Metabolic dysfunction associated steatotic liver disease (MASLD) is increasing throughout the world, affecting nearly one in three individuals. Kidney stone disease, which is also increasing, is associated with MASLD. Common risk factors for both, including obesity, diabetes, dyslipidemia, hypertension, and metabolic syndrome, are likely drivers of this association. We present here a review of the associations and possible interconnections between these two common disease processes.

Epidemiological studies are discordant regarding the impact of sex on this association and on the impact of MASLD on incident stone risk. The nature of kidney stones is rarely taken into account.A favorable milieu for uric acid kidney stone formation may be created by a lower urine pH resulting from defective ammonium production associated with insulin resistance, common in MASLD.Endogenous oxalate synthesis, a major risk factor for calcium oxalate kidney stones, may be increased in MASLD via decline in the activity of enzymes involved in the detoxification of glyoxylate, the immediate precursor of oxalate.

The nature of kidney stones associated with MASLD and factors driving this association remain to be elucidated. Potential mechanisms identified underlying this include an increase in the risk factors for both uric acid and calcium oxalate kidney stones.

To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis.

Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq.

Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis.

This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.

Obesity can result in persistent metabolic changes despite weight loss, which may affect liver health. We aimed to investigate associations between young adulthood obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), at-risk steatohepatitis and increased liver stiffness measurement (LSM) in a general population setting.

We studied NHANES 2017-2020 community-dwelling participants aged > 40 years with BMI ≥ 18.5 and no heart failure. Weight at age 25 was obtained through questionnaires and compared to current weight. Assessment included controlled attenuation parameter (CAP) and LSM. Associations between obesity status change with MASLD or at-risk metabolic dysfunction-associated steatohepatitis (MASH) and increased LSM were investigated and adjusted for demographics and metabolic health.

The cohort comprised 4,580 participants (57% stable non-obesity, 33% gained obesity, 2% lost obesity and 8% stable obesity). Compared to stable no-obesity, stable obesity was strongly associated with MASLD (odds ratio [OR]: 5.47, 95% confidence interval [95%CI]: 3.97-7.66) as was gained obesity (OR: 4.68, 95% CI: 3.93-5.59), whereas no increased risk was demonstrated for lost obesity (OR: 1.26, 95% CI: 0.76-2.10). Similar associations for stable obesity and gained obesity with at-risk MASH and LSM ≥ 8 kPa were demonstrated. No residual risk was found for lost obesity (MASH-OR: 1.05 95% CI: 0.36-2.49; LSM ≥ 8 kPa-OR: 0.85, 95% CI: 0.29-1.97). Results were consistent in sensitivity analysis where obesity change was calculated over the past 10 years and weight change was stratified in normal weight/overweight/obesity.

Young adulthood obesity is an important risk factor for MASLD, at-risk MASH and increased LSM among the general population aged 40-80 years. Losing obesity resulted in normalisation of odds for MASLD, at-risk MASH and increased LSM. These findings underline the importance of preventing and treating young adulthood obesity to maintain liver health.

With the high burden of Metabolic dysfunction-associated steatotic liver disease (MASLD), (previously known as Non-Alcoholic Fatty Liver Disease - NAFLD) in the community, current models of care that require specialist review for disease risk stratification overwhelm hospital clinic capacity and create inefficiencies in care. The LOCal Assessment and Triage Evaluation of Non-Alcoholic Fatty Liver Disease (LOCATE-NAFLD) randomised trial compared usual care to a community-based nurse delivered liver risk assessment. This study evaluates the implementation strategy of the LOCATE model.

The evaluation used mixed methods (quantitative trial data and qualitative framework analysis of semi-structured interviews) to explore the general practitioner (GP) and patient perspectives of acceptability (Acceptability Framework), and factors associated with reach, effectiveness, adoption, implementation, and maintenance (RE-AIM framework) of the LOCATE model of care.

The LOCATE model was considered highly acceptable by both patients and GPs. The model of care achieved appropriate reach across the participating health services, reaching high-risk patients faster than usual care and with predominantly positive patient experiences. A notable reduction in anxiety and stress was experienced in the intervention group due to the shorter waiting times between referral and assessment. There was an overall perception of confidence in nursing staff capability to perform the community-based screening and GPs indicated confidence in managing low-risk MASLD without the need for specialist review. Challenges to implementation, adoption and maintenance included variable prioritisation of liver disease assessment in complex cases, the need for further GP training in MASLD assessment and treatment pathways, available funding and referral pathways for community screening, and accessibility of effective diet and exercise professional support.

Nurse delivered community-based liver screening is highly acceptable to GPs and patients and has shown to be an effective mechanism to identify high risk patients. Adoption and maintenance of the model of care faces significant challenges related to affordable access to screening, prioritisation of liver disease in complex patient cohorts, and unresolved difficulties in prescribing effective strategies for sustained lifestyle intervention in the primary care setting.

The trial was registered on 30 January 2020 and can be found via Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12620000158965.

Vibration-controlled transient elastographies (VCTEs) are used to surveil disease progression in metabolic dysfunction-associated steatotic liver disease (MASLD), but this test is not covered by Florida Medicaid. This study aims to quantify the number of MASLD adults in a tertiary care center who did not obtain VCTEs despite indications for one based on their fibrosis-4 (FIB-4) scores, estimate the downstream costs associated with lack of VCTE access, and extrapolate these findings to the broader Florida Medicaid population.

