To examine the relationship between lipid profile and non-alcoholic fatty liver (NAFL), compare the predictive strengths of different lipid indicators to NAFL, and explore the possible mechanisms.

Male workers from a baseline survey of a cohort of workers in southern China were included. Basic information was collected through face-to-face interviews. Plasma concentrations of fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were determined using a blood biochemical analyzer. Liver sonography was used to identify NAFL cases. Regression models were used to calculate ORs, and examine the association between C-reactive protein (CRP) levels and lipid profiles. Restricted cubic spline regression with four knots was used to examine the dose-response relationship, and mediation analysis was employed to examine the mediation effect.

h Among the 4016 male workers, 829 (20.64%) were diagnosed with NAFL. Compared with normal lipid profile, individuals with abnormal lipid profile had higher prevalence of NAFL (OR=2.27, 95%CI: 1.85-2.79 for TG; OR=1.45, 95%CI: 1.03-2.04 for TC; OR=1.56, 95%CI: 1.21-2.02 for HDL; OR=1.65, 95%CI: 1.25-2.18 for LDL; OR=2.28, 95%CI: 1.87-2.77 for dyslipidaemia) after adjusting for potential confounders. Dose-response relationships were observed among TG, HDL, and NAFL. In addition, no significant mediation effect of C-reactive protein (CRP) was found in the association between lipid profiles and NAFL.

Abnormal TG, TC, HDL, and LDL levels were all positively associated with NAFL, while CRP has no mediating effect, and TG tended to be a better predictor of NAFL.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising sharply, yet treatment options remain inadequate. To uncover new therapeutic targets for MASLD, we conducted a comprehensive proteome-wide Mendelian randomization (MR) and phenome-wide association study (PheWAS).

Discovery MR utilized protein quantitative trait loci (pQTL) data on 4907 plasma protein levels from 35,559 individuals, alongside genome-wide association study (GWAS) on MASLD from the Million Veteran Program (68,725 cases / 95,482 controls). Validation comprised five pairwise combinations of these discovery datasets with three additional datasets: pQTL data for 2923 proteins from the UK Biobank, and liver biopsy-confirmed MASLD GWAS (1483 cases/17,781 controls) and MRI-liver fat GWAS (31,377 subjects) (excluding discovery pair). Candidate proteins underwent druggability assessment and on-target side effect evaluation via PheWAS.

We identified 26 proteins associated with MASLD after Bonferroni correction (P < 1.16 × 10-5), with 19 of them showing no significant reverse association. Interleukin-6 (IL-6), alpha-1-antitrypsin (α1-antitrypsin), 5-hydroxytryptamine receptor 7 (5-HT7R), ephrin-B1 (EFNB1), and protein MENT (CA056) were replicated. Notably, IL-6 (OR = 2.02; 95 % CI 1.54-2.64), 5-HT7R (OR = 2.73; 95 % CI 1.96-3.80), and EFNB1 (OR = 1.82; 95 % CI 1.59-2.08) were positively associated with MASLD risk, whereas α1-antitrypsin (OR = 0.84; 95 % CI 0.78-0.90) and CA056 (OR = 0.90; 95 % CI 0.86-0.94) appeared protective. Among these, IL-6, 5-HT7R, and α1-antitrypsin were druggable. PheWAS identified potential cardiovascular side effects for 5-HT7R and α1-antitrypsin.

The integrative study identified several plasma proteins associated with MASLD. IL-6, α1-antitrypsin, 5-HT7R, EFNB1 and CA056 deserve further investigation as potential drug targets for MASLD.

Lonicerae Japonica Flos (LJF) is an edible-medicinal herb, rich in phenolic acids, flavonoids, iridoids and other bioactive ingredients, that has anti-inflammatory, antioxidant, antilipemic, and hepatoprotective effects. However, its effect on non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. The aim of this study was to determine the effect of LJF on liver injury in rats with high-fat diet (HFD)-induced NAFLD. The administration of LJF extract to rats with HFD-induced NAFLD significantly improved their body weight and daily food intake, liver tissue steatosis, lipid droplet vacuolization, and inflammatory cell infiltration. In addition, the LJF extract also improved to varying degrees the serum biochemical parameters, liver lipid content, levels of inflammatory factors, and oxidative stress markers. Among the treatment groups, the LJF high-dose group (LJF-H) showed the most significant improvement effect. Additionally, the correlation matrix heatmap visualization indicated that LJF may ameliorate NAFLD mainly by lowering liver lipid content and improving serum biochemical parameters.

Skeletal muscle alterations (SMA) are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting disease progression and outcomes. Sarcopenia is common in patients with MASLD, with a prevalence ranging from 20% to 40% depending on the population and diagnostic criteria used. In advanced stages, such as metabolic dysfunction-associated steatohepatitis and fibrosis, its prevalence is even higher. Sarcopenia exacerbates insulin resistance, systemic inflammation, and oxidative stress, all of which worsen MASLD. It is an independent risk factor for fibrosis progression and poor outcomes including mortality. Myosteatosis refers to the abnormal accumulation of fat within muscle tissue, leading to decreased muscle quality. Myosteatosis is prevalent (> 30%) in patients with MASLD, especially those with obesity or type 2 diabetes, although this can vary with the imaging techniques used. It reduces muscle strength and metabolic efficiency, further contributing to insulin resistance and is usually associated with advanced liver disease, cardiovascular complications, and lower levels of physical activity. Altered muscle metabolism, which includes mitochondrial dysfunction and impaired amino acid metabolism, has been reported in metabolic syndromes, including MASLD, although its actual prevalence is unknown. Altered muscle metabolism limits glucose uptake and oxidation, worsening hyperglycemia and lipotoxicity. Reduced muscle perfusion and oxygenation due to endothelial dysfunction and systemic metabolic alterations are common in MASLD associated with comorbidities, such as obesity, hypertension, and atherosclerosis. It decreases the muscle capacity for aerobic metabolism, leading to fatigue and reduced physical activity in patients with MASLD, aggravating metabolic dysfunction. Various SMA in MASLD worsen insulin resistance and hepatic fat accumulation, may accelerate progression to fibrosis and cirrhosis, and increase the risk of cardiovascular disease and mortality. Management strategies for SMA include resistance training, aerobic exercise, and nutritional support (e.g., high-protein diets, vitamin D, and omega-3 fatty acids), which are essential for mitigating skeletal muscle loss and improving outcomes. However, pharmacological agents that target the muscle and liver (such as glucagon-like peptide-1 receptor agonists) show promise but have not yet been approved for the treatment of MASLD.

Non-alcoholic fatty liver disease (NAFLD) is a major global health concern, with rising prevalence linked to obesity, insulin resistance, and metabolic syndrome. Timely and accurate identification of individuals at risk is crucial for improving outcomes. Recently, systemic inflammatory and nutritional markers such as the Neutrophil Percentage-to-Albumin Ratio (NPAR) and the Neutrophil-to-Albumin Ratio (NAR) have emerged as promising non-invasive biomarkers for NAFLD. Both ratios reflect inflammation and hepatic nutritional status, offering potential utility in predicting disease presence and progression. This systematic review and meta-analysis aimed to evaluate the diagnostic value of NPAR and NAR in patients with NAFLD.

