Little is known about the associations between changes in hepatic steatosis and changes in abdominal adiposity after metabolic bariatric surgery.

To evaluate the serial changes in hepatic steatosis and abdominal adiposity following sleeve gastrectomy (SG).

University hospital, Taiwan.

In this prospective study, patients who underwent SG and intraoperative liver biopsy were enrolled. Magnetic resonance imaging (MRI) was performed to assess the liver fat fraction (LFF), visceral adipose tissue (VAT) area, and subcutaneous adipose tissue (SAT) area. Liver fibrosis was assessed preoperatively via biopsy and the fibrosis-4 index (FIB-4) and postoperatively with the FIB-4.

Seventy-six metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including 67 pure MASLD patients and 9 MASLD patients with combined etiologies, were enrolled. LFF and visceral-to-subcutaneous fat ratio were associated with metabolic dysfunction-associated steatohepatitis, and VAT area was associated with significant fibrosis (≥F2). Twelve months after SG, all MRI measurements significantly improved. The median LFF of pure MASLD patients decreased from 17.4% at baseline to 4.2% and 3.7% at the 6th and 12th postoperative months, respectively. Complete resolution of steatosis was achieved in 97.5% of patients at the 12th postoperative months. Using %VAT and %SAT reductions at the sixth postoperative month as references, LFF decreased more rapidly, with fold ratios of 1.3 and 1.8, respectively.

SG resulted in a significant decrease in hepatic steatosis and abdominal adiposity in patients with severe obesity, but hepatic steatosis improved faster than abdominal adiposity. Hepatic steatosis resolved in almost all patients 12 months after SG.

PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD.

PubMed and Embase databases were searched until December 30, 2023, for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalized linear mixed model with Clopper-Pearson intervals. Continuous and dichotomous variables were analyzed using the DerSimonian-Laird method. International Prospective Register of Systematic Reviews registration number: CRD42023449838.

A total of 109 studies involving 118,302 individuals with MASLD were identified. The overall minor allele frequency of the G allele [MAF(G)] at PNPLA3 was 0.45 (95% confidence interval [CI]: 0.43; 0.48) with high heterogeneity (I2 = 98%). The highest MAF(G) was found in Latin America (0.63) and the lowest in Europe (0.38). No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism, and worse liver damage/histology than noncarriers. There was significant heterogeneity in the clinical/histological analyses (I2 > 50%). Only the PNPLA3 GG genotype was associated with higher mortality and liver-related events with no heterogeneity (I2 = 0%). Metaregressions showed the influence of adiposity, age, diabetes mellitus, and glucose on some PNPLA3 expression parameters. Overall, there was a moderate risk of bias in the included studies.

This study reveals the global pattern of PNPLA3 and its clinical, histological, and outcome implications in MASLD. Patients with MASLD and PNPLA3 variant have different clinical features and worse liver severity, and only PNPLA3 GG has a higher risk of mortality and liver outcomes. Our findings highlight the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches.

The present study aimed to assess whether Time-Restricted Feeding (TRF) modulates inflammation and hepatic Notch1 signalling in C57BL/6J-aged mice.

Adult mice submitted to the ad libitum diet, aged (24 months-old) submitted to the ad libitum diet and, aged-TRF (24 months-old) subjected to the TRF (12 hours fed in the active cycle and 12 hours fasting in the light cycle) for 8 weeks. We investigated metabolic parameters, liver histology, metabolic-dysfunction-associated fatty liver disease activity score, collagen fiber, hepatic mitochondrial respiration, and publicly available liver Rna-seq datasets from human livers in diverse clinical conditions to clarify Notch1 involvement in liver health.

Our results demonstrated that aged mice (24 months old) showed increases in body weight, liver mass, Notch1 intracellular domain (NICD), and inflammatory markers (NFκB and TLR4 protein levels) in the liver when compared to adult animals. On the other hand, aged mice submitted to a TRF protocol showed reductions in inflammation and collagen fibers, which was accompanied by lower protein content of JAGGED1 and NICD in the liver. Furthermore, aged-TRF mice demonstrated increased liver mitochondrial respiration coupled with ATP production compared to the aged groups. Publicly available liver RNA-seq datasets in humans support our findings, indicating the upregulation of NOTCH1 in fibrosis and inflammation development.

TRF can reduce inflammatory markers and protein content of JAGGED1 and NICD in the liver of aged mice, which can contribute to tissue health and cellular longevity.

Fibrosis is the pathological outcome of many chronic inflammatory diseases, affecting various human organs. It is a significant contributor to global morbidity and mortality that affects nearly half of the elderly population. Pirfenidone (PFD) and nintedanib are approved by the FDA for treating pulmonary fibrosis, but these treatments are associated with poor tolerability and limited efficacy. Moreover, no antifibrotic drugs are approved for other fibrosis-related diseases, highlighting an urgent unmet medical need for more effective therapies. Here we report the in vivo pharmacological activities of AK3280, a novel, orally bioavailable small molecule designed to enhance pharmacokinetics, antifibrotic activity, and tolerability over PFD. AK3280 demonstrated antifibrotic effects across multiple organs, including the lungs, liver, heart, and skin, in various animal models. These results suggest that AK3280 holds promise as a clinically beneficial antifibrotic therapy for a range of fibrotic diseases, especially pulmonary, hepatic, cardiac, and skin fibrosis.

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.

