Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and its prevalence has risen sharply. However, whether nutrition, dietary strategies, exercise, lifestyle and environment have preventive value for NAFLD remains unclear.

Through searching 4 databases (PubMed, Web of Science, Embase and the Cochrane Library) from inception to January 2025, we selected studies about nutrition, dietary strategies, exercise, lifestyle and environment in the prevention of NAFLD and conducted a narrative review on this topic.

Reasonable nutrient intake encompassing macronutrients and micronutrients have an independent protective relationship with NAFLD. Besides, proper dietary strategies including mediterranean diet, intermittent fasting diet, ketogenic diet, and dietary approaches to stop hypertension diet have their inhibitory effects on the developmental process of NAFLD. Moreover, right exercises including walking, jogging, bicycling, and swimming are recommended for the prevention of NAFLD because they could effectively reduce weight, which is an important risk factor for NAFLD, and improve liver function. In addition, embracing a healthy lifestyle including reducing sedentary behavior, not smoking, sleeping well and brushing teeth regularly is integral since it not only could reduce the risk of NAFLD but also significantly contribute to overall prevention and control. Finally, the environment, including the social and natural environments, plays a potential role in NAFLD prevention.

Nutrition, dietary strategies, exercise, lifestyle and environment play an important role in the prevention of NAFLD. Moreover, this review offers comprehensive prevention recommendations for people at high risk of NAFLD.

Currently, the Fibrosis-4 (FIB-4) and nonalcoholic fatty liver disease fibrosis score (NFS) are used to predict fibrosis and steatosis in patients with or at risk for metabolic dysfunction-associated steatotic liver disease (MASLD). More recently, the fibrotic nonalcoholic steatohepatitis (NASH) index (FNI) and steatosis-associated fibrosis estimator (SAFE) have been created. We have compared the accuracy of these noninvasive scoring systems in MASLD patients.

This is a retrospective analysis of 244 biopsy-proven MASLD patients from a tertiary health care system. Score performances were determined by calculating the area under the receiver operating characteristic (AUROC) curve with 95% confidence intervals, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).

About 25 (10.3%) patients had fibrotic metabolic dysfunction-associated steatohepatitis (MASH). The FNI score was best at predicting fibrotic MASH with an AUROC of 0.78, while NFS was the worst at predicting fibrotic NASH with an AUROC of 0.60. In the entire cohort, FNI of 0.33, FIB-4 of 2.67, SAFE >100, and NFS >0.675 had PPVs of 17%, 31%, 17%, and 16%, respectively, and NPVs of 97%, 92%, 96%, and 91%, respectively. Specificity was greatest for FIB4 at 92% and NFS at 86%, whereas the sensitivity was greatest for FNI and SAFE scores at 88% and 80%, respectively.

FNI and SAFE scores have superior diagnostic accuracy for fibrotic MASH compared to other scoring systems. While liver biopsy remains the gold standard diagnostic method, noninvasive scores like FNI, and SAFE scores can be used in everyday clinical practice to assess for fibrotic MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease among people living with HIV, and preliminary evidence shows that lifestyle modification can reduce liver fat in people living with HIV with MASLD. We aimed to assess a dietitian-led lifestyle modification programme in inducing resolution of MASLD in this population.

In this single-blind, randomised controlled trial at the Prince of Wales Hospital, Hong Kong, people living with HIV with fatty liver defined by intrahepatic triglyceride content ≥5% on proton magnetic resonance spectroscopy (1H-MRS) were enrolled if they were aged 18 years or older, were on antiretroviral therapy, and had HIV RNA of ≤50 copies per mL for 6 months or longer. Participants were randomly assigned (1:1) to either receive a dietitian-led lifestyle modification programme or standard care for 12 months. Randomisation was performed using computer-generated random numbers in blocks of 4 stratified by presence or absence of diabetes. The primary outcome, assessed in the intention-to-treat population, was resolution of MASLD, defined as intrahepatic triglyceride content less than 5% at month 12, measured by 1H-MRS. This trial was registered with ClinicalTrials.gov, NCT03913351, and is completed.

From May 21, 2019, to March 22, 2022, 203 people were screened for eligibility, of whom 84 were randomly assigned to either the lifestyle modification programme (n=43) or standard care (n=41). 74 (88%) participants were male and ten (12%) were female. 78 participants completed all assessments during the 12-month intervention. In the intention-to-treat analysis, 12 (28%) participants in the intervention group and four (10%) in the control group had resolution of MASLD (p=0·040 adjusted for baseline diabetes status). No deaths were reported during the follow-up period. One serious adverse event (hospitalisation due to cellulitis) was reported in the control group. The occurrence of adverse events was similar in the intervention and control groups. The majority of adverse events were of mild severity, and none were considered to be related to study intervention.