A comprehensive search was performed across databases including PubMed, Embase, Scopus, and Web of Science from inception to December 28, 2024. Data extraction was carried out using a standardized form, and the methodological quality of included studies was assessed using the Newcastle-Ottawa Scale. Statistical analyses were performed using STATA version 18, employing a random-effects model.

The meta-analysis demonstrated that both the Neutrophil Percentage-to-Albumin Ratio (NPAR) and the Neutrophil-to-Albumin Ratio (NAR) were significantly higher in patients with NAFLD compared to healthy individuals. NPAR showed a standardized mean difference (SMD) of 0.28 (95% CI: 0.22-0.35, P < 0.01), while NAR had a higher effect size with an SMD of 0.69 (95% CI: 0.44-0.93, P < 0.01). The pooled diagnostic performance of NPAR yielded a sensitivity of 69.5% (95% CI: 56.3-82.6%), specificity of 63.1% (95% CI: 46.6-70.0%), and an area under the curve (AUC) of 76.05% (95% CI: 66.3-85.7%). For NAR, the pooled sensitivity was 65.0% (95% CI: 49.0-82.0%), specificity was 63.0% (95% CI: 47.0-79.0%), and AUC was 69.0% (95% CI: 48.0-89.0%).

In conclusion, both NPAR and NAR were found to be elevated in individuals with NAFLD, supporting their potential as non-invasive and accessible biomarkers. These ratios reflect key aspects of systemic inflammation and nutritional status, offering clinical value in early detection and risk stratification. However, given the limited number of studies available-particularly for NAR-further research is needed to confirm these findings, establish standardized thresholds, and assess their performance across diverse populations and clinical settings.

Not applicable.

Metabolic associated steatohepatitis characterized by lipid accumulation, inflammation and fibrosis, is a growing global health issue, contributing to severe liver-related mortality. With limited effective treatments available, there is an urgent need for novel therapeutic strategies. Moringa oleifera, rich in antioxidants, offers potential for combating steatohepatitis, but its cytotoxicity presents challenges. Aloe vera, renowned for its cytocompatibility and anti-inflammatory effects, shows promise in mitigating these risks. Using infrared spectrometry and mass spectrometry, we identified 1586 metabolites from both plants across 84 chemical classes. By encapsulating these phytochemicals in nanoparticles, we achieved increased solubility, cytocompatibility, and gene modulation to hepatic stellate cells affected by steatohepatitis. Chemoinformatic analysis revealed bioactive metabolites, including hesperetin analogs, known to inhibit TGF-β. Our results demonstrate that these nanoparticles not only improved gene expression modulation related to metabolic associated steatohepatitis, particularly TGF-β and COL1A1, but also outperformed free compounds, highlighting their potential as a novel therapeutic approach.

Nonalcoholic fatty liver disease (NAFLD), now known by the name of metabolic dysfunction-associated fatty liver disease (MAFLD), with increased global incidence, has been recognized as a significant metabolic disorder. NAFLD includes a spectrum liver disease from hepatocellular fat accumulation (isolated steatosis) to an advanced form of liver injury known as nonalcoholic steatohepatitis (NASH), which refers to distinct histologic features, including hepatocellular steatosis and injury, necroinflammation, and eventually fibrosis. Nonobese or lean individuals associated with metabolic dysregulation usually demonstrated diverse risk factors compared to obese MAFLD. The presence of normal range body mass index (BMI) and excess visceral adiposity with increased cardiometabolic and renal comorbidities, along with sarcopenia, has been evidenced to be associated with lean MASH. Genetic predispositions accompanying lifestyle and environmental factors contribute to disease initiation and progression. The genetic influence in pathophysiology indicated the significant contributions of the following genes: PNPLA3, TM6SF2, APOB, LIPA, MBOAT7, and HSD17B13, and the impact of their disease-specific variants in the development of obesity-independent MASH. The epigenetic modifications exhibited differential DNA methylation patterns in the genes involved in lipid metabolism, particularly hypomethylation of PEMT. Diet-induced and genetic animal models of lean MASH, including Slc: Wistar/ST rats, PPAR-α, PTEN, and MAT1A knockout mice models, are indicated to be pivotal in the exploration of disease progression and observing the effect of therapeutic interventions. This comprehensive review comprises the molecular and genetic pathophysiology, molecular diagnostics, and therapeutic aspects of lean MASH to enunciate a diagnostic approach that combines detailed clinical phenotyping regarding genomic analysis.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) can be recapitulated in mice fed a high-fat diet. The development of MASLD and the diet per se can both perturb metabolism in key extrahepatic tissues such as the heart, kidney, and skeletal muscle. To date, these alterations have not been well described in this animal model of diet-induced MASLD. Methodology: Male C57BL/6J mice were fed either standard (SC, n = 12) or high-fat chow (HF, n = 11) for 18 weeks. Metabolites were extracted from the heart, kidney, and skeletal muscle and analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy, along with multivariate and univariate statistical analyses. Results: Kidney metabolite profiles exhibited the largest differences between HF and SC diets, followed by those of skeletal muscle and then the heart. Some alterations were common across all tissues, namely decreased trimethylamine and elevated levels of linoleic acid and polyunsaturated fatty acids in HF compared to SC (p < 0.05 for all three metabolites). Overall, the metabolite variations were consistent with shifts in carbohydrate and lipid substrate selection for oxidation, increased tissue stress in the heart and kidneys, and altered choline metabolism. These findings may serve as additional important descriptors of MASLD onset and progression.

Perfluorooctanoic acid (PFOA) is a prevalent and chemically stable environmental contaminant. Our preliminary data suggest that chronic exposure to PFOA induces colonic damage in mice that resembles inflammatory bowel disease (IBD). Anti-TNF therapies are commonly used in the clinical management of IBD. Building upon our previous findings, we administered anti-TNF treatment to mice exposed to PFOA. Our results show that anti-TNF therapy significantly reduces the colonic inflammatory response, activation of the NLR family pyrin domain containing 3 (NLRP) inflammasome, and apoptosis induced by PFOA. Additionally, anti-TNF treatment restores intestinal barrier integrity, which is disrupted by PFOA exposure, and enhances the regenerative capacity of the colon by promoting intestinal stem cell function. Furthermore, anti-TNF therapy effectively mitigates hepatic inflammation, liver dysfunction, lipid metabolism disturbances, NLRP3 inflammasome activation, and apoptosis in the liver triggered by PFOA. In conclusion, our study provides compelling evidence that anti-TNF therapy can alleviate both colonic and hepatic injuries induced by PFOA exposure. This research expands our understanding of environmental toxin-induced diseases and offers potential therapeutic strategies for managing PFOA-related disorders in the future.

This study aimed to investigate the relationship between lung function and metabolic dysfunction-associated steatotic liver disease (MASLD), and the potential mediating role of type 2 diabetes.

Data from the 2007 to 2012 National Health and Nutrition Examination Survey were used. Logistic regression analysis was employed to assess the association between lung function parameters [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC] and MASLD prevalence while exploring type 2 diabetes mediation. Further analyses included linkage disequilibrium score regression, Mendelian randomization, and meta-analysis to examine the causal relationship between lung function and MASLD, considering type 2 diabetes mediation.