Capsaicin (CAP), the principal bioactive component of chili peppers (Capsicum annuum L.), is widely recognized for its anti-inflammatory properties. However, its oral bioavailability is low, likely due to extensive sulfonation metabolism. Despite the well-known pharmacological benefits of CAP, the role of sulfotransferase (SULT)-mediated sulfonation in modulating its therapeutic effects remains poorly understood. This study aims to elucidate the sulfonate metabolic profile of CAP, investigate the anti-inflammatory role of its sulfonate metabolite (CAP-S), and uncover the mechanisms underlying CAP-S's anti-inflammatory effects. In our study, the mono-sulfonate metabolite of CAP, designated as CAP-S ((E)-N-[(4-sulfo-3-methoxyphenyl)methyl]-8-methylnon-6-enamide), is identified using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and proton nuclear magnetic resonance (1H-NMR). The metabolic profile of CAP was investigated in liver S9 fractions from human, rat, and mouse samples, with sulfonation of CAP examined using seven major recombinant SULT isoforms. The results demonstrate that CAP is primarily catalyzed by SULT1A subfamily and SULT1E1. The anti-inflammatory effects of CAP-S are evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and an acute liver injury (ALI) mouse model. CAP-S significantly reduces inflammatory mediators and nitric oxide (NO) production in LPS-induced RAW264.7 cells. In vivo, CAP-S treatment alleviates hepatocyte necrosis, inflammatory cell infiltration, and reduces aspartate aminotransferase, alanine aminotransferase, and malondialdehyde levels, while enhancing superoxide dismutase activity and decreasing NO production. Additionally, CAP-S exerts comparable anti-inflammatory effects to CAP by suppressing NF-κB p65 phosphorylation and reducing pro-inflammatory cytokines, as evidenced by network pharmacology and western blot assays. These findings underscore the role of sulfonation in modulating CAP's therapeutic potential.

Osteopontin (OPN) promotes the ductular reaction and is a major driver of chronic liver disease (CLD) progression. Although CLD is characterised by the accumulation of inflammatory cells including macrophages around the peri-portal regions, the influence of OPN on recruitment is unclear. We investigated the role of OPN in cholangiocyte chemokine production and macrophage recruitment by combining in vivo, in vitro, and in silico approaches.

The effects of OPN on cholangiocyte chemokine production and macrophage migration were assessed in culture, alongside RNA-sequencing to identify genes and pathways affected by OPN depletion. Murine liver injury models were used to assess liver chemokine expression and liver macrophage/monocyte recruitment. OPN and chemokine expression were analysed in liver tissue and plasma from biopsy-proven metabolic dysfunction-associated alcoholic steatohepatitis (MASH) patients.

OPN-knockdown in cholangiocytes reduced chemokine secretion. RNA-sequencing showed OPN-related effects clustered around immunity, chemotaxis and chemokine production. Macrophage exposure to cholangiocyte-conditioned media showed OPN-supported migration via chemokines chemokine (C-C motif) ligand (CCL)2, CCL5 and chemokine (C-X-C motif) ligand (CXCL)1. These effects were related to NF-κB signalling. Murine liver fibrosis was accompanied by upregulated liver OPN, CCL2, CCL5 and CXCL1 mRNA, and accumulation of liver cluster of differentiation (CD)11b/F4/80+CC chemokine receptors (CCR2)high macrophages but treatment with OPN-specific neutralising aptamers reduced fibrosis, chemokine mRNAs and accumulation of liver CD11b/F4/80+CCR2high/lymphocyte antigen 6 complexhigh inflammatory monocytes. In human MASH, liver OPN correlated with chemokines CCL2 and IL8 in association with portal injury and fibrosis. Plasma OPN, serum CCL2 and IL8 also increased with fibrosis stage.

OPN promotes cholangiocyte chemokine secretion and the accumulation of pro-inflammatory monocytes. These data support neutralisation of OPN as an anti-inflammatory and anti-fibrotic strategy.

The global prevalence of Metabolic Dysfunction-Associated Steatohepatitis (MASH) has been rising sharply, closely mirroring the increasing rates of obesity and metabolic syndrome. MASH exhibits a strong sexual dimorphism where females are affected with more severe forms after menopause. Hexokinase domain-containing protein 1 (HKDC1) has recently been recognized for its role in liver diseases, where its expression is minimal under normal conditions but significantly increases in response to metabolic stressors like obesity and liver injury. This selective upregulation suggests HKDC1's potential specialization in hepatic glucose and lipid dysregulation, linking it closely to the progression of MASH. This study aims to clarify the role of HKDC1 in Western diet-induced MASH in female mice by examining its impact on hepatic glucose and lipid metabolism, offering insights into its potential as a therapeutic target and addressing the need for sex-specific research in liver disease. This study reveals that HKDC1 expression is elevated in obese women with MASH and correlates with liver pathology. In a mouse model, liver-specific HKDC1 knockout (HKDC1LKO) protected against Western diet-induced obesity, glucose intolerance, and MASH features, including steatosis, inflammation, and fibrosis. Transcriptomic analysis showed that HKDC1 deletion reduced pro-inflammatory and pro-fibrotic gene expression, while gut microbiome analysis indicated a shift toward MASH-protective bacteria. These findings suggest that HKDC1 may exacerbate MASH progression through its role in metabolic and inflammatory pathways, making it a potential therapeutic target.

Type 2 diabetes mellitus (T2DM) represents a chronic metabolic disorder characterized by disrupted carbohydrate and lipid balance, resulting in hyperglycemia. This study evaluated the impact of polysaccharides derived from Cynanchum auriculatum Royle ex Wight (CRP) on mitigating hyperglycemia and modulating intestinal microbiota in T2DM mice. Findings indicated that CRP is mainly linked by →6)α-D-Glcp-(1→ and CRP-H demonstrated greater efficacy than CRP-L in regulating hypoglycemic-related indicators such as serum high-density lipoprotein cholesterol (HDL-c) level. Additionally, CRP at varying doses enhanced the mRNA expression of insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT-1), and glucose transporter 2 (GLUT-2). Following a 4-week CRP-H treatment, a significant reduction in the Firmicutes/Bacteroidetes ratio at the phylum level was observed, alongside a marked increase in the relative abundance of beneficial genera such as Limosillactobacillus and Prevotella. Overall, CRP-H displayed enhanced hypoglycemic properties by activating the IRS-1/PI3K/AKT-1/GLUT-2 pathway and enriching beneficial gut bacteria, including Prevotella and Limosillactobacillus. This study establishes a foundational framework for further development and application of Cynanchum auriculatum Royle ex Wight resources, emphasizing the hypoglycemic potential of CRP.