Our findings suggest that a lifestyle modification programme could be a routine behavioural strategy to improve a range of health outcomes in people living with HIV with MASLD.

Health and Medical Research Fund from the Health Bureau, Hong Kong Special Administrative Region.

For the Chinese translation of the abstract see Supplementary Materials section.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous disease caused by multiple etiologies. It is characterized by excessive fat accumulation in the liver. Without intervention, MASLD can progress from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis and even to cirrhosis and hepatocellular carcinoma. However, the pathogenesis of MASH and the mechanism underlying the development of fibrosis remain poorly understood, posing challenges for accurate diagnosis of MASH and fibrosis. In this study, we analyzed tissue RNA-seq data and clinical information of healthy individuals and MASLD patients from multiple datasets, the key genes and pathways involved in the occurrence and progression of MASLD, MASH, and fibrosis were screened respectively. Our findings reveal that the development of MASLD, MASH and fibrosis is associated with lipid metabolism processes. Based on the RNA expression profiles of identified hub genes, we established three alternative diagnostic models for MASLD, MASH, and fibrosis. These models demonstrated excellent performance in the diagnosis of MASLD, MASH, and fibrosis, with AUC values exceeding 0.9, implicating its potential clinical values in disease diagnosis.

Liver fibrosis is a common response to chronic liver injury due to multiple etiologies and plays a crucial in the progression of chronic liver disease to cirrhosis, hepatocellular carcinoma, and other liver-related clinical outcomes. Currently, available treatments to block liver fibrosis are designed to eliminate the underlying causes of liver disease. The lack of truly effective drugs to regress or reverse fibrosis is a major unmet clinical need. In this context, this article briefly describes the pathological process of hepatic fibrosis and focuses on reviewing the progress of clinical studies on mechanism-based anti-fibrotic drug development and therapy, highlighting that the positive effect of thyroid hormone receptor-β (THR-β) analogs, fibroblast growth factor 21 (FGF21) analogues, Glucagon-like peptide 1 receptor (GLP-1R) agonists, pan-peroxisome proliferator-activated receptor (pan-PPAR) agonists, fatty acid synthase (FASN) inhibitors, and hydronidone in reducing liver fibrosis caused by specific etiologies. Moreover, multi-pathway guided combination therapy or traditional Chinese medicine demonstrate significant advantages in combating liver fibrosis. Finally, new technologies and approaches affecting the clinical development of anti-hepatic fibrosis drugs were discussed.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV.

MASLD in PWH (MASLD-HIV) follows a more aggressive clinical course compared to HIV-negative individuals. While MASLD-HIV shares common pathogenic mechanisms with MASLD in the general population, HIV-specific factors - including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy - exacerbate disease progression. Despite an expanding pipeline of MASLD therapies, a critical gap remains in evaluating these interventions specifically among PWH. Nonetheless, dedicated studies of glucagon-like peptide-1 receptor agonists and the growth hormone-releasing hormone analog tesamorelin have shown promise in MASLD-HIV.

MASLD is a key contributor to liver-related and cardiovascular-morbidity in PWH. While there have been exciting advances to improve diagnosis and management of MASLD in the general population, differences in MASLD pathophysiology demonstrate the need to tailor our approach specifically for PWH.

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.

Both metabolic dysfunction-associated fatty liver disease (MAFLD) and gestational diabetes mellitus (GDM) during pregnancy are emerging as an adverse synergistic relationship of growing concern. This narrative review focuses on the maternal and fetal consequences associated with women who have MAFLD and/or GDM during pregnancy, including an exploration of long-term cardiometabolic risks for postpartum maternal and childhood health. We conclude that implementation of a life course approach to management of these high-risk women remains paramount.

Non-alcoholic fatty liver disease (NAFLD) represents the most widespread liver disease globally, ranging from non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH) to fibrosis/cirrhosis, with potential progression to hepatocellular carcinoma (HCC). Genome-wide association studies (GWASs) have identified several single nucleotide polymorphisms (SNPs) associated with NAFLD. However, numerous GWAS signals associated with NAFLD locate in non-coding regions, posing a challenge for interpreting their functional annotation.

In this study, we utilized the Activity-by-Contact (ABC) model to construct the enhancer-gene maps of liver by integrating epigenomic data from 15 liver tissues and cell lines. We constructed the most comprehensive genome-wide regulatory maps of the liver, identifying 543,486 enhancer-gene connections, including 267,857 enhancers and 16,872 target genes. Enrichment analyses revealed that the ABC SNPs are significantly enriched in active chromatin regions and active chromatin state. By combining the ABC regulatory maps and NAFLD GWAS data, we systematically identified ABC SNPs associated with NAFLD risk. Through the functional annotations, such as pathway enrichment and drug-gene interaction analyses, we identified 6 genes (GGT1, ACTG1, SPP1, EPHA2, PROZ and SHMT1) as candidate NAFLD genes, with SHMT1 previously reported. Among the SNPs connected to the candidate genes, the ABC SNP rs2017869 (odds ratio [OR] for the C allele = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10- 4) had the highest ABC score. According to the ABC maps, rs2017869 links to GGT1, and several drugs targeting this gene, such as liothyronine, showed potential benefits to patients with NAFLD. Furthermore, we identified that another novel gene, EPHA2, may play a crucial role in NAFLD by regulating the GGT levels.