The results showed that higher FVC and FEV 1 levels were associated with decreased MASLD risk, with type 2 diabetes partially mediating this relationship. Genetic analyses supported a causal link between lung function and MASLD, with type 2 diabetes acting as an intermediary. However, no significant association was found between FEV 1 /FVC and MASLD.

The study identified a causal relationship between lung function and MASLD, with type 2 diabetes playing a partial mediating role.

In this article, we discuss the recently published article by Soni et al. This study explores the effectiveness of a comprehensive digital health program, RESET care, which integrates personalized dietary plans, structured exercise, and cognitive behavioral therapy delivered through a mobile app equipped with Internet of Things devices such as body composition analyzers and smartwatches. Metabolic dysfunction-associated liver disease (MASLD), a global health burden affecting approximately 25% of the population, demands sustainable lifestyle modifications as its primary management strategy. The study reports that 100% of participants in the comprehensive intervention group (diet + exercise + cognitive behavioral therapy) achieved a weight reduction ≥ 7% (6.99 ± 2.98 kg, 7.00% ± 3.39%; P = 0.002), a clinically significant threshold for MASLD improvement. In addition, participants showed a mean weight reduction of 6.99 kg (101.10 ± 17.85 vs 94.11 ± 17.38, P < 0.001) and a body mass index reduction of 2.18 kg/m² (32.90 ± 3.02 vs 30.72 ± 3.41, P < 0.001). These results underscore the potential of digital health platforms to provide scalable, evidence-based solutions for the treatment of MASLD. While these results highlight the potential of digital platforms in the scalable and personalized management of MASLD, the small study sample size and short duration of follow-up limit the generalizability of the results. Future large-scale, long-term trials are needed to confirm sustained benefits, cost-effectiveness, and broader applicability. This letter contextualizes the study within the evolving landscape of MASLD management and emphasizes the clinical implications of integrating digital technologies into standard care.

Non-alcoholic fatty liver disease (NAFLD) is a long-term metabolic condition marked by unusual fat buildup in the liver, with an increasing occurrence worldwide. Forsythoside A (FA), a bioactive component of Forsythia suspensa, has anti-inflammatory, antioxidative, and hepatoprotective effects. This study investigates the mechanisms by which FA may treat NAFLD. Using bioinformatics tools, 35 potential targets of FA were identified, and a protein-protein interaction network was constructed. KEGG and GO enrichment analyses highlighted important pathways associated with NAFLD. The effects of FA were confirmed using both in vitro and in vivo NAFLD models. Matrix Metalloproteinase 9 (MMP9), and Tumour Necrosis Factor Alpha (TNFɑ), were identified as core targets. KEGG analysis showed that FA affects metabolic, TNF signalling, and insulin resistance pathways. In vitro and in vivo, FA reduced lipid accumulation and modulated TNFɑ, MMP9, and ALB expression. FA may treat NAFLD by modulating the TNFɑ/MMP9/ALB pathway, providing new therapeutic targets and insights for NAFLD treatment.

Psoriasis is associated with a higher cardiovascular disease burden, with systemic inflammation being the root cause of this association. The concept of residual inflammation (RI) was defined in patients with features of high-risk atherosclerosis who had increased inflammatory markers in blood, as characterized by high-sensitivity CRP, despite receiving optimal medical therapy. This study aims to assess RI in patients with psoriasis undergoing biologic therapy, specifically defined as high-sensitivity CRP ≥ 2 mg/l despite achieving a PASI ≤ 2. A prospective observational study was conducted across 3 international cohorts (Spain, United States, and Sweden) comprising 209 patients with psoriasis who achieved a PASI ≤ 2 after stable biologic therapy. RI was observed in 36.3% of patients and was significantly associated with higher body mass index, metabolic dysfunction-associated steatotic liver disease, increased baseline systemic inflammation, and visceral adipose tissue. Female sex was identified as a predictor of RI in the 3 cohorts. The study concludes that RI persists despite optimal skin response and is strongly linked with obesity and fatty liver disease. These conditions are highlighted as critical drivers and treatment targets of inflammation in psoriasis.

Drug development for complex diseases such as NAFLD is often lengthy and expensive. Drug repurposing, the process of finding new therapeutic uses for existing drugs, presents a promising alternative to traditional approaches. This study aims to identify potential repurposed drugs for NAFLD by leveraging disease-disease relationships and drug-target data from the BioSNAP database.

A bipartite network was constructed between drugs and their target genes, followed by the application of the BiClusO bi-clustering algorithm to identify high-density clusters. Clusters with significant associations with NAFLD risk genes were considered to predict potential drug candidates. Another set of candidates was determined based on disease similarity.

A novel ranking methodology was developed to evaluate and prioritize these candidates, supported by a comprehensive literature review of their effectiveness in NAFLD treatment.

This research demonstrates the potential of drug repurposing to accelerate the development of therapies for NAFLD, offering valuable insights into novel treatment strategies for complex diseases.

Current pharmacological treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) are often accompanied by adverse side effects. Consequently, probiotics, prebiotics, and synbiotics, which are bioactive compounds from fermented foods and offer fewer side effects, have garnered significant attention as alternative therapeutic strategies.

This study aims to assess the efficacy of microbial therapies-probiotics, prebiotics, and synbiotics-in managing MASLD and to identify the optimal treatment modality for various clinical indicators through a comprehensive umbrella review of meta-analyses.

A thorough literature search was conducted across PubMed, Web of Science, EMBASE, Cochrane Library, and Scopus to identify 23 meta-analyses over 18,999 MASLD patients as of November 2024.

The findings indicate that microbial treatments positively influence levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), homeostasis model assessment of insulin resistance (HOMA-IR), insulin, tumour necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and body mass index (BMI) in MASLD patients. Notably, probiotics were most effective in reducing TC, ALT, AST, GGT, insulin, TNF-α, and BMI; prebiotics were most effective in reducing TG; and synbiotics were most effective in reducing LDL-C, HOMA-IR, and CRP.

Our study provides robust evidence for microbial treatments of MASLD, enabling targeted interventions for different indicators.

To evaluate inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, 8, 6, soluble IL-6 receptors (sIL-6R) and fragmented cytokeratin-18 (FCK-18) as indicators of non-alcoholic steatohepatitis (NASH).

173 NASH patients aged 47.0±10.8 years were examined: 118 (68.2%) - men, 55 (31.8%) - women. The following markers were determined: TNF-α (Human TNFα Platinum ELISA, eBioscience, Austria), IL-1β, 8, 6 (Vector-Best, Russia), sIL-6R (Human sIL-6R ELISA, eBioscience, Austria), FCK-18 (TPS ELISA, Biotech, Sweden), insulin (Insulin TEST System, USA), HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) and NAFLD fibrosis score (NFS) were calculated.