The nonalcoholic steatohepatitis clinical research network (NASH-CRN) system is commonly used for histologic assessment of disease activity and fibrosis in NASH. Despite this, the system does not fully capture the range of disease activity and fibrosis. As such, an expanded NAS (E-NAS) grading and staging system with a calculated E-NAS index was developed by our group. In this follow up study, we aim to revalidate the E-NAS system and compare its reliability to existing systems. Hematoxylin and eosin and trichrome stained sections from 40 liver biopsies were reviewed digitally by four hepatopathologists and assessed using the NASH-CRN and E-NAS systems as well as a modified Ishak fibrosis stage. The pathologist's gestalt impression of disease activity and fibrosis was scored on a Visual Analogue Scale (VAS), which ranged from 0 (no activity/fibrosis) to 100 (the worst activity/fibrosis ever seen). Inter-rater reliability was assessed, and Spearman correlation coefficients were calculated. The E-NAS index had higher inter-rater agreement versus the NAS score (ICC 0.70 vs 0.61). The inter-rater agreement for ballooning in the E-NAS system was also higher at 0.67 compared to the NAS (ICC 0.60). ICCs for fibrosis were comparable between all the systems assessed (0.78 to 0.88). Finally, the calculated E-NAS index was higher with increasing stage of fibrosis compared to the NAS suggesting that it associates better with fibrosis. In summary, the E-NAS system demonstrates substantial inter-rater reliability as well as improved correlation with disease activity VAS and fibrosis compared to the NAS score.

Notch1 protein plays a significant role in hepatic metabolism, as evidenced by its correlation with insulin resistance in the livers of obese individuals, making it an intriguing research target. Therefore, this study aims to investigate the impact of aerobic exercise on Notch1 pathways in the hepatic tissue of obese mice and its role in controlling hepatic metabolism.

Therefore, we conducted a cross-sectional study utilising liver biopsies from lean and obese humans, as well as an intervention study involving mice subjected to a high-fat diet. The obese-trained mice group underwent a treadmill-running protocol for 4 weeks.

Our findings revealed that obese individuals exhibited increased NOTCH1 mRNA levels compared to lean subjects. The detrimental effects of Notch1 signalling were confirmed by Notch1-overexpressed HepG2 cell lines. Obese mice with higher hepatic Notch1 signalling demonstrated a reduction in this pathway when subjected to a 4-week treadmill running. Another benefit noticed in this trained group was the amelioration of insulin resistance, as well as a reduction in pyruvate intolerance and gluconeogenic enzymes. Additionally, we observed that these protective findings were accompanied by a decrease in mTORC1 pathway activity and lipid accumulation in the liver. Pharmacological inhibition of Notch1 in obese mice led to an increase in mitochondrial respiration in the liver.

We conclude that Notch1 signalling may be a potentially useful therapeutic target in obesity, while aerobic exercise training suppresses the Notch1 pathway in the liver, contributing to the regulation of hepatic glucose and lipid metabolism in obese mice.

The functional food application of edible fungus polysaccharides has been widely studied based on their variety of potential pharmacological activities. However, the hepatoprotective effects and mechanisms of Morchella esculenta polysaccharide against nonalcoholic fatty liver disease (NAFLD) remain unknown. A high-fat diet (HFD) fed C57BL/6 J mice for 8 weeks was employed to establish NAFLD with simple steatosis, methionine choline deficiency (MCD) diet for 4 weeks induced hepatic steatohepatitis and fibrosis. The M. esculenta polysaccharide (MCP) or saline was administered intragastrically. MCP markedly reduced hepatic and serum triglyceride (TG) and cholesterol contents in HFD-fed mice. Moreover, treatment with MCP ameliorated nonalcoholic steatohepatitis (NASH) progression in MCD-fed mice, as evidenced by ameliorated hepatic steatosis, inflammatory response, and fibrosis. Mechanistically, MCP suppressed the expression of lipogenic genes and inflammatory cytokines and upregulated peroxisome proliferator-activated receptor (PPAR)-α expression to induce fatty acid β-oxidation. These beneficial effects were attributed to activating the AMP-activated kinase (AMPK)/Sirtuin 1 (Sirt1) signaling pathway. Therefore, we provided evidence that MCP might be an effective dietary supplement to ameliorate NAFLD.

To assess the performance and the reproducibility of ultrasound-guided attenuation parameter (UGAP) and two-dimensional shear wave elastography (2D-SWE) in patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD).

This study included consecutive adult patients with MASLD who underwent ultrasound with UGAP, 2D-SWE and percutaneous liver biopsy. The median values of 12 consecutive UGAP measurements were acquired by two independent radiologists (R1 and R2). Hepatic steatosis was graded by liver biopsy as: (0) < 5%; (1) 5-33%; (2) > 33-66%; (3) > 66%. Areas under the curve (AUCs) were calculated to determine the diagnostic performance. Inter- and intra-observer reliability was assessed with intraclass correlation coefficient (ICC).

A hundred patients (median age 55.0 years old) with MASLD were prospectively enrolled. At histopathology, 70 and 42 patients had grade ≥ 2 and 3 steatosis, respectively. Median UGAP was 0.78 dB/cm/MHz (IQR/Med: 5.55%). For the diagnosis of grade ≥ 2 steatosis, the AUCs of UGAP were 0.828 (95% CI: 0.739, 0.896) for R1 and 0.779 (95% CI: 0.685, 0.856) for R2. The inter- and intra-operator reliability of UGAP were excellent, with an ICC of 0.92 (95% CI: 0.87-0.95) and 0.95 (95% CI: 0.92-0.96), respectively. The median liver stiffness was 6.76 kPa (IQR/Med: 16.30%). For the diagnosis of advanced fibrosis, 2D-SWE had an AUC of 0.862 (95% CI: 0.757, 0.934), and the optimal cutoff value was > 6.75 kPa with a sensitivity of 80.6% and a specificity of 75.7%.