Our study provides the most comprehensive ABC regulatory maps of the liver to date. This resource offers a valuable reference for identifying regulatory variants and prioritizing susceptibility genes of liver diseases, such as NAFLD.

The close interplay between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes supports the need to identify beneficial combination therapies of antidiabetic medications targeted for the treatment of MASLD. This study aimed to investigate the complementary effects of combination therapy with pioglitazone (PIO) and empagliflozin (EMPA) on MASLD in individuals with type 2 diabetes.

In a randomized, open-label trial, 50 participants with type 2 diabetes and MASLD were assigned 1:1:1 to receive PIO 15 mg, EMPA 10 mg, or a combination (PIO 15 mg plus EMPA 10 mg) daily for 24 weeks. Liver fat fraction and stiffness were evaluated using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE), respectively.

Combination therapy resulted in the largest reduction in liver fat and stiffness among treatment groups. Participants experiencing a relative reduction ≥ 30% or an absolute reduction ≥ 5% in liver fat were the most prevalent in the combination group (100.0% vs. 57.1% in PIO and 87.5% in EMPA, p = 0.010). In addition, the combination group showed the highest proportion of individuals with a relative reduction ≥ 30% in liver fat and ≥ 20% in liver stiffness than the monotherapy groups (50.0% vs. 21.4% in PIO and 6.3% in EMPA, p = 0.029). Combination therapy did not induce the changes in subcutaneous fat deposition observed in the monotherapy groups, but it did show the most substantial reduction in visceral fat, concurrently showing the largest increase in adiponectin level across the three groups (p = 0.036).

Combination therapy of PIO with EMPA showed synergistic benefits for MASLD in individuals with type 2 diabetes, compensating for the inadequate or unfavorable effects of monotherapies; ClincialTrials.gov number, NCT03646292.

The trial was registered at ClinicalTrials.gov (registration number: NCT03646292).

This study aims to establish the effect of bruceine E in attenuating nonalcoholic steatohepatitis (NASH) through the PI3K/AKT/NFκB pathway.

High-fat-diet (HFD) male Wistar rats were orally administered with glibenclamide (20 mg/kg) or bruceine E (400, 800, or 1600 µg/kg) for 4 weeks. After 4 weeks of treatment, blood serum was analysed for liver markers. Liver histology was used to identify the degree of inflammation. The liver tissue was evaluated on the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and inflammatory genes (nuclear factor-kappa B [NFκB], tumor necrosis factor alpha [TNFα], interleukin-6 [IL6], and interleukin-10 [IL10]) and protein expressions.

The alanine transferase and aspartate transferase were reduced in HFD rats administered orally with bruceine E. In liver histology, steatosis, ballooning, and lobular inflammation were alleviated in bruceine E-treated HFD rats. The PI3K/AKT genes and proteins were activated while the inflammatory genes and protein expressions were suppressed in the bruceine E-treated HFD rats showing improvement towards insulin resistance (IR), liver steatosis, and inflammation.

In conclusion, bruceine E attenuated NASH through activation of the PI3K/AKT/NFκB inflammation pathway and may further delay the progression of NASH to hepatocellular carcinoma .