The highest level in NASH patients compared with healthy individuals was observed for IL-6 - 8.4±1.6 pg/ml versus 2.8±0.9 pg/ml (p=0.001), FCK-18 - 295.3±56.3 U/l versus 110.5±30.2 U/l (p=0.0001), then IL-8 - 17.3±6.7 pg/ml vs 7.6±1.9 pg/ml (p=0.003), TNF-α - 6.3±0.4 pg/ml versus 4.1±0.8 pg/ml (p=0.0001), sIL-6R - 151.5±21.2 ng/ml vs 95.9±12.5 ng/ml (p<0.05); IL-1β did not change - 5.3±1.4 pg/ml versus 4.7±1.5 pg/ml (p=0.3) respectively. FCK-18 showed the highest correlations with TNF-α (r=0.73), HOMA-IR (r=0.73), alanine aminotransferase (r=0.71), erythrocyte sedimentation rate (r=0.23), IL-6 (r=0.22); p<0.05. TNF-α correlated with FCK-18 (r=0.73), cholesterol (r=0.61), albumin (r=-0.42), fibrinogen (r=0.21), leukocyte count (r=0.21); p<0.05. IL-8 correlated with triglycerides (r=0.79) and HDL (r=-0.77), IL-6 - with NFS (r=0.63) and FCK-18 (r=0.22), rIL-6R - with aspartate aminotransferase (r=0.62); p<0.05.

TNF-α, IL-8, 6, sIL-6R and FCK-18 should be used as non-invasive biomarkers of NASH.

Metabolic dysfunction-associated steatohepatitis (MASH) has become a serious public health problem, posing an increasingly dangerous threat to human health owing to its increasing prevalence and accompanying intra- and extrahepatic adverse outcomes. Rifaximin is considered to have therapeutic potential for MASH; however, its efficacy remains controversial. Our study aimed to observe the ameliorative effects of rifaximin and explore its possible mechanisms at the cellular level. 1. 42 male C57BL/6J mice were divided into 3 groups, the CON group and MCD group were fed with normal feed and MCD feed for 12 weeks respectively, and the MCD + RFX group was treated with rifaximin by gavage for 4 weeks on the basis of MCD feed. Hematoxylin-eosin staining, Sirius red staining and immunohistochemical staining were used to observe the histopathological changes of liver and intestine. Differences in liver transaminases, inflammatory factors, fibrosis indexes and intestinal tight junction proteins were compared among the 3 groups of mice. 2. A MASH cell model was constructed by inducing HepG2 cells with free fatty acids to observe the effects of rifaximin on MASH in vitro. In addition, the effects of rifaximin on TLR4/NF-κB signaling pathway were explored by applying TLR4 agonist LPS and TLR4 inhibitor TAK-242. Hepatic histopathology was significantly improved in MASH mice after rifaximin treatment, and their serum alanine aminotransferase and aspartate aminotransferase levels were (72.72 ± 5.68) U/L and (222.8 ± 11.22) U/L, respectively, which were significantly lower than those in the MCD group [(293.3 ± 10.69) U/L and (414.1 ± 36.29) U/L, P < 0.05], and the levels of inflammatory factors and fibrosis indicators were reduced. Rifaximin ameliorated intestinal barrier injury with increased expression of intestinal tight junction protein ZO-1 in the MCD + RFX group of mice, and the concentration of LPS-binding proteins (4.92 ± 0.55 vs. 15.82 ± 1.71, P < 0.05) was lower than that in the MCD group. In the NASH cell model, rifaximin similarly exerted inhibitory effects on its inflammatory factors and TLR4/NF-κB signaling pathway. Application of TLR4 inhibitors weakened the inhibitory effect of rifaximin on MASH. Our study supports rifaximin as a potential treatment for MASH, with potential mechanisms related to improving intestinal barrier integrity and downregulating the TLR4/NF-κB signaling pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a globally prevalent liver disease, closely linked to the rising incidence of obesity, diabetes, and metabolic syndrome. Dapagliflozin (DaPa), a sodium-glucose cotransporter-2 inhibitor, is primarily prescribed for diabetes management. It has shown potential efficacy in managing MASLD in clinical settings. However, the molecular mechanisms underlying the effects of DaPa on MASLD remain poorly understood. Hence, we aimed to investigate the role of and mechanisms underlying DaPa in MASLD.

Male diet-induced obese (DIO) C57BL/6J mice were injected with streptozotocin (STZ), followed by a high-fat diet regimen to stimulate metabolic dysfunction. Subsequently, they received DaPa via gavage for 5 weeks. Hepatic lipid accumulation, pathological alterations, inflammatory markers, and liver fibrosis were assessed.

DaPa administration reduced liver fat accumulation in DIO mice. Additionally, it decreased oxidative stress and lipid peroxide levels, which was attributed to the upregulation of glutathione and the downregulation of malondialdehyde and reactive oxygen species levels. Notably, DaPa downregulated the inflammatory response and reduced liver fibrosis.

DaPa protects against MASLD by inhibiting lipid accumulation, inflammation, oxidative stress, and liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease, characterized by hepatic lipid accumulation. The Fufangduzhong formula (FFDZ) is a traditional Chinese medicine (TCM) formulation composed of Eucommia ulmoides Oliv., Leonurus artemisia (Lour.) S. Y. Hu, Prunella vulgaris Linn, Uncariarhynchophylla (Miq.) Miq. ex Havil., and Scutellaria baicalensis Georgi. It has demonstrated hepatoprotective effects and the ability to reduce lipid accumulation. However, its mechanisms against NAFLD remain unclear.

UPLC-MS/MS was used to identify FFDZ metabolites. C57BL/6J mice were fed a high-fat diet (HFD) supplemented with or without FFDZ (HFD+L, 0.45 g/kg/d; HFD+H, 0.9 g/kg/d) for 12 weeks. Biochemical indicators and histopathological observations were utilized to assess the extent of metabolic homeostasis disorder and hepatic steatosis. An analysis of differentially expressed genes and regulated signaling pathways was conducted using hepatic transcriptomics. Metabolomics analysis was performed to investigate the significantly changed endogenous metabolites associated with NAFLD in mice serum using UPLC-Q-TOF/MS. Western blot was employed to detect proteins involved in the lipid metabolism-related signaling pathways. Oleic acid-induced hepatic steatosis was used to examine the lipid-lowering effect of FFDZ-containing serum in vitro.

A total of eight active metabolites were identified from the FFDZ formula and FFDZ-containing serum through UPLC-MS/MS analysis. FFDZ reduced body weight, liver weight, and levels of inflammatory cytokines, and it ameliorated hepatic steatosis, serum lipid profiles, insulin sensitivity, and glucose tolerance in mice with HFD-induced NAFLD. Transcriptomics revealed that FFDZ modulated the lipid metabolism-related pathways, including the PPAR signaling pathway, Fatty acid metabolism, and AMPK signaling pathway. Meanwhile, Western blot analysis indicated that FFDZ downregulated the expression of lipid synthesis-related proteins (Srebp-1c, Acly, Scd-1, Fasn, Acaca, and Cd36) and upregulated the fatty acid oxidation-related proteins (p-Ampk, Ppar-α, and Cpt-1). Furthermore, metabolomics identified FFDZ-mediated reversal of phospholipid dysregulation (PC, PE, LPC, LPE). Additionally, FFDZ-containing serum remarkedly reduced OA-induced lipid accumulation in HepG2 cells.