UGAP and 2D-SWE provide a good performance for the staging of steatosis and fibrosis in patients with MASLD with an excellent intra-operator reliability of UGAP.

Question How well do ultrasound-guided attenuation parameter (UGAP) and two-dimensional shear wave elastography (2D-SWE) perform for quantifying hepatic steatosis and fibrosis? Findings UGAP had a maximum AUC of 0.828 for the diagnosis of grade ≥ 2 steatosis, and 2D-SWE had an AUC of 0.862 for diagnosing advanced fibrosis. Clinical relevance UGAP and 2D-SWE allow rapid, reproducible, and accurate quantification of hepatic steatosis and fibrosis that can be used for the noninvasive assessment of patients with metabolic dysfunction-associated steatotic liver disease.

Advanced liver fibrosis in cases of metabolic dysfunction-associated steatotic liver disease (MASLD) leads to cirrhosis and hepatocellular carcinoma. The current gold standard for liver fibrosis is invasive liver biopsy. Therefore, a less invasive biomarker that accurately reflects the stage of liver fibrosis is highly desirable.

This study enrolled 269 patients with liver biopsy-proven MASLD. Patients were divided into three groups (F0/1 (n = 41/85), F2 (n = 47), and F3/4 (n = 72/24)) according to fibrosis stage. We performed serum N-glycomics and identified glycan biomarker for fibrosis stage. Moreover, we explored the carrier proteins and developed a sandwich ELISA to measure N-glycosylation changes of carrier protein.

Comprehensive N-glycomic analysis revealed significant changes in the expression of A2F bisect and its precursors as fibrosis progressed. The sum of neutral N-glycans carrying bisecting GlcNAc and core Fuc (neutral sum) had a better diagnostic performance to evaluate advanced liver fibrosis (AUC = 0.804) than conventional parameters (FIB4 index, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), and serum level of Mac-2-binding protein glycol isomer (M2BPGi). The combination of the neutral sum and FIB4 index enhanced diagnostic performance (AUC = 0.840). IgM, IgA, and complement C3 were identified as carrier proteins with A2F bisect N-glycan. A sandwich ELISA based on N-glycans carrying bisecting GlcNAc and IgA showed similar diagnostic performance than the neutral sum.

A2F bisect N-glycan and its precursors are promising candidate biomarkers for advanced fibrosis in MASLD patients. Analysis of these glycan alterations on IgA may have the potential to serve as a novel ELISA diagnostic tool for MASLD in routine clinical practice.

UMIN000030720.

Magnetic resonance elastography (MRE) can quantify tissue biomechanics noninvasively, including pathological hepatic states like metabolic dysfunction-associated steatohepatitis.

To compare the performance of 2D/3D-MRE using the gravitational (GT) transducer concept with the current commercial acoustic (AC) solution utilizing a 2D-MRE approach. Additionally, quality index markers (QIs) were proposed to identify image pixels with sufficient quality for reliably estimating tissue biomechanics.

Prospective.

One hundred seventy participants with suspected or confirmed liver disease (median age, 57 years [interquartile range (IQR), 46-65]; 66 females), and 11 healthy volunteers (median age, 31 years [IQR, 27-34]; 5 females).

Participants were scanned twice at 1.5 T and 60 Hz vibration frequency: first, using AC-MRE (2D-MRE, spin-echo EPI sequence, 11 seconds breath-hold), and second, using GT-MRE (2D- and 3D-MRE, gradient-echo sequence, 14 seconds breath-hold).

Image analysis was performed by four independent radiologists and one biomedical engineer. Additionally, superimposed analytic plane shear waves of known wavelength and attenuation at fixed shear modulus were used to propose pertinent QIs.

Spearman's correlation coefficient (r) was applied to assess the correlation between modalities. Interreader reproducibility was evaluated using Bland-Altman bias and reproducibility coefficients. P-values <0.05 were considered statistically significant.

Liver stiffness quantified via GT-2D/3D correlated well with AC-2D (r ≥ 0.89 [95% CI: 0.85-0.92]) and histopathological grading (r ≥ 0.84 [95% CI: 0.72-0.91]), demonstrating excellent agreement in Bland-Altman plots and between readers (κ ≥ 0.86 [95% CI: 0.81-0.91]). However, GT-2D showed a bias in overestimating stiffness compared to GT-3D. Proposed QIs enabled the identification of pixels deviating beyond 10% from true stiffness based on a combination of total wave amplitude, temporal sinusoidal nonlinearity, and wave signal-to-noise ratio for GT-3D.

GT-MRE represents an alternative to AC-MRE for noninvasive liver tissue characterization. Both GT-2D and 3D approaches correlated strongly with the established commercial approach, offering advanced capabilities in abdominal imaging compared to AC-MRE.

1 TECHNICAL EFFICACY: Stage 2.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent pediatric liver disease, yet accurate risk scores for referral of children/adolescents with suspected clinically significant liver fibrosis are currently lacking.

Clinical and biochemical variables were collected in a prospective cohort of 327 children and adolescents with severe obesity, in whom liver fibrosis was evaluated by transient elastography. Logistic regression was performed to establish continuous (pFIB-c) and simplified (pFIB-6) diagnostic scores that accurately exclude significant (≥F2) fibrosis. Performance for each was compared to established noninvve fibrosis scores. These scores were validated in elastography (n=504) and multiple biopsy-proven MASLD (n=261) cohorts. Patient sex, ethnicity, weight z-score, homeostatic model assessment of insulin resistance index, ALT, and presence of hypertension were included in the scores. The pFIB-c and pFIB-6 exhibited good discriminatory capacity (c-statistic of 0.839 and 0.826), outperforming existing indices. Negative predictive values were >90% for both scores in the derivation and elastography validation cohorts. Performance in the histological cohorts varied (AUROCs for the pFIB-c between 0.710 and 0.770), as the scores were less accurate when applied to populations in tertiary referral centers characterized by a high prevalence of significant fibrosis and high ALT levels.