Malnutrition, defined as deficiency, excess, or imbalance of nutrients, is a common complication in patients with liver disease, especially those with cirrhosis. Malnutrition may present as an isolated micronutrient deficiency, such as zinc deficiency, and it commonly presents as frailty and/or sarcopenia in patients with advanced liver disease. Patients with cirrhosis and/or alcohol-associated hepatitis should be assessed for malnutrition because it adversely affects patient outcomes including mortality, as well as waitlist and posttransplant outcomes among liver transplant candidates. The prevalence of malnutrition varies based on the method of assessment and disease severity, being higher in those with advanced liver disease. Among stable outpatients with cirrhosis, counseling should be done to eat small frequent meals, a night-time snack between 7 PM and 10 PM, and 2 or more cups of coffee daily. In selected patients with metabolic dysfunction-associated steatohepatitis, vitamin E 800 IU/d should be provided. Among hospitalized patients with cirrhosis, nutritional supplementation preferably by enteral route should be implemented in those with poor oral intake of daily requirements of proteins and/or calories. Protein intake should not be restricted including patients with decompensated cirrhosis and hepatic encephalopathy. A vegetable source of protein seems to be better tolerated than an animal source of protein in patients with hepatic encephalopathy. Branched chain amino acids augment the efficacy of lactulose and rifaximin in the treatment of hepatic encephalopathy. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the auspices of the American College of Gastroenterology Practice Parameters Committee.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a contemporary classification of liver disease linked to metabolic dysfunction. It is recognized as the main form of chronic liver disease and significantly contributes to liver-related morbidity and mortality rates. The epidemiology of MASLD is affected by ethnic background, sex, age, and environmental factors. South Korea is one of the countries that has experienced rapid urbanization. Geographical differences also play a crucial role in the prevalence and progression of the disease. Consequently, it is essential to investigate the prevalence of MASLD; its associated risk factors, particularly in relation to liver fibrosis; and the effectiveness of non-invasive screening techniques within the Korean population. Methods: This review describes the prevalence of MASLD, the risk factors related to MASLD with liver fibrosis, and the non-invasive screening approaches suitable for the Korean general population. Results: This review underscores the rising incidence and implications of MASLD in South Korea. Notably, among younger demographics, there is a swift increase in both the prevalence of MASLD and its associated risk factors, indicating that MASLD is poised to become a significant public health concern. Non-invasive testing methods are increasingly utilized within at-risk groups to determine the presence of advanced fibrosis. Conclusions: Addressing these complex liver diseases necessitates not only ongoing monitoring of MASLD epidemiological patterns but also a unified approach to care that integrates medical interventions with lifestyle changes.

Background: Non-alcoholic steatohepatitis (NASH) is characterized by increased production of proinflammatory cytokines, fibrosis, and hepatocyte apoptosis. This study aimed to assess the efficacy of N-acetyl cysteine (NAC), rosuvastatin (RSV), and vitamin E (VE) in patients with NASH. Methods: A double-blinded, parallel, randomized, controlled study was conducted and registered on clinicaltrials.gov (Identifier: NCT06105060), involving 135 NASH participants, who were divided into three groups: the control group (group 1), consisting of patients receiving standard therapy VE at a dosage of 400 IU twice daily. In the treated group (group 2), patients were administered NAC at a dosage of 1200 mg twice daily, while treatment (group 3) received RSV at a dosage of 20 mg once daily. FibroScan® examination of liver tissue and fibrosis scores, along with tests for liver aminotransferases, lipid profile, glycemic parameters, and renal and hepatic functions, were assessed before and after six months of treatment. Results: The analyzed groups demonstrated a significant reduction in steatosis and lipid peroxidation (p < 0.05). The NAC group demonstrated greater anti-inflammatory and anti-apoptotic effects compared to the RSV group, although this difference was not significant in the control group. NAC is conceded as the only significant antifibrotic agent in liver stiffness measurement (LSM), biological marker findings, and non-invasive liver fibrosis scores (p < 0.05), in addition to its improvement of several metabolic parameters and health-related quality of life. Conclusions: Patients receiving NAC demonstrated safety and efficacy in enhancing steatosis, fibrosis, and metabolic parameters, representing a novel strategy in the management of NASH.

To evaluate whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or pioglitazone (PGZ) are associated with improved survival, reduced liver-related outcomes (LROs), and better metabolic outcomes in patients with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated liver disease (MASLD) or steatohepatitis (MASH).

We used the TriNetX platform to identify adults with T2DM and MASLD/MASH from 2006 onward (n = 558 075) using Internation Classification of Diseases codes. Patients with confounding liver diseases, overlapping study medications, or bariatric surgery were excluded. Three exclusive cohorts-GLP-1 RA, PGZ, and other antidiabetic agents (controls)-were formed. After 1:1 propensity score matching, time-to-event analyses were performed using Cox proportional hazards models and Kaplan-Meier methods.

Among matched groups, GLP-1 RAs (n = 17 465) were associated with a 40.9% reduction in all-cause mortality versus controls (hazard ratio [HR] 0.59; P < .0001) and significantly lower rates of LRO (HR 0.77) and liver transplantation (HR 0.33). In contrast, PGZ (n = 1803) showed reduced LRO rates (HR 0.68) but not mortality. In cirrhotic patients, GLP-1 RA was linked to fewer transplant events but did not significantly reduce mortality. GLP-1 RA therapy noted greater reductions in body mass index and hemoglobin A1c relative to controls.

In this large real-world cohort, GLP-1 RA use was associated with improved survival and hepatic outcomes in T2DM patients with MASLD/MASH, particularly among those without established cirrhosis. PGZ exhibited hepatic benefits. These findings highlight the potential importance of further prospective studies to evaluate early GLP-1 RA therapy in this high-risk diabetic population with MASLD/MASH.