The study population was categorized into fibrosis risk groups based on their FIB-4 scores. For each insurance group (Medicaid, Medicare, and private), elastography studies and costs were collected and compared in patients who did or did not receive them. This data were then extrapolated to the statewide Medicaid MASLD population.

Among 282 MASLD patients with Medicaid, 64 patients were categorized as "intermediate-risk" for fibrosis based on their FIB-4, but only 4 had VCTEs performed. The number of VCTEs performed was significantly lower in the Medicaid group in comparison to all "intermediate-risk" patients with Medicaid, Medicare, and private insurance [χ2(2, N = 622) = 19.8, p < 0.001]. In the "intermediate-risk" Medicaid patients, the VCTE and non-VCTE groups averaged $86.74 ± 23.91 and $424.95 ± 63.49 per patient-year (p = 0.01), respectively, in elastography costs. When extrapolating these findings to the statewide Medicaid MASLD population, performing at least one VCTE could reduce downstream elastography costs by $136,020,921.51 ± 27,299,855.72 annually.

VCTEs are underutilized in MASLD patients with Medicaid and VCTE use is associated with significantly lower downstream healthcare costs.

Nonalcoholic fatty liver disease (NAFLD) ranks among the most prevalent chronic liver diseases worldwide, yet effective treatments remain scarce. Old stalks of Asparagus officinalis L. are rich in polysaccharides. The anti-NAFLD mechanism of polysaccharides from old stalks of A. officinalis (AP) requires further study. Here, we studied the effects of AP on NAFLD mice and its impact on the gut microbiota. AP intervention reduces blood lipids and liver lipids and reduces liver injury and inflammation in mice with NAFLD. Moreover, AP intervention changed gut microbiota composition and increased the abundances of butyric acid-producing bacteria, thereby increasing plasma concentration of butyric acid. Furthermore, AP intervention regulated the AMPK/SREBPs signaling pathway, thereby affecting hepatic lipid synthesis. Additionally, AP intervention improved gut barrier function and reduced plasma LPS levels, which subsequently inhibited the LPS/TLR4/NF-κB signaling pathway, thereby alleviating inflammation in NAFLD model mice. Importantly, fecal microbiota transplant (FMT) outcomes demonstrated that AP-induced changes in the gut microbiota impact the AMPK/SREBPs and LPS/TLR4/NF-κB pathways. These data suggest that AP intervention ameliorates NAFLD by regulating the gut microbiota. These research provides a scientific foundation for the use of the stalks of A. officinalis in the treatment of NAFLD.

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.

Insulin resistance, lipotoxicity, and mitochondrial dysfunction contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Mitochondrial dysfunction impairs oxidative phosphorylation and increases reactive oxygen species production, leading to steatohepatitis and hepatic fibrosis. Artificial intelligence (AI) is a potent tool for disease diagnosis and risk stratification.

To investigate mitochondrial DNA polymorphisms in susceptibility to MASLD and establish an AI model for MASLD screening.

Multiplex polymerase chain reaction was performed to comprehensively genotype 82 mitochondrial DNA variants in the screening dataset (n = 264). The significant mitochondrial single nucleotide polymorphism was validated in an independent cohort (n = 1046) using the Taqman® allelic discrimination assay. Random forest, eXtreme gradient boosting, Naive Bayes, and logistic regression algorithms were employed to construct an AI model for MASLD.

In the screening dataset, only mt12361A>G was significantly associated with MASLD. mt12361A>G showed borderline significance in MASLD patients with 2-3 cardiometabolic traits compared with controls in the validation dataset (P = 0.055). Multivariate regression analysis confirmed that mt12361A>G was an independent risk factor of MASLD [odds ratio (OR) = 2.54, 95% confidence interval (CI): 1.19-5.43, P = 0.016]. The genetic effect of mt12361A>G was significant in the non-diabetic group but not in the diabetic group. mt12361G carriers had a 2.8-fold higher risk than A carriers in the non-diabetic group (OR = 2.80, 95%CI: 1.22-6.41, P = 0.015). By integrating clinical features and mt12361A>G, random forest outperformed other algorithms in detecting MASLD [training area under the receiver operating characteristic curve (AUROC) = 1.000, validation AUROC = 0.876].