Analyzing several cohorts totaling approximately 1100 children and adolescents, we developed novel risk scores incorporating readily available clinical variables. In accordance with the aim of excluding pediatric MASLD-associated fibrosis, the scores performed better in nonselected cohorts of children and adolescents living with obesity than in patients referred to tertiary liver units.

Endocrine multisystem defect polycystic ovary syndrome (PCOS) causes hyperandrogenism and infertility. Half of PCOS women have (non-alcoholic fatty liver disease) NAFLD, which increases metabolic disease risk. We tested decorin's effect on NAFLD and related processes in PCOS. NAFLD+PCOS, PCOS+decorin, and control rats were studied. Decorin was evaluated on NAFLD/PCOS rats. Test group rats received HF for eight weeks to generate NAFLD. The rats got 1 mg/kg letrozole orally daily for 21 days to diagnosis PCOS. Afterward, rats got injectable decorin for 14 days. Body weight, liver weight, liver coefficient Abdominal Circumference (AC) and body mass index (BMI) were determined. Blood triglycerides (TG), total cholesterol, LDL-c, AST, and glucose were measured. The insulin, testosterone, estrogen, LH, and FSH were measured by ELISA. GPx, SOD, MDA, TNF-, and Caspase-3 liver immunohistochemistry were evaluated. NAFLD liver tissues in PCOS models showed biochemical and histological alterations. NAFLD+PCOS raised BMI, AC, liver weight, and coefficient. Blood glucose, insulin resistance, TG, ALT, and AST increased. Lipid abnormalities (TG, cholesterol, LDL-c, and HDL-c), oxidative stress markers (MDA, SOD, and GPx), and liver dysfunction were found. Low serum E2 and high T supported PCO. Decorin reduced model rat BMI, liver weight, coefficient, insulin resistance, TG, ALT, and AST. It reduced liver inflammation, improved liver extract lipids, and normalized MDA, SOD, and GPx. In the model group, decorin lowered serum T, E2, LH, caspase 3, and TNF-alpha. Decorating improved NAFLD/PCOS group liver histology and function. Decorin reduces hepatosteatosis by reducing liver inflammation, oxidative stress, and dyslipidemia.

Amidst the global rise of metabolic dysfunction-associated steatotic liver disease (MASLD), driven by increasing obesity rates, there is a pressing need for precise, non-invasive diagnostic tools. Our research aims to validate MRI Proton Density Fat Fraction (MRI-PDFF) utility, compared to liver biopsy, in grading hepatic steatosis in MASLD.

A systematic search was conducted across Embase, PubMed/Medline, Scopus, and Web of Science until January 13, 2024, selecting studies that compare MRI-PDFF with liver biopsy for hepatic steatosis grading, defined as grades 0 (< 5% steatosis), 1 (5-33% steatosis), 2 (34-66% steatosis), and 3 (> 66% steatosis).

Twenty-two studies with 2844 patients were included. The analysis showed high accuracy of MRI-PDFF with AUCs of 0.97 (95% CI = 0.96-0.98) for grade 0 vs ≥ 1, 0.91 (95% CI = 0.88-0.93) for ≤ 1 vs ≥ 2, and 0.91 (95% CI = 0.88-0.93) for ≤ 2 vs 3, diagnostic odds ratio (DOR) from 98.74 (95% CI = 58.61-166.33) to 23.36 (95% CI = 13.76-39.68), sensitivity and specificity from 0.93 (95% CI = 0.88-0.96) to 0.76 (95% CI = 0.63-0.85) and 0.93 (95% CI = 0.88-0.96) to 0.89 (95% CI = 0.84-0.93), respectively. Likelihood ratio (LR) + ranged from 13.3 (95% CI = 7.4-24.0) to 7.2 (95% CI = 4.9-10.5), and LR - from 0.08 (95% CI = 0.05-0.13) to 0.27 (95% CI = 0.17-0.42). The proposed MRI-PDFF threshold of 5.7% for liver fat content emerges as a potential cut-off for the discrimination between grade 0 vs ≥ 1 (p = 0.075).

MRI-PDFF is a precise non-invasive technique for diagnosing and grading hepatic steatosis, warranting further studies to establish its diagnostic thresholds.

This study underscores the high diagnostic accuracy of MRI-PDFF for distinguishing between various grades of hepatic steatosis for early detection and management of MASLD, though further research is necessary for broader application.

MRI-PDFF offers precision in diagnosing and monitoring hepatic steatosis. The diagnostic accuracy of MRI-PDFF decreases as the grade of hepatic steatosis advances. A 5.7% MRI-PDFF threshold differentiates steatotic from non-steatotic livers.

The transcription factor sex-determining region Y-related high-mobility group-box gene 9 (SOX9) plays a critical role in organ development. Although SOX9 has been implicated in regulating lipid metabolism in vitro, its specific role in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly understood. This study aimed to investigate the role of SOX9 in MASH pathogenesis and explored the underlying mechanisms.

MASH models were established using mice fed either a methionine- and choline-deficient (MCD) diet or a high-fat, high-fructose diet. To evaluate the effects of SOX9, hepatocyte-specific SOX9 deletion or overexpression was performed. Lipidomic analyses were conducted to assess how SOX9 influences hepatic lipid metabolism. RNA sequencing was employed to identify pathways modulated by SOX9 during MASH progression. To elucidate the mechanism further, HepG2 cells were treated with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor to test whether SOX9 acts via AMPK activation.