The present results demonstrate that FFDZ exerts anti-NAFLD effects by enhancing glucose tolerance and insulin sensitivity, as well as regulating the Ampk signaling pathway to ameliorate lipid metabolism disorder, lipotoxicity, hepatic steatosis, and inflammatory responses.

Spirulina platensis low-molecular-weight peptides (SP) have been reported to exhibit antioxidant and hepatoprotective properties. However, the limited bioavailability and solubility of SPs limit their potential applications. In this study, to examine the potential anti-obesity effects and underlying mechanisms of SPs, high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) model rats were treated with SPs and SP-loaded nanoliposomes. Furthermore, hepatic biochemical parameters, inflammatory markers, histopathological changes, and genes involved in AMPK signaling were analyzed. SP-loaded nanoliposomes demonstrated a spherical shape with slower and sustained SP release. SP and SP-loaded nanoliposomes mitigated hepatic damage by lowering serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and increasing hepatic antioxidant enzymes, which are manifested in improving histopathological findings. In addition, notably, SP-loaded nanoliposomes downregulated lipogenic fatty acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c) in the liver. Meanwhile, an upregulation of phosphorylated AMP-activated protein kinase (P-AMPK), lipid acid oxidation-related genes carnitine palmitoyltransferase-1 (CPT-1), and peroxisome proliferator-activated receptor alpha (PPAR-α) was found in the rat liver. This data implies that SP and SP-loaded nanoliposomes exhibit protective potential in rats against the HFD-induced NAFLD, which is mediated through the activation of the AMPK signaling pathway.

The world is experiencing a sudden surge in urban population, especially in developing Asian and African countries. Consequently, the global burden of cardio-metabolic disease (CMD) is also rising owing to gut microbiome dysbiosis due to urbanization factors such as mode of birth, breastfeeding, diet, environmental pollutants, and soil exposure. Dysbiotic gut microbiome indicated by altered Firmicutes to Bacteroides ratio and loss of beneficial short-chain fatty acids-producing bacteria such as Prevotella, and Ruminococcus may disrupt host-intestinal homeostasis by altering host immune response, gut barrier integrity, and microbial metabolism through altered T-regulatory cells/T-helper cells balance, activation of pattern recognition receptors and toll-like receptors, decreased mucus production, elevated level of trimethylamine-oxide and primary bile acids. This leads to a pro-inflammatory gut characterized by increased pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin-2, Interferon-ϒ and elevated levels of metabolites or metabolic endotoxemia due to leaky gut formation. These pathophysiological characteristics are associated with an increased risk of cardio-metabolic disease. This review aims to comprehensively elucidate the effect of urbanization on gut microbiome-driven cardio-metabolic disease. Additionally, it discusses targeting the gut microbiome and its associated pathways via strategies such as diet and lifestyle modulation, probiotics, prebiotics intake, etc., for the prevention and treatment of disease which can potentially be integrated into clinical and professional healthcare settings.

Subclinical ketosis (SCK) is highly prevalent and easily overlooked, with insidious and slow progression of hepatic injury, often characterized by an imbalance in immune homeostasis. In nonruminants, macrophage polarization plays an important regulatory role in hepatic lipid accumulation, fibrosis, and inflammatory processes. Thus, we aimed to investigate the status of hepatic macrophage polarization in SCK cows and to corroborate its association with liver injury and inflammation. Twelve Holstein dairy cows (parity 2-4) were selected, and liver biopsy and blood were collected on the second week postpartum (10-14 d DIM). On the basis of serum beta-hydroxybutyric acid (BHBA) concentrations, selected cows were categorized into healthy (n = 6; BHBA <1.0 mM) and SCK (n = 6; 1.2 mM ≤ BHBA < 3.0 mM) groups. Serum biochemical parameters were measured using an automatic biochemical analyzer, which indicated higher serum levels of BHBA and nonesterified fatty acids and an upregulation of liver injury indicators (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total protein, globulin) in SCK cows compared with healthy cows. The ELISA assays revealed that SCK cows displayed systemic low-grade inflammation, as demonstrated by increased serum levels of haptoglobin, serum amyloid A, TGF-β, IFN-γ, and IL-1β. Liver biopsies revealed pathological histological alterations, hepatic inflammation, and macrophage polarization status. Oil Red staining indicated steatosis, whereas Sirius red staining demonstrated mild extracellular matrix deposition in the liver of SCK cows. The expression of inflammatory response-related proteins (TLR4, p-NFκB, p-I-κB, NLRP3, and Caspase 1) was elevated in the liver of SCK cows, with the increased mean fluorescence intensity of NFκB further confirming the activation of the inflammatory pathway. Furthermore, the levels of pro-inflammatory factors, TNF-α and IFN-γ, were elevated in the tissue homogenate. Macrophage phenotypic changes in SCK cows were further explored based on the results of liver injury and inflammation. Compared with healthy cows, the protein and mRNA abundance of the macrophage marker CD68 in the liver of SCK cows was higher, along with an increased mean fluorescence intensity of CD68. The SCK cows also exhibited reduced mRNA expression of the Kupffer cell marker CLEC4F and elevated chemokine levels (CXCL1 and CCL2). As evidenced by greater protein and mRNA abundance of macrophage M1 polarization markers (iNOS, IL-1β, CD86, IL-6, IL-12b, and CCL3), higher fluorescence intensity of iNOS and CD86, and an increased number of CD68+/CD86+-positive cells observed via immunofluorescence, the macrophage polarization phenotype in the liver of SCK cows was predominantly M1. In contrast, the protein and mRNA abundances of M2 polarization markers (CD206, IL-10, and Arg1) were lower in SCK cows, accompanied by a reduced fluorescence intensity of CD206 and a lower number of CD68+/CD206+-positive cells. Overall, the present study revealed that the number of macrophages in liver is enhanced during subclinical ketosis and is dominated by pro-inflammatory macrophages (M1 macrophages). This could partly explain the increased risk of steatosis, fibrosis, and inflammatory response processes in these cows.

Prior research has highlighted associations between inflammatory cytokines and non-alcoholic fatty liver disease (NAFLD), but causal relationships remain unclear. Employing the Mendelian randomization (MR) approach, this investigation aims to explore the connection between 41 inflammatory cytokines and NAFLD-related diseases.

Our research implemented bidirectional study focusing on 41 cytokines in 8,293 Finns, predicting genetic associations with NAFLD, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. We primarily utilized the inverse variance weighted (IVW) method to evaluate the bidirectional relationships. Additionally, a sensitivity analysis was carried out to ensure the reliability of our findings.

An elevated risk for NAFLD was correlated with both IL-2 (OR = 1.226, 95 % CI = 1.018-1.477, p = 0.031) and TNF-β (OR = 1.151, 95 % CI = 1.011-1.310, p = 0.033). IL-16 is associated with decreased NAFLD risk (OR = 0.820, 95 % CI = 0.719-0.934, p = 0.033). β-NGF (OR = 2.495, 95 % CI = 1.019-6.108, p = 0.045) and SCGFβ (OR = 1.541, 95 % CI = 1.052-2.256, p = 0.026) are linked to higher NASH risk. No significant associations were found for fibrosis and cirrhosis. Furthermore, the causal relationship between genetic predisposition to NAFLD-related diseases and various inflammatory cytokines was established.