Many treatments for patients with metabolic dysfunction-associated steatohepatitis (MASH) have been proposed; however, most studies showed the results for a single medication and a short duration of treatment. The long-term outcomes of the multidrug therapies remain indeterminate. We conducted a study to investigate the usefulness of multidrug combination therapy for every kind of MASH patient and the differences between treatment-sensitive and treatment-resistant patients.

Fifty-one patients (middle-aged, in their 40s to 60s, metabolic generation) with MASH-determined fibrosis staging were enrolled. Primary treatment (weight control and medication of vitamin E and sodium-glucose cotransporter 2 inhibitor (SGLT2i)) was done and then pemafibrate treatment was added.

Regarding responses to the step-by-step multidrug therapy, patients with MASH were divided into 3 groups, with use of 3 markers-alanine aminotransferase (ALT) (hepatitis), elasticity value (E value, liver stiffness measurement) (hepatitis/fibrosis), and type IV collagen (fibrosis); group 1: sensitive to primary treatment (n = 35), group 2: resistant to primary treatment and sensitive to pemafibrate treatment (n = 11), and group 3: resistant to both treatments (n = 5).To determine the parameters related to treatment resistance, the baseline levels of parameters-obesity (body mass index), metabolic factor (visceral fat, controlled attenuation parameter), diabetes mellitus (DM) (glycated hemoglobulin (HbA1c), fasting immunoreactive insulin), lipid metabolism (triglyceride), and hepatitis (ALT)-were compared between treatment-sensitive group 1+group 2 and treatment-resistant group 3. However, none of them had differences statistically. The same analysis showed that type IV collagen, E value, FIB-4 index (age (year) x AST (IU/L)/platelet count (104/L) x ALT (IU/L)1/2), and MASH fibrosis had differences statistically.

The most effective treatment for patients with MASH could not be determined, according to the baseline levels of characteristics; however, weight control and step-by-step multidrug therapies made it possible to stabilize more than 90% of patient conditions and to solve MASH without worsening fibrosis. Since high levels of liver fibrosis-related markers affected the treatment resistance, MASH treatments should be started in an early stage while the levels of each marker are still low; type IV collagen <5.3 ng/mL, E value <13.7 kPa, FIB-4 index <1.89 and MASH fibrosis stage 2 or less.

Chronic inflammation and gut barrier breakdown contribute to the progression of metabolic syndrome and affect the development of cardiometabolic diseases, especially in persons consuming low-quality diets with limited bioactive compounds. Almonds are a rich source of bioactive compounds with antioxidant and anti-inflammatory properties. We hypothesize almond consumption can help disrupt metabolic syndrome progression by improving gut and cardiometabolic health and decreasing inflammation and oxidative stress. To test this hypothesis, adults with metabolic syndrome were randomized to consume either almonds (2 oz, whole, dry roasted, n = 38) or crackers (control, equal caloric content, n = 39), as a daily snack for 12 weeks, and samples were collected (0, 4, and 12 weeks). Compared with participants consuming crackers, almond consumption resulted in lower plasma total and low-density lipoprotein-cholesterol concentrations, a modest improvement in waist circumference (week 4), and improved dietary intakes of α-tocopherol, soluble fiber, copper, biotin, magnesium, polyunsaturated fatty acids, and monounsaturated fatty acids. Almond consumption raised plasma α-tocopherol concentrations (relative to cholesterol concentrations) and increased excretion of a vitamin E biomarker (α-CEHC). Almond consumption improved biomarkers of gut barrier function and intestinal inflammation (fecal calprotectin, myeloperoxidase) in participants with elevated inflammation at baseline. Total body weight, caloric intake, and markers of carbohydrate metabolism (glucose, insulin), systemic inflammation (plasma interleukin-6, C-reactive protein, lipopolysaccharide-binding protein, CD14), and oxidative damage (malondialdehyde) were not altered by almond consumption. In conclusion, daily almond snacking improves nutrient intake and decreases gut inflammation in participants with metabolic syndrome. These beneficial dietary and inflammatory changes may contribute to the improvements in cardiovascular health observed.

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple fat accumulation to severe conditions such as inflammation, fibrosis, cirrhosis, and liver cancer. Major risk factors for MASLD include obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia.

This narrative review employed a comprehensive search of recent literature to identify the latest studies on the relationship between MAFLD and obesity, the health consequences and the latest treatment options to prevent long-term damage to the liver and other organs. Additionally, the article presents perspectives on diagnostic biomarkers.

Childhood obesity is linked to a multitude of comorbid conditions and remains a primary risk factor for adult obesity. This abnormal fat accumulation is known to have long-term detrimental effects into adulthood. Scientific evidence unequivocally demonstrates the role of obesity-related conditions, such as insulin resistance, dyslipidemia, and hyperglycemia, in the development and progression of MASLD. Oxidative stress, stemming from mitochondrial dysfunction, is a leading factor in MASLD. This review discusses the interconnections between oxidative stress, obesity, dyslipidemia, and MASLD.