SOX9 expression was significantly elevated in hepatocytes of MASH mice. Hepatocyte-specific SOX9 deletion exacerbated MCD-induced MASH, whereas overexpression of SOX9 mitigated high-fat, high-fructose-induced MASH. Lipidomic and RNA sequencing analyses revealed that SOX9 suppresses the expression of genes associated with lipid metabolism, inflammation, and fibrosis in MCD-fed mice. Furthermore, SOX9 deletion inhibited AMPK pathway activation, while SOX9 overexpression enhanced it. Notably, administration of an AMPK inhibitor negated the protective effects of SOX9 overexpression, leading to increased lipid accumulation in HepG2 cells.

Our findings demonstrate that SOX9 overexpression alleviates hepatic lipid accumulation in MASH by activating the AMPK pathway. These results highlight SOX9 as a promising therapeutic target for treating MASH.

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix components, leading to the distortion of liver architecture and function. Recent studies have shown that antagonizing 5-hydroxytryptamine receptor 2B (5HT2B) stimulates the apoptosis of activated hepatic stellate cells and inhibits their proliferation while concurrently regressing hepatocyte proliferation. In this study, we present compound 19c, which demonstrates promising efficacy both in vitro and in vivo. 19c showed robust in vitro activity with an IC50 value of 1.09 nM and limited blood-brain barrier penetration. Furthermore, 19c did not significantly inhibit hERG and cytochrome P450 enzymes. 19c markedly reduced fibrotic deposition, with a decrease in fibrosis stage and area in the CCl4-induced liver fibrosis mouse model. Additionally, treatment with 19c led to downregulation of key fibrosis-related genes, including α-SMA, Timp1, Col1a1, and Col3a1. Taken together, these results suggest that 19c has the potential to be a novel antifibrotic agent.

Based on liver stiffness measurement by vibration controlled transient elastography (LSM by VCTE), the Agile 3+ and 4 are novel noninvasive scores that accurately identify advanced fibrosis (≥ F3) and cirrhosis (F4), respectively. We investigated and compared the Agile 3+ and 4 scores' performances in predicting adverse events to LSM alone, FIB-4 and Fibroscan-AST (FAST) score.

This retrospective analysis included NAFLD patients with LSM by VCTE and laboratory testing from a tertiary care center from 2013 to 2022. Adverse events were defined as major adverse liver outcomes (MALO), hepatocellular carcinoma, liver transplant, and death. MALO was defined as ascites, hepatic encephalopathy, or esophageal variceal bleeding. We used the Cox proportional hazard rate model and the Harrell's concordance (C) statistic to compare predictive performances.

733 total subjects with median follow-up of 27.0 months were included. Average age was 58.1 years and 32.8% had type 2 diabetes. Average alanine aminotransferase was 46.6 IU/L, aspartate aminotransferase: 34.5 IU/L, albumin: 4.4 g/dL, and platelets: 241.1 × 109/L. Fourteen subjects had 21 adverse outcomes, including 10 MALO, 5 HCC, 4 liver transplants, 3 progression of MELD score, and 6 deaths. Agile 3+ and 4 respectively had the highest C stats of 0.911 (C stat SE 0.028) and 0.909 (C stat SE 0.029) compared to LSM (C stat 0.857, C stat SE 0.045), FIB-4 (C stat 0.843, C stat SE 0.037) or FAST (C stat 0.703, C stat SE 0.085).

The Agile 3+ and 4 scores had the highest likelihood of accurately predicting adverse outcomes including MALO and death compared to LSM alone, FIB-4 or FAST score.

The objective of this study was to validate the diagnostic accuracy of the acFibroMASH index in a population of metabolic dysfunction-associated steatotic liver disease (MASLD) patients with at-risk metabolic dysfunction-associated steatohepatitis (MASH) and to compare it with other scoring systems.

394 patients with biopsy-proven MASLD were retrospectively enrolled. The patients were divided into the at-risk MASH (NAFLD activity score ≥ 4 and significant fibrosis) group (n = 103) and the non-at-risk MASH group (n = 291). The diagnostic performance of the acFibroMASH index was compared to that of fibroScan-aspartate aminotransferase (FAST) and other noninvasive fibrosis scores by plotting the receiver operating characteristic curve (ROC), including the area under the curve (AUC), sensitivity, and specificity. Cut-offs of the acFibroMASH index for sensitivity (≥ 0.90) and specificity (≥ 0.90) were obtained in our cohort.

The AUC of the acFibroMASH index in assessing at-risk MASH was 0.780, while the AUC of FAST was 0.770. The comparison of acFibroMASH with FAST showed no significant difference (P = 0.542). When the cut-off value for acFibroMASH was < 0.15, 95.5% of at-risk MASH patients could be excluded in 89 patients correctly. Conversely, when the cut-off value was set at > 0.39, 49.3% of at-risk MASH patients could be diagnosed in 140 patients correctly. When the NPV was set at 0.900, the critical value for exclusion was determined to be 0.23, with a sensitivity of 0.835 and a specificity of 0.526.

This study validated the efficacy of the acFibroMASH index in predicting at-risk MASH in a population of MASLD patients, demonstrating comparable performance to that of the FAST. The acFibroMASH index may provide a valuable clinical basis for screening and identifying at-risk MASH in primary care settings.

Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction associated steatotic liver disease (MASLD), has reached epidemic levels in multiple regions worldwide and contributes to cirrhosis and hepatocellular carcinoma. We have previously reported that the CC motif chemokine ligand 11 (CCL11) is a key regulator of NAFLD and expression of interferon regulatory factor 1 (IRF1) can be up-regulated by CCL11 in hepatocytes, the relevance of which is not clear. In the present study we investigated the role of IRF1 in NAFLD pathogenesis.

NAFLD was investigated in mice fed a high-fat high carbohydrate (HFHC) diet or in the genetically predisposed obese mice (db/db).

Hepatocytes from CCL11 knockout mice displayed a less severe NAFLD phenotype, when treated with palmitic acid (PA), compared to wild type hepatocytes, which could be normalized by IRF1 over-expression. On the contrary, IRF1 knockdown in hepatocytes significantly down-regulated expression of pro-inflammatory mediators and dampened lipid accumulation induced by PA treatment. More importantly, IRF1 knockdown in mice led to amelioration of NAFLD in mice. RNA-seq and CUT&Tag-seq identified pro-NAFLD genes, including Osbpl3, Ddit4, and Ccl2, as potential targets for IRF1 in hepatocytes.