The mt12361A>G variant increased the severity of MASLD in non-diabetic patients. AI supports the screening and management of MASLD in primary care settings.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Background: Omentin (omentin-1, intelectin-1, ITLN-1) is an adipokine considered to be a novel substance. Many chronic, inflammatory, or civilization diseases are linked to obesity, in which omentin plays a significant role. Methods: MEDLINE and SCOPUS databases were searched using the keywords "omentin" or "intelectin-1". Then the most recent articles providing new perspectives on the matter and the most important studies, which revealed crucial insight, were selected to summarize the current knowledge on the role of omentin in a literature review. Results and Conclusions: The valid role of this adipokine is evident in the course of metabolic syndrome. In most cases, elevated omentin expression is correlated with the better course of diseases, including: type 2 diabetes mellitus, polycystic ovary syndrome, rheumatoid arthritis, metabolic dysfunction-associated steatotic liver disease, Crohn's disease, ulcerative colitis, atherosclerosis, or ischemic stroke, for some of which it can be a better marker than the currently used ones. However, results of omentin studies are not completely one-sided. It was proven to participate in the development of asthma and atopic dermatitis and to have different concentration dynamics in various types of tumors. All of omentin's effects and properties make it an attractive subject of research, considering still unexplored inflammation mechanisms, in which it may play an important role. Omentin was proven to prevent osteoarthritis, hepatocirrhosis, and atherosclerosis in mouse models. All of the above places omentin among potential therapeutic products, and not only as a biomarker. However, the main problems with the omentin's research state are the lack of standardization, which causes many contradictions and disagreements in this field.

Metabolic Dysfunction-Associated Steatohepatitis (MASH) represents the severe condition of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Currently, there is a need to identify non-invasive biomarkers for an accurate diagnosis of MASH. Previously, omics studies identified alterations in lipid metabolites involved in MASLD. However, these studies require validation in other cohorts. In this sense, our aim was to perform lipidomics to identify the circulating lipid metabolite profile of MASH. We assessed a liquid chromatography coupled to a mass spectrometer-based untargeted lipidomic assay in serum samples of 216 women with morbid obesity that were stratified according to their hepatic diagnosis into Normal Liver (NL, n =  44), Simple Steatosis (SS, n =  66) and MASH (n =  106). First, we identified a profile of lipid metabolites that are increased in MASLD, composed of ceramides, triacylglycerols (TAG) and some phospholipids. Then, we identified that patients with SS have a characteristic profile of increased levels of ceramides, diacylglycerols DG (36:2) and DG (36:4), some TAG and a few phospholipids such as PC (32:1), PE (38:3), PE (40:6), PI (32:0) and PI (32:1). Later, in MASH patients, we found increased levels of ceramides, deoxycholic acid, a set of TAG, and some phospholipids such as PC, PE, PI and LPI; while we found decreased levels of the DG (36:0). Finally, we have reported a panel of lipid metabolites that might be used to differentiate patients with MASH from SS patients, made up of increased levels of 9-HODE some PC and PE, the LPI (16:0) and decreased levels of DG (36:0). To conclude, our investigation has suggested a lipid metabolite profile associated with MASLD and MASH. Specifically, a set of lipid metabolites seems to be discriminatory in MASH subjects compared to SS individuals. Thus, this panel of lipid metabolites could be used as a non-invasive diagnostic tool.

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.

Owing to long-term antiretroviral therapy (ART), the incidence of non-HIV-related chronic diseases is increasing, and liver disease is the leading cause of increased AIDS mortality. Moreover, the prevalence of NAFLD and liver fibrosis has been reported to vary widely across regions and studies. There is no precise description of the trend and characteristics of NAFLD in PLWH. Here, we aimed to explore the prevalence and outcomes of NAFLD in people living with HIV (PLWH).

The PubMed, Web of Science, Embase, and Cochrane Library databases were searched on August 15, 2023, for studies that evaluated the prevalence of NAFLD or liver fibrosis among PLWH. The meta-synthesized effects of NAFLD and liver fibrosis were the primary outcomes, and potential moderators were the secondary outcomes. The meta-analysis of the combined event rate (ER) and random effects was conducted on the basis of the number of individuals with NAFLD, the number of individuals with liver fibrosis, and the total sample size.

Of the 3520 studies identified, 41 studies were eligible for the meta-analysis. The results revealed that the combined ERs of NAFLD and liver fibrosis were 0.38 (95% CI: 0.33-0.43, p < 0.01) and 0.25 (95% CI: 0.18-0.32, p < 0.01), respectively.

This meta-analysis provided empirical evidence that the prevalence of NAFLD and liver fibrosis in PLWH is greater than that in the general population, which requires sufficient attention. In the HIV population, noninvasive imaging to monitor NAFLD changes should be strengthened, and a high TG level might be an early predictive indicator for HIV-associated fatty liver disease; however, large-scale prospective clinical research data are still needed for further validation and evaluation.

The efficacy and safety of a lower dose of vitamin E for metabolic dysfunction-associated steatohepatitis (MASH) treatment are unclear. This multi-center, randomized, double-blind, placebo-controlled study includes 124 non-diabetic participants with biopsy-proven MASH. Participants are randomly assigned to receive oral vitamin E 300 mg or the placebo in a 1:1 ratio. The primary outcome is improvement in hepatic histology. In the modified intention-to-treat population, 29.3% of participants in the vitamin E group achieve the primary outcome compared with 14.1% in the placebo group. Significant improvement in steatosis, lobular inflammation, and fibrosis stages is observed in the vitamin E group. 12 serious adverse events are reported in this trial but are not considered to be related to the treatment. Vitamin E 300 mg daily achieves sound improvements in liver histology in the Chinese population with MASH. This study is registered at ClinicalTrials.gov (NCT02962297).