Atherogenic dyslipidemia, oxidative stress, inflammation, insulin resistance, endothelial dysfunction, and cytokines collectively contribute to the development of MASLD. Potential treatment targets for MASLD are focused on prevention and the use of drugs to address obesity and elevated blood lipid levels.

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and progression of cardiometabolic disorders remain poorly understood. Adipokines are adipocyte-specific cytokines that are central to deleterious cardiometabolic alterations. They exhibit both pro-inflammatory and anti-inflammatory effects, complicating their association with cardiometabolic disturbances. Thus, understanding the cardiometabolic association of adipokines from a molecular and signaling perspective assumes great importance. This review presents a comprehensive outline of the most prominent adipokines exhibiting pro-inflammatory and/or anti-inflammatory functions in cardiometabolic dysfunction. The review also presents an insight into the pathophysiological implications of such adipokines in different cardiometabolic dysfunction conditions, the status of adipokine druggability, and future studies that can be undertaken to address the existing scientific gap. A clear understanding of the functional and mechanistic role of adipokines can potentially improve our understanding of cardiovascular disease pathophysiology and enhance our current therapeutic regimen in the years to come.

Given the high prevalence of the population who have metabolic dysfunction-associated steatohepatitis (MASH), interest is growing in MASH-targeted treatments. However, currently, there has been only one regulatory approved drug for MASH (Rezdiffra). Pioglitazone, a commonly used type 2 diabetes mellitus drug, is currently used off-label for the treatment of MASH. Our study aimed to perform a model-based meta-analysis to quantitatively examine the efficacy of pioglitazone in improving histological parameters and liver enzymes in patients with MASH. A comprehensive search was performed in Pubmed and clinicaltrials.gov. We collected histological outcomes (including steatosis, inflammation, ballooning, and fibrosis) and liver enzyme data. Due to sparse data, the gathered histological outcomes were used to generate virtual data. Next, model development for the virtual histological dataset was performed using a logistic model. In addition, Weibull and exponential models were tested to find the best fit for liver enzyme data. Model evaluations were carried out by visual predictive check, bootstrap method, and stacked bar plot. Eight studies with 540 patients were included. A logit model was used to analyze four outcomes. The results showed that using pioglitazone improved all four histological parameters. These effects are dose- and time-dependent under the Emax-time model for steatosis and ballooning, and under the linear relationship for inflammation and fibrosis. For liver enzymes, the Weibull model fitted well for both ALT and AST data. In conclusion, the developed models of pioglitazone may serve as a benchmark to assess the effectiveness of novel MASH-targeted treatments.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), encompasses a spectrum of liver diseases characterized by hepatic steatosis, the presence of at least one cardiometabolic risk factor, and no other apparent cause. Metabolic syndrome (MetS) is a cluster of clinical conditions associated with increased risk of cardiovascular disease, type 2 diabetes, and overall morbidity and mortality. This narrative review summarizes the changes in the management of people with MetS and NAFLD/MASLD from screening to therapeutic strategies that have occurred in the last decades. Specifically, we underline the clinical importance of considering the different impacts of simple steatosis and advanced fibrosis and provide an up-to-date overview on non-invasive diagnostic tests (i.e., imaging and serum biomarkers), which now offer acceptable accuracy and are globally more accessible. Early detection of MetS and MASLD is a top priority as it allows for timely interventions, primarily through lifestyle modification. The liver and cardiovascular benefits of a global and multidimensional approach are not negligible. Therefore, a holistic approach to both conditions, MetS and related chronic liver disease, should be applied to improve overall health and longevity.

Oral nutritional interventions for nonalcoholic steatohepatitis (NASH) have garnered significant interest due to their potential benefits. Astaxanthin (AXT) has the potential to enhance liver function and act as an effective antioxidant for NASH intervention, but its application is limited by its stability and bioavailability. This study aims to develop dual-targeted AXT nanoparticles (AXT@TWG) for precise liver-targeted delivery by ″hitchhiking″ on Lactobacillus rhamnosus bacterial ghosts (LBGs) to effectively intervene in NASH. In vitro experiments demonstrated that AXT@TWG nanoparticles significantly reduced LPS-induced reactive oxygen species production and apoptosis while effectively alleviating lipid accumulation. In vivo experiments demonstrated that LBGs significantly enhanced the intestinal accumulation efficiency of AXT@TWG. Pharmacokinetic evaluations revealed that the efficiency of AXT@TWG@LBGs entering the bloodstream was approximately 2.7 times higher than that of AXT@TWG nanoparticles and their accumulation in the liver was about 1.3 times greater. AXT@TWG@LBGs effectively alleviated NASH by reducing triglycerides, free fatty acids, and malondialdehyde levels by 23.07, 65.32, and 21.42%, respectively, compared to the model group, thereby mitigating lipid accumulation and enhancing antioxidant capacity. Additionally, AXT@TWG@LBGs effectively reduced insulin resistance, lowered inflammatory cytokine levels, and corrected disturbances in lipid metabolism. Therefore, this study provides a potentially effective strategy for the treatment of NASH.