Our data reveal a novel regulatory role of IRF1 in NAFLD pathogenesis. Targeting IRF1 can be considered as a reasonable approach for NAFLD intervention.

Liver fibrosis is the primary predictor of complications in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, there are currently no non-invasive prognostic tests to stratify patients at risk for hepatic fibrosis progression. This study aimed to explore whether plasma proteins could serve as non-invasive biomarkers for monitoring MASLD disease progression.

Blood plasma protein analysis was performed on samples from a long-term follow-up study of patients with MASLD with repeated liver biopsies. Over 1100 proteins covering a broad range of biological processes were analyzed using 13 Olink® Target 96 panels. Protein level changes were compared between the different time points and between patients with or without an increase in the liver fibrosis stage between the two biopsies.

Increased vascular endothelial growth factor A (VEGFA) plasma levels were significantly associated with liver fibrosis progression in patients with a histologically assessed increase in the fibrosis stage.

These findings suggest that the plasma protein VEGFA may be an effective biomarker for monitoring fibrosis progression in patients with MASLD.

Liver biopsy assessment by pathologists remains the gold standard for diagnosing metabolic dysfunction-associated steatotic liver disease (MASLD). Current automated image analysis tools for patient risk stratification are often proprietary or not applicable to whole slide images (WSIs). Here, we introduce "Liver-Quant," an open-source Python package for quantifying steatosis and fibrosis in liver WSIs.

Liver-Quant leverages colour and morphological features to measure Steatosis Proportionate Area (SPA) and Collagen Proportionate Area (CPA). We evaluated the method using an internal dataset of 414 WSIs from adult patients (Leeds Teaching Hospitals NHS Trust, 2016-2022) and an external public dataset (109 WSIs). Semi-quantitative scores were extracted from pathological reports. The Spearman rank coefficient (ρ) assessed correlations between computed SPA/CPA and pathologist scores.

Steatosis quantification showed a substantial correlation (ρ = 0.92), while fibrosis quantification yielded a moderate correlation (ρ = 0.51). We further investigated the impact of three staining dyes (Van Gieson (VG), Picro Sirius Red (PSR), and Masson's Trichrome (MTC)) on fibrosis quantification (n = 18). Stain normalisation yielded excellent agreement in CPA measurements across all three stains. Without normalisation, PSR achieved the strongest correlation with human scores (ρ = 0.9) followed by VG (ρ = 0.8) and MTC (ρ = 0.59). Finally, we explored the impact of apparent magnification on SPA and CPA. High-resolution images (0.25 or 0.50 μm per pixel (MPP)) were necessary for accurate SPA measurement, while lower resolution (10 MPP) sufficed for CPA measurements.

Liver-Quant offers an open-source solution for rapid and precise MASLD quantification in WSIs applicable to multiple histological stains.

Emamectin benzoate (EMB) is a lipophilic pesticide that enters aquatic systems and adversely affects non-target organisms. This study investigated the long-term effects of EMB on zebrafish, exposing them to concentrations of 0, 0.1, 1, and 10 μg/L from the 4-hour post-fertilization (hpf) embryo stage to the 120-day post-fertilisation (dpf) adult stage. We found that exposure to 1 μg/L EMB induced liver damage, manifested as impaired liver function (elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), histopathological damage (lipid accumulation), as well as inflammatory and oxidative damage, with a dose - dependent effect. Non-targeted metabolomic analysis revealed an increase in lipid molecules in the liver, affecting the pathways related to glycerophospholipid metabolism. In addition, EMB exposure resulted in damage to the intestinal barrier and inflammatory responses in zebrafish. 16S rRNA sequencing demonstrated that EMB exposure resulted in notable alterations in the gut microbiota composition. Notably, the abundance of Plesiomonas and Cetobacterium increased in the EMB exposure group and exhibited a positive correlation with the majority of liver lipid metabolites. In contrast, reductions in Muribaculaceae and Alloprevotella were negatively correlated. The results of this study indicate that long-term exposure to EMB disrupts the gut microbiota, leading to the dysregulation of hepatic phospholipid metabolism. These findings provide new insights into the health risks associated with EMB and highlight its potential threats to higher organisms, including mammals.

Using common clinical parameters, we aimed to noninvasively identify and predict metabolic dysfunction-associated steatohepatitis (MASH)/MASH with clinically significant fibrosis.

Patients aged ≥18 with electronic health record (EHR) documented liver function tests and liver biopsies between 2016 and 2021 were retrospectively identified from the Geisinger Health System Research Liver Registry. MASH cases were confirmed using the nonalcoholic fatty liver disease (NAFLD) activity score. Training and validation datasets were used to create an algorithm/predictive model assessing EHR-derived predictors of MASH/MASH with clinically significant fibrosis (fibrosis stage F2-F4). Predictive accuracy was evaluated using the area under the curve.

The analysis included 2698 patients. We created a composite likelihood score using variables significant for MASH and/or MASH with clinically significant fibrosis: liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), prior year AST, metabolic disease, pulse (heart rate), and body mass index. The score had higher sensitivity and specificity for predicting MASH than Fibrosis-4 (FIB-4) Index, AST to platelet ratio index (APRI), and NAFLD fibrosis score (NFS); sensitivity and specificity were comparable to FIB-4 and APRI for predicting MASH with clinically significant fibrosis but superior to NFS.

The composite likelihood score could potentially be a tool for early MASH screening.