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is the most prevalent liver disorder globally, linked to obesity, type 2 diabetes, and cardiovascular risk. Understanding its potential progression from simple steatosis to cirrhosis and hepatocellular carcinoma (HCC) is crucial for patient management and treatment strategies. The disease's complexity requires innovative approaches for early detection and personalized care. Omics technologies-such as genomics, transcriptomics, proteomics, metabolomics, and exposomics-are revolutionizing the study of MASLD. These high-throughput techniques allow for a deeper exploration of the molecular mechanisms driving disease progression. Genomics can identify genetic predispositions, whilst transcriptomics and proteomics reveal changes in gene expression and protein profiles during disease evolution. Metabolomics offers insights into the metabolic alterations associated with MASLD, while exposomics links environmental exposures to MASLD progression and pathology. By integrating data from various omics platforms, researchers can map out the intricate biochemical pathways involved in liver disease progression. This review discusses the roles of omics technologies in enhancing the understanding of disease progression and highlights potential diagnostic and therapeutic targets within the MASLD spectrum, emphasizing the need for non-invasive tools in disease staging and treatment development.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Hawthorn fruit, renowned as both a functional food and herbal medicine with lipid-lowering effects, is abundant in polysaccharides. However, there is limited research on the effects and mechanisms of hawthorn fruit polysaccharides (HP) in addressing non-alcoholic fatty liver disease (NAFLD).

This study aims to investigate the effects of HP on NAFLD both in vivo and in vitro, and to elucidate the underlying mechanisms by which HP exerts its anti-NAFLD activity.

NAFLD mice induced by a high-fat diet were employed as the in vivo model, while oleate/palmitate-induced HepG2 cells served as the in vitro model. H&E and Oil Red O staining were employed to examine fat accumulation in hepatocytes. Serum aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were measured using corresponding ELISA kits. Hepatic metabolomics analysis based on UHPLC-QTOF/MS was utilized to examine the role of HP in improving hepatic metabolic disorders. 16S rRNA sequencing was conducted to explore the effect of HP in alleviating gut microbiota dysbiosis. GC-MS was applied to detect short-chain fatty acids (SCFAs) to clarify the impact of HP in NAFLD mice.

HP significantly inhibited weight gain and hepatic fat accumulation in NAFLD mice. The reduction in serum ALT and AST levels indicated that HP mitigated liver function damage, while the decreased MDA levels and increased SOD activity suggested that HP alleviated hepatic oxidative stress. Furthermore, HP diminished the release of inflammatory cytokines such as IL-1β and IL-6 in the liver. HP significantly regulated metabolic pathways related to amino acids, lipids, and vitamins. Key metabolites such as l-tyrosine, urocanic acid, undecanedioic acid, oleamide, vitamin A, and vitamin B7 were restored to near-normal levels under the regulatory effects of HP. Gut microbiota dysbiosis in NAFLD mice was also ameliorated by HP, with genera such as unclassified_f__Lachnospiraceae and Dubosiella being notably affected. Correlation analysis indicated a significant correlation between the regulatory effects of HP on liver metabolism and gut microbiota. Additionally, HP showed no effect in vitro but increased acetic acid level in the gut of NAFLD mice.

These findings demonstrate that HP exhibits its anti-NAFLD effects, including alleviating lipid accumulation, liver dysfunction, oxidative stress, and inflammation. Mechanistically, HP primarily improves gut microbiota dysbiosis, thereby elevating intestinal SCFA levels and restoring hepatic metabolic disorders in NAFLD mice.

Serum ferritin has been suggested as a potential biomarker associated with disease progression in metabolic dysfunction-associated steatotic liver disease (MASLD).

We investigated the association between serum ferritin levels and liver-related events (LREs) in individuals with steatotic liver disease (SLD).

This cohort study included 17,560 adults with SLD (MASLD [n = 15,744], MASLD with increased alcohol intake (MetALD) [n = 1103] and cryptogenic SLD [n = 713]) without LRE at baseline. A steatotic liver was diagnosed using ultrasound, and LRE was defined as the development of decompensation (ascites, variceal bleeding and hepatic encephalopathy) or hepatocellular carcinoma. Participants were categorised into high (≥ 300 μg/L for males, ≥ 200 μg/L for females) or normal to low (< 300 μg/L for males, < 200 μg/L for females) ferritin levels.

During 211,425 person-years of follow-up (median: 12.3 years), 74 incident LRE cases were identified, with 63 cases in MASLD, 10 in MetALD and 1 in cryptogenic SLD. The multivariable-adjusted hazard ratio (aHR) for LRE comparing individuals with high and normal-to-low ferritin level was 3.13 (95% confidence interval [CI] 1.89-5.18). Increased risk of LRE in individuals with high serum ferritin level compared to those with normal to low serum ferritin level was consistent across SLD subtypes (aHR 2.69, 95% CI 1.55-4.67 for MASLD; aHR 5.73, 95% CI 1.31-25.0 for MetALD), and SLD severity assessed by Fibrosis-4 (FIB-4) index (aHR 2.38, 95% CI 1.34-4.21 for FIB-4 ≥ 1.3; aHR 3.13, 95% CI 1.18-8.29 for FIB-4 < 1.3).

Serum ferritin levels correlated with the risk of LRE in patients with SLD.