Portal inflammation (PI) and ductular reaction (DR) in metabolic dysfunction-associated steatotic liver disease (MASLD) have shown associations with disease severity. We developed a histologic categorization of these features to correlate with known features of MASLD. This study proposes a scoring schema for PI, PP and DR, and relates them to histologic and clinical features in children and adults. This expanded scoring system was developed to identify clinically relevant categories and defined criteria for scoring biopsies. In adults (N:483), more severe PI, PP, and DR were associated with older age (p ≤ 0.002), and PP and DR were associated with increased alkaline phosphatase (ALP) (p ≤ 0.003), GGT (p ≤ 0.001), and total bilirubin (p ≤ 0.01). More severe PI, PP, and DR were associated with higher NAFLD activity score (NAS), fibrosis stage, and diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) (p ≤ 0.05). In children (N:151), PP and DR were associated with younger age (p ≤ 0.0001), and elevated AST, ALT, and ALP (p ≤ 0.05). More severe PI, PP, and DR were associated with advanced fibrosis stage, and PP and DR were associated with diagnosis of borderline or definite MASH in children (p ≤ 0.05). From multivariable ordinal logistic regression analysis, a higher fibrosis stage was independently associated with more severe PI in both adults and children. Interobserver agreement was substantial for PI, PP and DR. The proposed scoring system demonstrated reproducibility and associations between more severe portal-based disease and advanced liver histology, age, and elevated liver enzymes in adults and children. Evaluation of portal disease could provide insight into therapeutic response and disease progression.

In recent decades, the potentiality of marine natural products (MNPs) in the medical field has been increasingly recognized. Natural compounds derived from marine microorganisms, algae, and invertebrates have shown significant promise for treating inflammation-related diseases. In this review, we cover the three primary sources of MNPs and their diverse and unique chemical structures and bioactivities. This review aims to summarize the progress of MNPs in combating inflammation-related diseases. Moreover, we cover the functions and mechanisms of MNPs in diseases, highlighting their functions in regulating inflammatory signaling pathways, cellular stress responses, and gut microbiota, among others. Meanwhile, we focus on key technologies and scientific methods to address the current limitations and challenges in MNPs.

Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.

Improved image quality, better scanners, innovative software technologies, enhanced computational power, superior network connectivity, and the ease of virtual image reproduction and distribution are driving the potential use of digital pathology for diagnosis and education. Although relatively common in clinical oncology, its application in liver pathology is under development. Digital pathology and improving subjective histologic scoring systems could be essential in managing obesity-associated steatotic liver disease. The increasing use of digital pathology in analyzing liver specimens is particularly intriguing as it may offer a more detailed view of liver biology and eliminate the incomplete measurement of treatment responses in clinical trials. The objective and automated quantification of histological results may help establish standardized diagnosis, treatment, and assessment protocols, providing a foundation for personalized patient care. Our experience with artificial intelligence (AI)-based software enhances reproducibility and accuracy, enabling continuous scoring and detecting subtle changes that indicate disease progression or regression. Ongoing validation highlights the need for collaboration between pathologists and AI developers. Concurrently, automated image analysis can address issues related to the historical failure of clinical trials stemming from challenges in histologic assessment. We discuss how these novel tools can be incorporated into liver research and complement post-diagnosis scenarios where quantification is necessary, thus clarifying the evolving role of digital pathology in the field.

Despite the heavy individual patient and socioeconomic burden of metabolic dysfunction-associated steatohepatitis (MASH), until recently, no pharmacological therapy for MASH was approved, with available treatment options geared towards associated cardiometabolic risk factors. Accelerated approval of resmetirom, a thyroid hormone receptor-β agonist to be used in conjunction with diet and exercise, marks a significant step forward in the treatment of MASH, offering tempered optimism to healthcare providers and millions of patients around the world for more effective management. Evidence from phase 2 and 3 clinical trials suggests that resmetirom has the potential to alleviate hepatic fibrosis and inflammation and significantly reduce liver lipid content. Notwithstanding this landmark event, the clinical implementation of resmetirom comes with important challenges, for example, ensuring patient access to treatment and demonstrating effects on hard MASH-related outcomes, such as progression to cirrhosis and hepatocellular carcinoma. Additional considerations include the evaluation of co-administration with other hepatoprotective treatments and the assessment of the efficacy in specific MASH sub-phenotypes. Furthermore, the accumulation of real-world data and experience is expected to help answer the remaining questions about the (long-term) effectiveness and safety profile of the drug. The purpose of this article is to provide an updated and critical review of the mechanisms of action, efficacy, and safety of resmetirom based on the latest clinical trials, to define its place within the broader landscape of MASH management, and to highlight current knowledge gaps and opportunities for future research in the field.