To address the need for a simple model to predict ≥ F2 fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, a study utilized data from 791 biopsy-proven MASLD patients from the NASH Clinical Research Network and Jinan University First Affiliated Hospital. The data were divided into training and internal testing sets through randomized stratified sampling. A multivariable logistic regression model using key categorical variables was developed to identify ≥ F2 fibrosis. External validation was performed using data from the FLINT trial and multiple centers in China. The DA-GAG score, incorporating diabetes, age, GGT, aspartate aminotransferase/ platelet ratio, and globulin/ total protein ratio, demonstrated superior performance in distinguishing ≥ F2 fibrosis with an area under the receiver operating characteristic curve of 0.79 in training and over 0.80 in testing datasets. The DA-GAG score efficiently identifies MASLD patients with ≥ F2 fibrosis, significantly reducing the medical burden.

Nonalcoholic steatohepatitis (NASH) is a significant threat to human health. Our previous study revealed that salidroside attenuated NASH and regulated the gut microbiota. However, whether the therapeutic effect of salidroside depends on gut microbiota remains to be determined. Therefore, we conducted further experiments to elucidate the essential functions of gut microbiota-associated metabolic pathways in the anti-NASH effects of salidroside. Our results showed that salidroside effectively alleviated lipid accumulation and inflammatory injury in NASH mice. 16S rRNA sequencing revealed that salidroside increased the abundance of Bacteroides. Mice receiving fecal microbiota transplantation (FMT) from salidroside-treated also presented less hepatic steatosis and higher abundance of Bacteroides. Antibiotics eliminated the effects of salidroside on hepatic steatosis and the gut microbiota. Mechanistically, salidroside and FMT from salidroside-treated altered the bile acid (BA) profile by decreasing the levels of conjugated BAs and tauro-α/β-muricholic acid and activated downstream farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Furthermore, we found that inhibitors of bile salt hydrolase (BSH) and FXR/TGR5 abolished the effects of salidroside and reduced downstream carnitine palmitoyltransferase 1α and lipoprotein lipase expression. These data demonstrate that salidroside attenuated NASH via gut microbiota-BA-FXR/TGR5 signaling pathway and reveal the underlying mechanism of salidroside on NASH.

Accentuated Lines (ALs) in tooth enamel can reflect metabolic disruptions from physiological or psychological stresses during development. They can therefore serve as a retrospective biomarker of generalized stress exposure in archaeological and clinical research. However, little consensus exists on when ALs are identified and inter-rater reliability is poorly quantified across studies. Here, we sought to address this gap by examining the reliability of accentuated (AL) markings across raters, in terms of both the presence versus absence of ALs and their intensity (HAL= Highly Accentuated, MAL= Mildly Accentuated, RL= Retzius Line). Ratings were made and compared across observers (with different levels of experience) and pairs of raters (who agreed on AL coding through consensus meetings) (N = 15 teeth, eight observers). Results indicated that more experience in AL assessment does not necessarily produce higher reliability between raters. Most disagreements in intensity ratings occurred in categories other than HAL. Furthermore, when AL assessment was performed by pairs of raters, reliability was significantly higher than individual assessments (Gwet's AC1 = 0.28 to 0.56 for line presence assessment; Gwet's AC1 = 0.48 to 0.64 for line intensity assessment). Based on these results, we recommend a workflow called IRRISS (Improving Reliability and Reporting In Scoring of Stress-markers) to increase rigor and reproducibility in histological analysis of dental collections. The introduction of IRRISS is well-timed, given the surge in studies of teeth occurring across anthropological, epidemiological, medical, forensic, and climate research fields.

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

Drug-induced toxicity is considered a crucial clinical affair, as some adverse effects could be severe or life threatening. Drugs may have adverse effects by altering biological pathways that aren't always involved in the drug's reaction. From this perspective, the purpose of the current study was to assess the impacts of paricalcitol, a synthetic, active, and selective vitamin D receptor activator, on dexamethasone-induced liver injury, and discover the probable implicated signaling pathways as well. Male Wistar rats were treated with paricalcitol at a dose of 0.2 μg/kg, daily, i.p for 12 days and injected with 8 mg/kg dexamethasone i.p daily over the last 6 days. Administration of paricalcitol improved liver function markers, lipid profile, reduced histopathologic changes in hepatic sections, and restored normal oxidative status. Moreover, paricalcitol markedly decreased hepatic collagen deposition as confirmed by Masson's trichrome staining. Paricalcitol effectively inhibited endoplasmic reticulum stress through decreasing expression of tissue PERK and Chop, increasing hepatic Nrf2, and HO-1 activity. Besides, paricalcitol decreased levels of NLRP3 and IL-1β as well as decreased expression of active caspase-1 p20, GSDMD-N-terminal indicating suppression of NLRP3/caspase-1/GSDMD pyroptosis pathway. Paricalcitol can protect against dexamethasone-induced liver injury showing a promising therapeutic value in drug-induced liver injuries.

Treating metabolic dysfunction-associated fatty liver disease (MAFLD) and reducing the occurrence of MAFLD-associated liver cancer remain challenging. Two-dimensional (2D) tantalum carbide (Ta4C3) MXene nanozymes (MXenzymes) exhibit antioxidant and anti-inflammatory activities and have thus attracted considerable attention in the fields of oncology and engineering. However, the potential mechanism of action and bioactive properties of Ta4C3 in MAFLD remain uncertain. In our study, Ta4C3 not only inhibited lipid accumulation and disrupted lipid metabolism in hepatocytes but also reduced cell death caused by fatty acids by decreasing intracellular reactive oxygen species (ROS) levels, which significantly promoted the polarization of M1 macrophages to M2 macrophages by alleviating oxidative stress and further suppressing inflammatory factor expression. In mice fed a methionine-choline-deficient (MCD) diet, Ta4C3 reduced lipid accumulation, the infiltration of inflammatory cells, and liver cell apoptosis by modulating the cellular microenvironment through its anti-inflammatory and antioxidant properties. Therefore, Ta4C3 can be used as a multifunctional bioactive material to alleviate hepatic steatosis and inflammation in individuals with MAFLD/metabolic dysfunction-associated steatohepatitis (MASH) because of its robust antioxidant and anti-inflammatory effects.