Introduction: This study aims to investigate the combined association between insulin resistance (IR) levels, relative grip strength (RGS), and the incidence of nonalcoholic fatty liver disease (NAFLD), stratified by sex, using longitudinal data. Methods: The study included 1702 adult participants aged 51-88 years who completed surveys in both 2013-2014 and during a subsequent follow-up in 2019-2020. NAFLD was assessed using the hepatic steatosis index, and RGS was measured using the JAMA-5030J1 equipment (SAEHAN, Korea). To assess the interaction between RGS and IR levels and their impact on NAFLD risk, we employed a proportional hazards Cox regression model. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated for NAFLD incidence. Results: After adjusting for various confounding variables, we observed a significant decrease in NAFLD risk in the middle RGS group (HR = 0.70, 95% CI = 0.53-0.93) and high RGS group (HR = 0.31, 95% CI = 0.22-0.44) compared to the low RGS group. In addition, significant sex differences were noted in the relationship between IR, RGS levels, and NAFLD incidence across different groups. Conclusions: This study highlights that higher RGS levels are independently associated with a reduced risk of developing NAFLD. Notably, RGS emerges as a predictive indicator for assessing NAFLD risk.

Liver fibrosis staging is challenging in patients with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Liver biopsies are invasive, whereas noninvasive tests such as vibration-controlled transient elastography (VCTE) can be inaccurate in patients with obesity. We hypothesized that EUS-guided shear wave elastography (EUS-SWE) is more accurate for liver fibrosis staging in patients with MASLD and obesity; the aim of this pilot study was to test this hypothesis and establish optimal fibrosis stage cutoffs for EUS-SWE.

This was a multicenter, cross-sectional study from prospectively collected data. Consecutive patients who underwent EUS-SWE with subsequent liver biopsy were included. EUS-SWE was compared with Fibrosis-4 Index (FIB-4) and VCTE. Area under the receiver-operating characteristic (AUROC) curve analysis was performed, and 90% sensitivity and specific cutoffs were calculated to determine optimal cutoffs.

Sixty-two patients were included. Mean body mass index was 40.74 kg/m2. EUS-SWE was superior to FIB-4 in discriminating significant fibrosis (F2; AUROC, .87 vs .61; P < .0048) and advanced fibrosis (F3; AUROC, .93 vs .63; P < .0001), but not cirrhosis (F4; AUROC, .95 vs .81; P = .099). EUS-SWE was superior to VCTE in predicting advanced fibrosis and cirrhosis (P = .0067 and P = .0022, respectively). The 90% sensitivity cutoffs for EUS-SWE were 7.50, 8.48, and 11.30 for F2, F3, and F4, and the 90% specificity cutoffs were 9.82, 10.20, and 14.60.

In this pilot study, EUS-SWE was superior to FIB-4 and VCTE for liver fibrosis staging in patients with MASLD and obesity. (Clinical trial registration number: NCT05728697.).

Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF's effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. In vivo, QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF's mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5'-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. In vitro, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.

Chronic hepatitis B (CHB) poses a major global public health challenge and is a leading cause of cirrhosis and liver cancer. Hepatic steatosis is common in individuals with CHB compared to the non-CHB population and is particularly prevalent in hepatitis B virus (HBV)-endemic regions, affecting about one-third of CHB patients. The interaction between hepatic steatosis and CHB-related disease progression is complex and still under debate. Evidence demonstrates that co-existing steatosis may worsen liver fibrosis while paradoxically increasing the likelihood of achieving better HBV control. In particular, despite the association of steatotic liver disease (SLD) with lower HBV viral loads and higher rates of HBsAg seroclearance, the coexistence of CHB and SLD can potentially accelerate liver disease progression. Factors such as fat deposition, lipotoxicity, oxidative stress, and chronic inflammation in SLD may foster a pro-fibrotic and pro-carcinogenic environment, accelerating the disease progression. Additionally, loss of global DNA methylation, changes in the immune microenvironment, and genetic susceptibility further contribute to the development of CHB-related cirrhosis and hepatocellular carcinoma (HCC). This review examines the mechanisms driving liver disease progression and the heightened risk of cirrhosis and HCC in patients with concurrent CHB and steatotic liver disease, underscoring the importance of prioritizing antiviral therapy for CHB in addition to addressing SLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition encompassing metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), which can progress to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). The heterogeneous and complex nature of MASLD complicates optimal drug development. Ebastine, an antihistamine, exhibits antitumor activity in various types of cancer. However, its effects on MASH remain unexplored. In the present study, we identified ebastine as a potential treatment for MASH. Our results indicated that ebastine acts as a novel MKRN1 inhibitor by promoting MKRN1 destabilization through self-ubiquitination, leading to AMP-activated protein kinase (AMPK) activation. Ebastine appeared to bind to the C-terminal domain of MKRN1, particularly at residues R298 and K360. Notably, Mkrn1 knockout (KO) mice demonstrated resistance to MASH, including obesity, steatosis, inflammation, and fibrosis under high-fat-high-fructose diet (HFHFD) conditions. Additionally, liver-specific Mkrn1 knockdown using AAV8 alleviated MASH symptoms in HFHFD-fed mice, implicating MKRN1 as a potential therapeutic target. Consistent with these findings, treatment with ebastine significantly reduced the risk of MASH in HFHFD-fed mice, with a decrease in MKRN1 expression and an increase in AMPK activity. Our study suggests that ebastine binds to MKRN1, promoting its destabilization and subsequent degradation by stimulating its ubiquitination. This enhances AMPK stability and activity, suppressing lipid accumulation, inflammation, and fibrosis. Moreover, the knockout of Mkrn1 mice decreased the risk of MASH, suggesting that ebastine could be a promising therapeutic agent for the treatment of MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a primary cause of chronic liver disease, with potential progression to cirrhosis and hepatocellular carcinoma (HCC). Although systemic inflammatory biomarkers are associated with liver diseases, their specific role in MASLD remains unclear. This study examines the association between systemic inflammatory biomarkers and MASLD.