Our MR analysis identifies specific cytokines as genetic predictors for NAFLD and NASH. IL-2 and TNF-β increase NAFLD risk, IL-16 appears protective, and β-NGF and SCGFβ are associated with greater NASH risk. These insights are crucial for understanding the etiology and treatment of NAFLD-related diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been linked with sepsis outcomes. However, the immune mechanisms by which MASLD aggravates sepsis severity are unknown. This prospective cohort study aimed to analyze serum cytokine and chemokine kinetics in patients with MASLD and community-acquired sepsis. Out of the 124 patients, 68 (55%) were diagnosed with MASLD. There were no differences in age, sex, comorbidities, baseline sepsis severity, or etiology between the groups. Serum concentrations of 27 cytokines and chemokines on admission and day 5 of hospitalization were analyzed using a multiplex bead-based assay. Patients with MASLD had significantly higher serum concentrations of IL17A, IL-23, IL-33, CXCL10 and TGF-β1. Different cytokine kinetics were observed; patients with MASLD had a decrease in IL-10, IL-23, CXCL10 and TGF-β1, and an increase in IL-33, CXCL5 and CXCL1 on day 5. In the non-MASLD group, there was a decrease in IFN-γ, IL-6, IL-23 and CCL20, and an increase in CCL11 and CXCL5. While TGF-β1 significantly increased in non-MASLD, in MASLD, it decreased on day 5. Kinetics of TGF- β1 and CCL11 were associated with mortality in patients with MASLD. In conclusion, MASLD is linked with distinct cytokine and chemokine profiles during sepsis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally widespread chronic liver condition that may progress to severe liver diseases, including advanced liver fibrosis. The high-sensitivity C-reactive protein-to-high-density lipoprotein cholesterol (hs-CRP/HDL-C) index may be a potential indicator for MASLD and advanced liver fibrosis, given its relevance to inflammation and plasma lipids. In this study, the hs-CRP/HDL-C index was investigated in relation to prevalent MASLD and advanced liver fibrosis. The study analyzed secondary data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 database. The hs-CRP/HDL-C index was calculated by the quotient of hs-CRP and HDL-C. Multiple logistic regression models, Cochran-Armitage trend tests, smooth curve fitting, threshold effect analyses, and stratified analyses were used to evaluate whether the hs-CRP/HDL-C index associated with MASLD and advanced liver fibrosis. The study cohort comprised 3684 participants, of whom 1268 (34.42%) were diagnosed with MASLD and 156 (12.28%) with advanced liver fibrosis. Logistic analyses adjusted for covariates revealed positive associations of the hs-CRP/HDL-C index with MASLD and advanced liver fibrosis, consistent across all subgroups. Smooth curve fitting and threshold effect analyses revealed nonlinear relationships of hs-CRP/HDL-C index with MASLD and advanced liver fibrosis, with inflection points at 0.8 for MASLD and 1.2 for advanced liver fibrosis. Additionally, significant interactions were observed between MASLD and covariates such as gender, smoking status, chronic kidney disease (CKD), and cancer. Similarly, the hs-CRP/HDL-C index exhibited positive correlations with advanced liver fibrosis across diverse subgroups, with notable interactions related to cancer. MASLD and advanced liver fibrosis were associated with hs-CRP/HDL-C index, indicating its potential utility as a clinical marker for these conditions.

The relationship between vascular endothelial function and bone mineral density (BMD) in T2DM patients with metabolic dysfunction associated fatty liver (MAFLD) is still unclear. This study aims to analyse the correlation between vascular endothelial function and BMD or fracture risk in T2DM patients with MAFLD.

A total of 872 T2DM patients aged ≥50 years were enrolled and divided into two groups according to the diagnostic criteria of MAFLD: MAFLD (+) and MAFLD (-). Flow-mediated dilation (FMD) was measured by high-resolution ultrasound to reflect vascular endothelial function. BMD was measured by dual-energy X-ray bone densitometry, and FRAX scores were calculated for 10-year hip fracture risk (HF1) and major osteoporotic fracture risk (MOF).

After multivariate adjustment, there was no significant correlation between FMD and BMD in MAFLD (-) group (p > 0.05). In MAFLD (+) and FMD < 4% group, FMD was positively correlated with WB, LS, and FN BMD, while FMD was negatively correlated with fracture risk and osteoporotic fracture history, and this correlation was only observed in female patients. However, FMD was not correlated with BMD and fracture risk and osteoporotic fracture history in 4%≤FMD ≤ 7% and FMD > 7% groups.

The association of FMD with BMD in T2DM patients with MAFLD varies according to FMD level. The decrease of FMD is associated with reduced BMD and increased fracture risk in female patients with FMD < 4% group. FMD may be an influential factor for the occurrence and development of osteoporosis, and has some clinical value in early diagnosis of osteoporosis in T2DM patients with MAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic disease worldwide, consisting of a broad spectrum of diseases such as simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatic inflammation plays a key role in the pathophysiology of NAFLD. Inflammatory mediators such as cytokines and chemokines are considered as contributing factors to NAFLD development and progression. In the present study, we aimed to investigate the inflammatory protein signatures as predictive disease-specific markers for non-alcoholic fatty liver disease (NAFLD). This cross-sectional study included healthy control (n = 64), NAFL (n = 109), and NASH (n = 60) human subjects. Serum concentrations of various cytokines and chemokines were evaluated using sensitive multiplex assays. We used principal component analysis (PCoA) to reveal distinct differences in the levels of cytokines and chemokines between each of the study groups. Further, a random forest classification model was developed to identify the panel of markers that could predict diseases. The protein-protein network analysis was performed to determine the various signaling pathways associated with the disease-specific panel of markers. Serum concentrations of TNF-α, IL-1β, IL-1ra, G-CSF, PDGF-BB, MCP-1, MIP-1a, MIP-1b, RANTES, eotaxin, IL-8 and IP-10 were significantly increased in NASH group as compared to control group. Furthermore, serum concentrations of IL-9 and IL-13 were significantly lower in the NASH group, whereas IL-2 levels were significantly decreased in the NAFL group when compared to the control group. PCoA results demonstrated statistically significant differences in cytokines and chemokines between each of the study groups (PERMANOVA p = 0.001; R2 = 0.102). RANTES, IL-1ra, MIP-1b, IL-2, and G-CSF could differentiate the NAFL group from the controls; G-CSF, IL-1ra, TNF-α, RANTES, and IL-9 could differentiate the NASH group from the controls; and G-CSF, IL-9, IL-13, eotaxin, and TNF- α could differentiate the NASH group from the NAFL group. Our protein-protein network revealed that these markers are involved in cytokine-cytokine receptor interaction, Th1 and Th2 cell differentiation, TNF, chemokine, JAK/STAT, P13K/Akt, TLR, NOD-like receptor, NF-kB, and adipocytokine signaling pathways which might be responsible for disease pathogenesis. Our study findings revealed a set of distinct cytokine and chemokine markers and they might be considered as biomarkers in distinguishing NASH from NAFL. Future multicentre studies with larger sample size are recommended to determine the potential utility of these panels of markers.