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one-fourth of the global adult population and is the leading cause of liver disease worldwide. To address this, the Asian Pacific Association for the Study of the Liver (APASL) has created clinical practice guidelines focused on MAFLD. The guidelines cover various aspects of the disease, such as its epidemiology, diagnosis, screening, assessment, and treatment. The guidelines aim to advance clinical practice, knowledge, and research on MAFLD, particularly in special groups. The guidelines are designed to advance clinical practice, to provide evidence-based recommendations to assist healthcare stakeholders in decision-making and to improve patient care and disease awareness. The guidelines take into account the burden of clinical management for the healthcare sector.

Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice.

Streptozotocin-injected male mice were fed a high-fat diet to induce MASH. Mice receiving the ATGL inhibitor atglistatin (ATGLi) were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated the benefits of ATGLi on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model.

ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic triacylglycerol species containing polyunsaturated fatty acids, like linoleic acid, as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signalling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors.

Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BA composition, interfering with dietary lipid absorption, and improving metabolic disturbances. Validation with NG-497 opens a new therapeutic perspective for MASLD.

Despite the recent approval of drugs novel mechanistic insights and pathophysiology-oriented therapeutic options for MASLD (metabolic dysfunction-associated steatotic liver disease) are still urgently needed. Herein, we show that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, using atglistatin (ATGLi), improves MASH (metabolic dysfunction-associated steatohepatitis), fibrosis, and key features of metabolic dysfunction in mouse models of MASH and liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings reveal a possible new avenue for MASLD treatment.

Metabolic dysfunction associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH), has emerged as one of the leading indications for liver transplantation in the United States. The disease is associated with increased cardiovascular mortality in patients with early-stage liver fibrosis and a heightened risk of hepatic complications in those with advanced fibrosis. Despite its growing prevalence and significant healthcare burden, there were no approved drugs to treat this chronic disease. In March 2024, Resmetirom, a selective thyroid hormone receptor-beta agonist, became the first drug to receive FDA approval for the treatment of patients with MASH and fibrosis stages F2/F3. This accelerated approval was granted based on significantly higher rates of MASH resolution and fibrosis.

This review summarizes the current literature on the mechanism of action, preclinical data, pharmacokinetics, clinical efficacy, indications, and contraindications of resmetirom in the management of patients with MASH.

The approval of resmetirom for patients with MASH and moderate to advanced hepatic fibrosis is a major advance in the management of MASH. The recent positive results of the ESSENCE trial of semaglutide, if associated with conditional approval, may offer clinicians two options to treat MASH in patients with moderate to advanced fibrosis.

Lipid accumulation in hepatocytes in non-alcoholic steatohepatitis (NASH) is attributed partly to loss of insulin-responsiveness and/or an increased pro-inflammatory state. Since the rare sugar D-allulose has insulin mimetic and anti-inflammatory properties, its effects on lipid accumulation in liver-derived cells was tested. In HepG2 cells exposed to 200 μM oleic acid for 72 h, D-allulose treatment decreased intracellular lipid accumulation with an IC50 = 0.45 ± 0.07 mM. A similar effect was observed in cells treated with 10 μM gemfibrozil. D-allulose and gemfibrozil treatment increased oleic acid β-oxidation. Both D-allulose and gemfibrozil increased peroxisome proliferator-activated receptor α (PPARα) expression (two-fold) relative to control cells, while retinoid X receptor was unchanged. D-allulose and gemfibrozil increased PPARα-dependent genes including those involved in fatty acid β-oxidation (acyl-coenzyme A oxidase 1, long-chain-fatty-acid-coenzyme A ligase 5, and carnitine palmitoyltransferase 1 A). D-allulose and gemfibrozil also increased PPARα reporter gene expression and phosphorylation (Serine 12) which were both inhibited by the mitogen-activated protein (MAP) kinase inhibitor PD098059. Other MAP kinase inhibitors, including SB203580, SP600125, and BIX10289 had no effect on reporter gene expression. Oleic acid treatment, but not D-allulose or gemfibrozil, decreased sterol response element binding protein 1 and sterol response element binding protein 2 expression relative to cells not exposed to oleic acid, while peroxisome proliferator-activated receptor γ expression did not change. These results indicate that D-alluose mimics gemfibrozil effects on lipid content in HepG2 cells by promoting fatty acid β-oxidation via PPARα.