This cross-sectional study enrolled 6613 adults aged 20 years or older from the National Health and Nutrition Examination Survey (NHANES) spanning from 2017 to March 2020. Among these participants,, 34.67% were aged 40-59 years, 50.85% were female, and 63.26% were Non-Hispanic White. We investigated 10 inflammatory biomarkers: ALI, SIRI, SII, SIPS, IBI, NLR, PLR, CAR, LMR, and PNI. Logistic regression models were performed to assess the linear association between systemic inflammatory biomarkers and MASLD. Restricted cubic spline (RCS) regression was employed to explore potential nonlinear relationships between biomarkers and MASLD risk. Additionally, subgroup analyses were conducted to examine the influence of various demographic and clinical characteristics on the observed associations.

After adjusting for key confounders, NLR and PLR exhibited negative association with MASLD risk, while ALI, CAR, and PNI exhibited the opposite association (P < 0.05). Most biomarkers, including ALI, SIRI, IBI, CAR, LMR, and PNI, exhibited significant non-linear correlations with MASLD (P < 0.05). Subgroup analyses revealed substantial age-related differences in the association between ALI and MASLD risk, as well as varying relationships between PNI and MASLD risk across various cardiovascular outcomes (P < 0.05).

Systemic inflammatory biomarkers are significantly associated with MASLD risk. Large-scale prospective studies are warranted to confirm these findings and elucidate the underlying mechanisms.

Over 30% of people worldwide suffer from metabolic dysfunction-associated steatotic liver disease (MASLD), a significant global health issue. Identifying and preventing high-risk individuals for MASLD early is crucial. The purpose of our study is to investigate the factors related to the development of MASLD and develop a risk prediction model for its occurrence.

The study included 5107 subjects, divided into training and validation groups in a 7:3 ratio using a random number table method. Collinearity diagnosis and Cox regression were used to identify factors associated with MASLD incidence, and a risk prediction model was created. The model's accuracy, reliability, and clinical applicability were assessed.

Our study indicated that male, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), serum uric acid to creatinine ratio (SUA/Cr) and white blood cell (WBC) were associated with MASLD incidence. The elements were determined to be crucial for creating a risk prediction model. The model showed strong discriminative potential with a C-index of 0.783 and the time-dependent AUCs of 0.781, 0.789, 0.814 and 0.796 for 1-4 years in the training group, and a C-index of 0.788 and the time-dependent AUCs of 0.798, 0.782, 0.787 and 0.825 for 1-4 years in validation. Calibration curves confirmed the model's accuracy, and decision curve analysis (DCA) validated its clinical utility.

The model may provide clinical physicians with a reliable method for identifying high-risk populations for MASLD and serve as a guide for developing prediction models for other diseases.

Chronic hepatitis B (CHB) affects > 300 million people worldwide. The combination of CHB and cardiometabolic co-morbidities increases the risk of liver-related morbidity and mortality. However, international guidelines for CHB treatment do not provide recommendations for follow-up examinations or treatment of patients with CHB and cardiometabolic comorbidities. In studies investigating cardiometabolic co-morbidity in patients with CHB, inconsistent findings have been observed, and both lower and higher prevalence of cardiometabolic co-morbidities compared to the general population have been reported. It is unclear whether patients with CHB living in Denmark have an increased prevalence of cardiometabolic co-morbidities.

To investigate the prevalence of cardiometabolic comorbidities in patients with CHB and matched non-CHB comparison group.

We examined patients with CHB and age-, sex-, body mass index (BMI)-, and country-of-birth matched comparison group. Defining cardiometabolic co-morbidity: Obesity (BMI > 25 kg/m2/abnormal waist-to-hip ratio), metabolic dysfunction-associated steatotic liver disease (MASLD), hypercholesterolemia (total-cholesterol > 5 mmol/L/statin use), hypertension (systolic ≥ 135 mmHg/ diastolic ≥ 85 mmHg/antihypertensive medication) and type 2 diabetes (T2D) (2-hour oral glucose tolerance test glucose > 11.1 mmol/L/HbA1c > 48 mmol/mol/ antidiabetic medication). Physical activity was evaluated using maximal oxygen consumption (VO2max), activity monitors, and a questionnaire.