Herpetospermum pedunculosum (Ser.) C.B. Clarke (HP), a traditional Tibetan medicine used to treat hepatobiliary diseases, was confirmed that lignans-enriched ethyl acetate extract of HP (EAHP) could alleviate the hepatic injury by modern pharmacological evidence. However, the effects and potential mechanisms of EAHP against nonalcoholic fatty liver disease (NAFLD) are still unknown.

To reveal the effects of EAHP on NAFLD and explore the potential mechanisms from the perspective of lipidomics and transcriptomics.

UPLC‒Q-TOF‒MS analysis was carried out to investigate the chemical components of EAHP. A Choline-deficient, L-amino acid defined, high fat diet (CDAHFD) was used to establish a NAFLD mouse model. The anti-NAFLD effects of various dosages of EAHP were evaluated by biochemical indexes and histological analysis. Hepatic lipidomic and transcriptomic analysis and multiple bioinformatics methods were used to screen biomarkers and signaling pathways. The levels of the corresponding genes were verified by qPCR.

36 kinds of compounds were identified by UPLC‒Q-TOF‒MS analysis. Oral treatment with EAHP significantly decrease the liver index and the levels of ALT and AST in the serum. The measurements lipid content and Oil Red O staining results suggested that EAHP ameliorated lipid metabolism disorders by reducing the content of TG and LDL-C, increasing HDL-C in the liver. H&E staining and ELISA revealed that EAHP restored hepatic inflammatory infiltration and decrease the levels of IL-1β, IL-6, TNF-α, and increase IL-10 in the serum. Lipidomic analysis showed that EAHP could regulate CDAHFD-induced lipid metabolic disorder. The different lipid metabolites included TG, phosphatidyl choline (PC), diacylglycerol (DG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide (Cer). Transcriptomic analysis revealed that Bmp8b, Nbl1, Rgma, Sphk1, Thbs1, and Ugt8a were important regulators, which were associated with TGF-β signaling pathway and sphingolipid metabolism. The expressions of above genes detected by were qPCR consistent with transcriptomic data.

The ameliorative effects of EAHP on NAFLD are potentially attributable to the regulation of sphingolipid metabolism and TGF-β signaling pathway, etc., which results in abnormal hepatic lipid metabolism and inflammatory response.

Consumption of phytosterols is a nutritional strategy employed to reduce cholesterol absorption, but recent research shows that their biological activity might go beyond cholesterol reduction for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), and novel phytosterol formulations, such as submicron dispersions, could improve these effects. We explored the therapeutic activity of phytosterols, either formulated as submicron dispersions of phytosterols (SDPs) or conventional phytosterol esters (PEs), in a mouse model of MAFLD. MAFLD was induced in mice by atherogenic diet (AD) feeding. The reversion of distorted serum and liver parameter values after a period of AD feeding was investigated after supplementation of the AD with SDPs, PEs, or a placebo (PT). Additionally, the metabolic parameters of fatty acid synthesis, fatty acid oxidation, and inflammation were studied to understand the mechanism of action of phytosterols. AD supplementation with SDPs was shown to reduce liver fat, along with showing a significant improvement in liver triglycerides (TGs), free fatty acids (FFAs), and liver cholesterol levels. These results were reinforced by the analyses of the liver steatosis scores, and liver histologies, where SDP intervention showed a consistent improvement. Treatment with PEs showed slighter effects in the same analyses, and no effects were observed with the PT treatment. Additionally, SDP intervention reversed, with a higher efficacy than PEs, the effect of AD on the serum levels of TGs, total- and LDL-cholesterol levels, and glucose levels. And, exceptionally, while SDP improved HDL-cholesterol serum levels, PEs did not show any effect on this parameter. We provide evidence for the therapeutical activity of phytosterols in MAFLD beyond the regulation of cholesterol levels, which is increased when the phytosterols are formulated as submicron dispersions compared to ester formulations.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an asymptomatic, multifaceted condition often associated with various risk factors, including fatigue, obesity, insulin resistance, metabolic syndrome, and sleep apnea. The increasing burden of MASLD underscores the critical need for early diagnosis and effective therapies. Owing to the lack of efficient therapies for MASLD, early diagnosis is crucial. Consequently, noninvasive biomarkers and imaging techniques are essential for analyzing disease risk and play a pivotal role in the global diagnostic process. The use of extracellular vesicles has emerged as promising for early diagnosis and therapy of various liver ailments. Herein, a comprehensive summary of the current diagnostic modalities for MASLD is presented, highlighting their advantages and limitations while exploring the potential of extracellular vesicles (EVs) as innovative diagnostic and therapeutic tools for MASLD. With this aim, this review emphasizes an in-depth understanding of the origin of EVs and the pathophysiological alterations of these ectosomes and exosomes in various liver diseases. This review also explores the therapeutic potential of EVs as key components in the future management of liver disease. The dual role of EVs as biomarkers and their therapeutic utility in MASLD essentially highlights their clinical integration to improve MASLD diagnosis and treatment. While EV-based therapies are still in their early stages of development and require substantial research to increase their therapeutic value before they can be used clinically, the diagnostic application of EVs has been extensively explored. Moving forward, developing diagnostic devices leveraging EVs will be crucial in advancing MASLD diagnosis. Thus, the literature summarized provides suitable grounds for clinicians and researchers to explore EVs for devising diagnostic and treatment strategies for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by hepatic steatosis associated with metabolic abnormalities. Recent research has shed light on the intricate interplay among interleukin-1 receptor 1 (IL1R1), gut microbiota, and bile acids in the pathogenesis of MASLD. This review aims to provide a comprehensive overview of the current understanding of the role of IL1R1, gut microbiota, and bile acids in MASLD, exploring their interrelationships and potential mechanisms. We summarize the evidence supporting the involvement of IL1R1 in inflammation, discuss the influence of gut microbiota on bile acid metabolism and its influence on liver health, and elucidate the bidirectional interactions among IL1R1 signaling, gut microbiota composition, and bile acid homeostasis in MASLD. Furthermore, we highlight emerging therapeutic strategies targeting these interrelated pathways for the management of MASLD.

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

This study investigates the novel therapeutic potential of quercetin and kaempferol, two bioactive compounds derived from Carthamus tinctorius L., in treating nonalcoholic fatty liver disease (NAFLD) by modulating the bile acid receptor NR1H4 (Nuclear Receptor Subfamily 1 Group H Member 4) and its associated metabolic pathways. A rat model of NAFLD was established, and RNA sequencing and proteomics were carefully employed to identify differential gene expressions associated with the disease. The active components of Carthamus tinctorius L. were screened, followed by the construction of a comprehensive network that maps the interactions between these components, NR1H4 and NAFLD-related pathways. Both in vitro (using HepG2 cells) and in vivo experiments were conducted to evaluate the effects on NR1H4 expression levels through Western blot and RT-qPCR analyses. Our findings identify NR1H4 as a pivotal target in NAFLD. Network pharmacology analysis indicates that quercetin and kaempferol play crucial roles in combating NAFLD, with in vitro and in vivo experiments confirming their ability to mitigate hepatocyte steatosis by enhancing NR1H4 expression. Notably, the protective effects of these compounds were inhibited by the NR1H4 antagonist guggulsterone, highlighting the importance of NR1H4 upregulation. This study demonstrates the novel therapeutic efficacy of quercetin and kaempferol from Carthamus tinctorius L. in treating NAFLD through NR1H4 upregulation. This mechanism contributes to the regulation of lipid metabolism, improvement of liver function, reduction of inflammation, and alleviation of oxidative stress, offering a promising direction for future NAFLD treatment strategies.

