances in understanding the potential epigenetic regulation of inflammation in NAFLD. Unraveling these epigenetic mechanisms may facilitate the identification of early diagnostic biomarkers and the development of targeted therapeutic strategies for NAFLD.

With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) as a significant etiology for hepatocellular carcinoma (HCC), lean NAFLD-HCC has emerged as a specific distinct subtype. This study sought to investigate long-term outcomes following curative-intent hepatectomy for early-stage NAFLD-HCC among lean patients compared with overweight and obese individuals.

A multicenter retrospective analysis was used to assess early-stage NAFLD-HCC patients undergoing curative-intent hepatectomy between 2009 and 2022. Patients were stratified by preoperative body mass index (BMI) into the lean (<23.0 kg/m2), overweight (23.0-27.4 kg/m2) and obese (≥27.5 kg/m2) groups. Study endpoints were overall survival (OS) and recurrence-free survival (RFS), which were compared among groups.

Among 309 patients with NAFLD-HCC, 66 (21.3 %), 176 (57.0 %), and 67 (21.7 %) were lean, overweight, and obese, respectively. The three groups were similar relative to most liver, tumor, and surgery-related variables. Compared with overweight patients (71.3 % and 55.6 %), the lean individuals had a worse 5-year OS and RFS (55.4 % and 35.1 %, P = 0.017 and 0.002, respectively), which were comparable to obese patients (48.5 % and 38.2 %, P = 0.939 and 0.442, respectively). After adjustment for confounding factors, multivariable Cox-regression analysis identified that lean bodyweight was independently associated with decreased OS (hazard ratio: 1.69; 95 % confidence interval: 1.06-2.71; P = 0.029) and RFS (hazard ratio: 1.72; 95 % confidence interval: 1.17-2.52; P = 0.006) following curative-intent hepatectomy for early-stage NAFLD-HCC.

Compared with overweight patients, individuals with lean NAFLD-HCC had inferior long-term oncological survival after hepatectomy for early-stage NAFLD-HCC. These data highlight the need for examination of the distinct carcinogenic pathways of lean NAFLD-HCC and its potential consequences in HCC recurrence.

Diabetes mellitus (DM) significantly impacts renal and hepatic function, necessitating comprehensive understanding and management strategies. Renal involvement, namely diabetic kidney disease (DKD), presents a global challenge, with increasing prevalence paralleling DM rates. Lifestyle modifications and pharmacotherapy targeting hypertension and glycemic control have pivotal roles in DKD management. Concurrently, hepatic involvement in DM, characterized by metabolic dysfunction-associated steatotic liver disease (MASLD), presents a bidirectional relationship. DM exacerbates MASLD progression, while MASLD predisposes to DM development and worsens glycemic control. Screening for MASLD in DM patients is of high importance, utilizing non-invasive methods like ultrasound and fibrosis scores. Lifestyle modifications, such as weight loss and a Mediterranean diet, mitigate MASLD progression. Promising pharmacotherapies, like SGLT2 inhibitors and GLP-1 agonists, demonstrate efficacy in both DM and MASLD management. Special populations, such as diabetic individuals undergoing hemodialysis or kidney transplant recipients, demand special care due to unique clinical features. Similarly, DM exacerbates complications in MASLD patients, elevating the risks of hepatic decompensation and hepatocellular carcinoma. Recognizing the interconnectedness of DM, renal, and hepatic diseases underscores the need for multidisciplinary approaches for optimal patient outcomes. The present review aims to present the main characteristics and crucial points not to be overlooked regarding the renal and hepatic involvement in DM patients focusing on the inter-relationships between the renal and the hepatic involvements.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol metabolism and cardiovascular diseases, has recently garnered attention for its emerging involvement in cancer biology. The multifunctional nature of PCSK9 extends beyond lipid regulation and encompasses a wide range of cellular processes that can influence cancer progression. Studies have revealed that PCSK9 can modulate signaling pathways, such as PI3K/Akt, MAPK, and Wnt/β-catenin, thereby influencing cellular proliferation, survival, and angiogenesis. Additionally, the interplay between PCSK9 and cholesterol homeostasis may impact membrane dynamics and cellular migration, further influencing tumor aggressiveness. The central role of the immune system in monitoring and controlling cancer is increasingly recognized. Recent research has demonstrated the ability of PCSK9 to modulate immune responses through interactions with immune cells and components of the tumor microenvironment. This includes effects on dendritic cell maturation, T cell activation, and cytokine production, suggesting a role in shaping antitumor immune responses. Moreover, the potential influence of PCSK9 on immune checkpoints such as PD1/PD-L1 lends an additional layer of complexity to its immunomodulatory functions. The growing interest in cancer immunotherapy has prompted exploration into the potential of targeting PCSK9 for therapeutic benefits. Preclinical studies have demonstrated synergistic effects between PCSK9 inhibitors and established immunotherapies, offering a novel avenue for combination treatments. The strategic manipulation of PCSK9 to enhance tumor immunity and improve therapeutic outcomes presents an exciting area for further investigations. Understanding the mechanisms by which PCSK9 influences cancer biology and immunity holds promise for the development of novel immunotherapeutic approaches. This review aims to provide a comprehensive analysis of the intricate connections between PCSK9, cancer pathogenesis, tumor immunity, and the potential implications for immunotherapeutic interventions.

Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.

To evaluate the predictive value of tumor and peritumor radiomics in the fatty acid binding protein 4 (FABP4) expression levels and overall survival in patients with hepatocellular carcinoma.

The genomic data of HCC patients were obtained from The Cancer Genome Atlas. The Dual-area CT images of corresponding patients were downloaded from The Cancer Imaging Archive, for radiomics feature extraction, model construction and prognosis analysis. Simultaneously, using patients from Sichuan Provincial People's Hospital, the prognostic value of the radiomics model in HCC patients was validated.

In the TCIA database, the area under the curve (AUC) values of the volumes of interest (VOI)whole model in the training set and internal validation set were 0.812 and 0.754, respectively, and the AUC value of VOIwhole+periphery in the training set and internal validation set were 0.866 and 0.779, respectively. In the VOIwhole and the VOIwhole+periphery model of the independent cohort, there were significant differences in OS between the high and low rad-score groups (P = 0.009, P = 0.021, respectively). Significant positive correlations can be observed between FABP4 expression and correlations with rad-score of VOIwhole model (r = 0.691) and VOIwhole+periphery model (r = 0.732) in the independent cohort.

Radiomics models of tumor and peritumor Dual-area CT images could predict stably the expression levels of FABP4 and may be helping in personalized treatment strategies.

Long-chain fatty acyl-Coa ligase 4 (ACSL4) is an important enzyme that converts fatty acids to fatty acyl-Coa esters, there is increasing evidence for its role in carcinogenesis. However, the precise role of ACLS4 in hepatocellular carcinoma (HCC) is not clearly understood. In the present study, we provide evidence that ACSL4 expression was specifically elevated in HCC and is associated with poor clinical outcomes. ACSL4 significantly promotes the growth and metastasis of HCC both in vitro and in vivo. RNA sequencing and functional experiments showed that the effect of ACSL4 on HCC development was heavily dependent on PAK2. ACSL4 expression is well correlated with PAK2 in HCC, and ACSL4 even transcriptionally increased PAK2 gene expression mediated by Sp1. In addition, emodin, a naturally occurring anthraquinone derivative, inhibited HCC cell growth and tumor progression by targeting ACSL4. In summary, ACSL4 plays a novel oncogene in HCC development by regulating PAK2 transcription. Targeting ACSL4 could be useful in drug development and therapy for HCC.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.