We included 98 patients with CHB and 49 persons in the comparison group. The two groups were well-matched, showing no significant differences in age, sex, BMI, country-of-birth, education, or employment. Among patients with CHB, the following prevalence of cardiometabolic co-morbidity was found: 77% were obese, 45% had MASLD, 38% had hypercholesterolemia, 26% had hypertension, and 7% had T2D, which did not differ significantly from the comparison group, apart from lower prevalence of hemoglobin A1c (HbA1c) ≥ 48 mmol/L or known T2D. Both groups had low VO2max of 27 mL/kg/minute in the patients with CHB and 30 mL/kg/minute in the comparison group, and the patients with CHB had a shorter self-assessed sitting time.

The patients with CHB and the comparison group were well-matched and had a similar prevalence of cardiometabolic comorbidities. Furthermore, both groups had low levels of physical fitness.

Fatty liver is considered to be the most common chronic liver disease with a high global incidence, which can lead to cirrhosis and liver cancer in severe cases, and there is no specific drug for the treatment of fatty liver in the clinic. The use of lipid nanosystems has the potential to be an effective means of fatty liver treatment. The pathogenesis and intervening factors associated with the development of fatty liver are reviewed, and the advantages and the disadvantages of different lipid nanosystems for the treatment of fatty liver are comprehensively discussed, including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, microemulsions, and phospholipid complexes. The composition and characterisation of these lipid nanosystems are highlighted and summarised with a view to improving the efficiency of lipid nanosystems for the treatment of fatty liver. In addition, active targeting and passive targeting strategies used for fatty liver therapy are discussed in detail.

Chronic liver diseases pose a serious public health issue. Identifying patients at risk for advanced liver fibrosis is crucial for early intervention. The Fibrosis-4 score (FIB-4), a simple non-invasive test, classifies patients into three risk groups for advanced fibrosis. This study aimed to estimate the prevalence of patients at risk for advanced hepatic fibrosis at a Swiss tertiary care hospital by calculating the FIB-4 score in routine blood analysis.

A retrospective study was conducted using data from 36,360 patients who visited outpatient clinics at eight main clinics of the University Hospital Bern in Switzerland. The data collection period ran from January 1st to December 31st, 2022. Patients attending the hepatology outpatient clinic were excluded. We then calculated the overall and clinic-specific prevalence of patients falling into the high risk category for advanced fibrosis according to FIB-4.

Among the 36,360 patients, 26,245 (72.2%) had a low risk of advanced fibrosis (FIB-4 <1.3), whereas 3913 (10.8%) and 2597 (7.1%) patients were flagged to have a high risk of advanced fibrosis (FIB-4 >2.67 and FIB-4 >3.25 respectively). Geriatrics and Cardiology had the highest proportions of patients at risk for advanced fibrosis over all clinics.

This study demonstrates a high prevalence of high FIB-4 score in a Swiss tertiary care hospital. The implementation of the automatically generated FIB-4 score in daily practice, not only in primary care, but also within tertiary care hospitals, could be crucial for early identification of outpatients at high risk of advanced liver fibrosis requiring further hepatological investigations.

With the rising prevalence of type 2 diabetes mellitus (T2DM) and obesity, several previously under-recognised complications associated with T2DM are becoming more evident. The most common of these emerging complications are metabolic dysfunction-associated steatotic liver disease (MASLD), cancer, dementia, sarcopenia, and frailty, as well as other conditions involving the lung, heart, and intestinal tract. Likely causative factors are chronic inflammation and insulin resistance, whereas blood glucose levels appear to play a lesser role. We discuss these complications and the new approaches being developed to prevent and manage them, especially incretin-based therapies. We argue that these new interventions may work in a complementary way to other proven cardiorenal protective therapies to reduce the burden of T2DM complications.

With the obesity pandemic, metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease and a leading cause of end-stage liver disease and liver-related deaths in the USA. Therefore, we aimed to compare the long-term outcomes of patients with MASLD and cirrhosis with and without bariatric surgery.

Patients were retrospectively identified from the California Department of Healthcare Access and Information database, 2005 to 2019, for a population-based cohort study. Propensity score matching (PSM) was used to balance background risks between patients with cirrhosis who underwent bariatric surgery and those who did not. Overall, liver-related and non-liver-related mortality were analyzed.

Of 91,708 eligible patients with MASLD and cirrhosis, PSM yielded 2,107 patients who underwent bariatric surgery and 8,428 non-bariatric controls. Compared to matched controls, patients who underwent bariatric surgery had lower 5-year overall (24.9% vs. 37.1%; p<0.0001), liver-related (3.3% vs. 14%; p<0.0001), and non-liver-related mortality (22.3% vs. 26.9%; p=0.046). In multivariable analysis, bariatric surgery was associated with decreased overall mortality (adjusted hazard ratio [aHR]=0.63; p<0.0001), liver-related (aHR=0.24; p<0.0001), and non-liverrelated (aHR=0.81; p=0.0026) mortality. However, only laparoscopic surgeries were associated with lower overall mortality (aHR=0.39; p<0.0001) whereas open surgeries were associated with higher overall mortality (aHR=1.24; p=0.022).

Patients with MASLD and cirrhosis who underwent bariatric surgery, specifically laparoscopic approaches, had significantly lower mortality risk than non-surgical counterparts.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LALD). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal-/- mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal-/- mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.