This study aimed to investigate the association between Metabolic-dysfunction-associated steatotic liver disease(MASLD)and C-reactive protein/lymphocyte ratio (CLR).

MASLD was defined as a Controlled Attenuation Parameter (CAP ≥ 274dB/m) and CLR = C-reactive protein/lymphocyte. A multifactor linear regression model was used to test the relationship between MASLD and CLR. Smoothed curves and threshold effects analyses were fitted to describe nonlinear relationships. Subgroup analyses and interaction tests were then performed according to gender, prevalence of diabetes, ethnicity, and smoking status.

A total of 1846 participants from the NHANES database were included in this study. In the unadjusted model and model 1 (adjusted for age, sex, and race), CLR was positively associated with MASLD pathogenicity. Unadjusted model (OR = 1.04, 95% CI: 1.02-1.07, P = 0.0017), model 1 (OR = 1.04, 95% CI: 1.01-1.07, P = 0.0056). The results of the fitted smoothed curves showed that CLR and the risk of developing MASLD were nonlinear. Interaction tests and subgroup analyses confirmed that there were no significant interactions between CLR and MASLD causation with gender, race, prevalence of diabetes mellitus, and smoking status(P interaction>0.05).

This study shows that CLR is positively associated with the risk of developing MASLD Targeting CLR levels may be a new approach to treating MASLD.

Elevated levels of pro-inflammatory adipokines and cytokines increase the risk of developing metabolic disorders and diseases. The aim of this study was to conduct a comparative analysis of selected adipokines/cytokines in the blood serum of adults with obesity and normal body weight. The study also evaluated the correlation of these adipokines/cytokines with selected biochemical blood parameters. The study included 46 individuals with first- and second-degree obesity and 35 individuals with normal body weight. The participants underwent nutritional status assessments, biochemical tests, and evaluations of adipokine and cytokine concentrations in blood serum. The study found higher median CRP concentrations in women with obesity than in those with normal weight. This increase was statistically significant. The results also showed significantly higher IL-6 levels in the obesity group compared to the control group in both women and men. Resistin and MMP-2 were significantly different between women with obesity and women with normal body weight. Multiple regression results indicated that higher total fat content was significantly associated with higher serum CRP and IL-6 levels and lower adiponectin levels. Interleukin 6 was the strongest predictor of adipose tissue dysfunction in both women and men. Potential markers in women could also include resistin and MMP-2. The findings suggest that gender significantly influences the regulation of inflammatory factors.

This study aimed to investigate the association of IL-6 with steatotic liver disease (SLD) and liver fibrosis (LF) in rheumatoid arthritis (RA) patients at a rheumatology center in Cartagena de Indias, Colombia.

This was a cross-sectional study that included RA and non-RA cases. The level of cellular expression of interleukin 6 (IL-6) was evaluated by flow cytometry in peripheral blood leukocytes, and the presence of SLD and LF was detected by elastosonography. The main outcome was to establish the association between the levels of cellular expression of IL-6 and the development of SLD and LF.

This study included 47 cases of RA and 34 cases on-RA, with a mean age of 54 and 55 years, respectively. The frequency of SLD was 55.3% in RA and 38.2% in non-RA. The frequency of LF was 12.8% in RA and 14.7% in non-RA, with no statistical difference. The levels of cellular expression of IL-6 were significantly higher in RA compared to non-RA. Cellular expression of IL-6 was associated with the presence of SLD (54% vs. 30.3%; p = 0.002). This association was not maintained in RA cases (49.5% vs. 47.6%; p = 0.571). No association was found between cellular expression of IL-6 and LF in the total population (43.8% vs. 42.7%; p = 0.813) nor in RA cases (59.41% vs. 48.3%; p = 0.526).

IL-6 levels were related to SLD in the evaluated sample, and RA was not a risk factor for SLD or LF. The prognostic role of IL-6 for SLD in patients with RA requires further studies.

Due to the requirement for a novel and effective treatment for non-alcoholic fatty liver disease (NAFLD), this study aimed to determine the effects of a novel supplement containing Lactocaseibacillus zeae and Limosilactobacillus reuteri on oxidative stress, inflammation, glucose and lipid metabolism, lipid accumulation, and liver function in the fructose-induced NAFLD rat model. To investigate the involvement of molecular pathways and validate a preclinical study, NAFLD was induced by feeding them fructose-containing drinking water (20% w/v) for 12 consecutive weeks. The fructose-induced male rats were administered a mixture of L. zeae TISTR 2529 and L. reuteri TISTR 2736 at a dose of 2 × 108 CFU/mL during weeks 0 to 12, daily. Weight and food intake were recorded daily. The production of oxidative stress, expression of the TNF-α, SREBP-1c, liver enzymes, and lipid profiles, including the densities of lipid droplets in liver cells, were also evaluated. The results revealed that fructose-induced rats co-treated with the mixed probiotics had significantly decreased body weights, triglycerides, cholesterol, and liver enzymes. Furthermore, the expression of TNF-α, MDA, and SREBP-1c and the densities of lipid droplets in the liver tissue were reduced. Based on the results, the novel probiotic supplement containing L. zeae TISTR 2529 and L. reuteri TISTR 2736 might alleviate NAFLD by normalizing oxidative stress, inflammation, lipid metabolism, and lipid accumulation in the liver of NAFLD-induced model rats.

The rising prevalence and severe consequences of nonalcoholic fatty liver disease (NAFLD) have driven the quest for preventive medications. Complanatoside A (CA) is the marked flavonoid of Astragali complanati semen, a traditional Chinese herb that acts on the liver meridian and is widely used to treat liver problems. CA has been proven to have considerable lipid-lowering and liver-protective effects in vitro. However, the efficacy of CA in preventing NAFLD has yet to be shown in vivo.

First, the effectiveness of CA against NAFLD was assessed using a high-fat diet (HFD) mouse model. Second, the CA protective mechanism against NAFLD was investigated using a combined metabolomics and network pharmacology strategy. Differential metabolites were identified by metabolomics-based analyses, and metabolic pathway analysis was accomplished by MetaboAnalyst. Potential therapeutic targets were obtained through network pharmacology. Finally, key targets were identified via compound-target networks and validated by molecular docking and western blotting.

CA prevented NAFLD mainly by reducing liver lipid accumulation in HFD mice. Metabolomics identified 22 potential biomarkers for CA treatment of NAFLD, primarily involving glycerophospholipid and arachidonic acid metabolism. Fifty-one potential targets were determined by network pharmacology. Co-analysis revealed that albumin, peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, interleukin-6, and tumor necrosis factor alpha were key targets.

This experiment revealed that CA has a preventive effect on NAFLD, primarily by regulating the peroxisome proliferator-activated receptor-alpha/retinoid X receptor alpha pathway. Furthermore, it provides evidence supporting the potential use of CA in the long-term prevention of NAFLD.