The principal limitations of the term non-alcoholic fatty liver disease (NAFLD) are the reliance on exclusionary confounder terms and the use of potentially stigmatizing language. Within three years, NAFLD went through two name changes, from NAFLD to metabolic-dysfunction-associated fatty liver disease (MAFLD) to metabolic dysfunction-associated steatotic liver disease (MASLD). However, there is no Asian consensus statement on the renaming of MASLD, and evidence on the epidemiology and characteristics in the Asia population under different diagnostic criteria remain limited. This study aimed to fill these gaps by analyzing the prevalence and characteristics of MASLD, NAFLD, and MAFLD in an Asian population.

A retrospective, cross-sectional study was conducted in regional China with participants from the health management database in 2017-2022. Demographic and laboratory metabolic profile and body composition data were obtained. Hepatic steatosis were diagnosed by ultrasound. The likelihood of having fibrosis was assessed using the NAFLD fibrosis score (NFS). Recently proposed criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) were applied.

A total of 20,226 subjects were included for final analysis. 7465 (36.91%) participants were categorized as MASLD patients, 10,726 (53.03%) participants were MAFLD, and 7333 (36.26%) participants were NAFLD. Compared with MAFLD, body composition of MASLD and NAFLD patients were obviously different. MASLD patients were older, had a higher body mass index and percentage of male gender, and had a higher ALT, diastolic blood pressure, triglyceride, and waist circumference but lower High-Density Lipoprotein Cholesterol (HDL-C) than non-MASLD patients. Using binary regression analysis, we found for the first time that putative bone mass (OR = 4.62, 95CI% 3.12-6.83) is associated with the risk of developing MASLD. The area under the receiver operating curve (AUC) for predicting cardiovascular outcomes (CV) was 0.644 for MAFLD and 0.701 for MASLD.

MASLD (36.91%) prevalence was closed to NAFLD (36.26%) and lower than MAFLD (53.03%). Presumed bone mass might be the predictor of disease progression in MASLD patients. MASLD better identifies patients likely to have a higher risk of metabolic disorders or CV events.

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a broad condition characterized by lipid accumulation in the liver tissue, which can progress to fibrosis and cirrhosis if left untreated. Traditionally, liver biopsy is the gold standard for evaluating fibrosis. However, non-invasive biomarkers of liver fibrosis are developed to assess the fibrosis without the risk of biopsy complications. Novel serum biomarkers have emerged as a promising tool for non-invasive assessment of liver fibrosis in MAFLD patients. Several studies have shown that elevated levels of Mac-2 binding protein glycosylation isomer (M2BPGi) are associated with increased liver fibrosis severity in MAFLD patients. This suggests that M2BPGi could serve as a reliable marker for identifying individuals at higher risk of disease progression. Furthermore, the use of M2BPGi offers a non-invasive alternative to liver biopsy, which is invasive and prone to sampling errors. Overall, the usage of M2BPGi in assessing liver fibrosis in MAFLD holds great promise for improving risk stratification and monitoring disease progression in affected individuals. Further research is needed to validate its utility in clinical practice and establish standardized protocols for its implementation.

We demonstrated in the randomized 18-month DIRECT PLUS trial (n = 294) that a Mediterranean (MED) diet, supplemented with polyphenol-rich Mankai duckweed, green tea, and walnuts and restricted in red/processed meat, caused substantial intrahepatic fat (IHF%) loss compared with 2 other healthy diets, reducing NAFLD by half, regardless of similar weight loss. Here, we investigated the baseline proteomic profile associated with IHF% and the changes in proteomics associated with IHF% changes induced by lifestyle intervention.

We calculated IHF% by proton magnetic resonance spectroscopy (normal IHF% <5% and abnormal IHF% ≥5%). We assayed baseline and 18-month samples for 95 proteomic biomarkers.Participants (age = 51.3 ± 10.8 y; 89% men; and body mass index = 31.3 ± 3.9 kg/m 2 ) had an 89.8% 18-month retention rate; 83% had eligible follow-up proteomics measurements, and 78% had follow-up proton magnetic resonance spectroscopy. At baseline, 39 candidate proteins were significantly associated with IHF% (false discovery rate <0.05), mostly related to immune function pathways (eg, hydroxyacid oxidase 1). An IHF% prediction based on the DIRECT PLUS by combined model ( R2 = 0.47, root mean square error = 1.05) successfully predicted IHF% ( R2 = 0.53) during testing and was stronger than separately inputting proteins/traditional markers ( R2 = 0.43/0.44). The 18-month lifestyle intervention induced changes in 18 of the 39 candidate proteins, which were significantly associated with IHF% change, with proteins related to metabolism, extracellular matrix remodeling, and immune function pathways. Thrombospondin-2 protein change was higher in the green-MED compared to the MED group, beyond weight and IHF% loss ( p = 0.01). Protein principal component analysis revealed differences in the third principal component time distinct interactions across abnormal/normal IHF% trajectory combinations; p < 0.05 for all).

Our findings suggest novel proteomic signatures that may indicate MRI-assessed IHF state and changes during lifestyle intervention. Specifically, carbonic anhydrase 5A, hydroxyacid oxidase 1, and thrombospondin-2 protein changes are independently associated with IHF% change, and thrombospondin-2 protein change is greater in the green-MED/high polyphenols diet.