Search Results (3,547)

Widespread exposure to per- and polyfluoroalkyl substances (PFAS) is a growing public health concern, but its link to muscle damage remains largely unexplored. As PFAS exposure is associated with liver dysfunction, which is an established risk factor for muscle damage, we examined their associations and potential mediating pathways. A total of 1261 participants were recruited from Guangdong province, China, from November 2018 to August 2019 and examined for muscle mass, strength, serum PFAS levels, and biomarkers of liver function. The key results demonstrated significant positive associations between serum PFAS exposure and sarcopenia risk. Specifically, a per ln ng/mL increase in linear perfluorooctane sulfonate (PFOS), branch PFOS, and perfluorooctanoic acid (PFOA) was associated with adjusted odds ratios of 2.32 (95% CI: 1.77 to 3.00), 2.18 (95% CI: 1.67 to 2.90) and 3.01 (95% CI: 1.96 to 4.70), respectively. Analysis of PFAS mixtures via the BKMR model revealed a linear dose–response relationship of sarcopenia, with PFOS and PFOA being the primary contributor. Importantly, mediation analyses showed that liver function biomarkers served as significant mediators of the PFAS–sarcopenia association. Notably, liver synthesis function markers (albumin and globin) mediated a substantial proportion of the association, ranging from 3.48% to 82.42%, whereas liver injury markers (aspartate aminotransferase and gamma-glutamyl transferase) accounted for only 1.93–15.44%. This study underscores the need to be aware of the increased risk of muscle damage associated with PFAS exposure, which may primarily operate through liver function abnormalities. Full article

Organoids are three-dimensional culture systems that self-organize and partially recapitulate the architecture, cellular composition, and functional properties of native tissues. In pediatric congenital hepatobiliary diseases, persistent cholestasis, bile duct maldevelopment, epithelial injury, and progressive fibrosis often lead to cirrhosis, liver failure, or the necessity for liver transplantation. Compared with conventional two-dimensional cell culture and animal models, hepatobiliary organoids provide patient-derived, human-relevant platforms for modeling disease mechanisms, evaluating therapeutic responses, and exploring regenerative strategies. Unlike previous reviews that mainly discuss general organoid culture systems or broad liver disease modeling, this review is organized around clinically oriented translational endpoints, including mechanistic target discovery, prognostic stratification, therapeutic validation, and regenerative reconstruction. We further discuss current barriers to clinical translation, including reproducibility, scalability, vascularization, immune integration, manufacturing standardization, and patient-specific genetic, environmental, and dietary modifiers. By integrating disease-specific mechanisms with translational applications, this review provides a framework for understanding how organoid-based platforms may contribute to future diagnosis, risk assessment, therapeutic decision-making, and regenerative medicine in pediatric congenital hepatobiliary disorders. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder linked to cardio-kidney–metabolic (CKM) syndrome, early vascular injury and redox imbalance. Inflammatory adipokines such as retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) may contribute to this hepatic–vascular interplay by integrating metabolic inflammation, oxidative stress and endothelial dysfunction. Therefore, the present study aimed to investigate the contribution of the inflammatory adipokines retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) to the hepatic–vascular interplay in MASLD within the cardio-kidney–metabolic (CKM) syndrome. Materials and Methods: We performed a systematic review and meta-analysis of studies evaluating circulating RBP4 and LCN2 levels in MASLD. PubMed, Scopus, and Web of Science were searched. Twenty studies were included in the qualitative synthesis, and ten in the quantitative meta-analysis. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Vascular findings were synthesized narratively because of heterogeneity in outcomes. Results: Circulating RBP4 levels were significantly higher in MASLD patients than in controls (SMD = 0.64, 95% CI: 0.08 to 1.20, p = 0.026; I² = 91.2%). LCN2 levels were also significantly elevated (SMD = 1.92, 95% CI: 0.83 to 3.00, p < 0.001; I² = 98.0%). Compared with RBP4, LCN2 showed a larger pooled effect size, although heterogeneity remained very high. In the qualitative synthesis, adipokines, particularly LCN2, were associated with markers of vascular injury, including carotid intima–media thickness, plaque burden, arterial stiffness, endothelial dysfunction, coronary severity, and cardiovascular events. Conclusions: Both RBP4 and LCN2 were elevated in MASLD, supporting a link between adipokine dysregulation and hepatic metabolic dysfunction within the broader cardio-kidney–metabolic (CKM) syndrome. LCN2 appeared to better reflect the inflammatory, metabolic, and vascular burden of disease. These findings support the view of MASLD as a systemic disorder within the CKM syndrome and highlight the potential of inflammatory adipokines as non-invasive biomarkers of integrated hepatic, metabolic, and vascular dysfunction. Full article

Ultrasound is widely used in pediatric imaging because it is safe, portable, real-time, and free of ionizing radiation, but interpretation remains qualitative and operator-dependent. Ultrasound radiomics can extract quantitative features from standard grayscale images, providing potential biomarkers of tissue patterns not readily apparent on visual assessment. This structured narrative review summarizes pediatric ultrasound radiomics applications across organ systems and key barriers to clinical translation. Current evidence suggests promise in neonatal brain injury, neurodevelopmental assessment, liver disease staging, renal characterization, oncologic risk stratification, and emerging lung and muscle applications. However, most studies remain limited by retrospective single-center designs, small cohorts, acquisition variability, segmentation inconsistency, and limited external validation. Future progress will require standardized workflows, prospective multicenter validation, and clinically interpretable integration into decision-support systems. Full article

Micro- and nanoplastics (MNPs) have emerged as pervasive contaminants in aquatic ecosystems, raising concerns regarding their biological impacts on aquatic organisms. The liver plays a central role in metabolism, detoxification, and immune regulation, making it particularly vulnerable to MNP-induced toxicity. Importantly, MNPs also function as vectors and modulators of co-occurring environmental contaminants, including heavy metals, pesticides, antibiotics, PFASs, algal toxins, and polycyclic aromatic hydrocarbons (PAHs), thereby influencing contaminant bioavailability and hepatic toxicity. This narrative review synthesizes current evidence on hepatic alterations induced by micro- and nanoplastic exposure in zebrafish (Danio rerio), with emphasis on histopathological changes and underlying mechanisms. Relevant peer-reviewed studies were identified through systematic searches of Web of Science, Scopus, PubMed, and ScienceDirect, covering the period 2013–2026, and screened according to predefined inclusion criteria focusing on hepatic endpoints in zebrafish exposed to micro- and nanoplastics. Across the available literature, MNPs consistently accumulate in hepatic tissue and induce structural alterations, including hepatocellular vacuolization, steatosis, inflammatory infiltration, and necrosis. Mechanistically, these pathological changes are closely linked to oxidative stress, impairment of antioxidant defense systems, reprogramming of lipid and glucose metabolism, and activation of inflammatory and regulated cell death signaling pathways. In addition, interactions with co-occurring environmental contaminants—such as heavy metals, pesticides, antibiotics, and algal toxins—frequently exacerbate hepatic injury through synergistic toxicological mechanisms. Disruption of the gut–liver axis and intestinal microbiota has also emerged as an important contributor to systemic metabolic and inflammatory responses. Overall, zebrafish studies demonstrate that the liver represents a critical target organ for MNP toxicity. Future research should prioritize environmentally realistic exposure scenarios, standardized particle characterization, and integrated multi-omics approaches to improve ecological and human health risk assessment. Full article

Pharmacological treatment of metabolic-dysfunction-associated steatohepatitis remains challenging due to its complex pathophysiology. The endocannabinoidome (eCB) has emerged as a promising therapeutic target given its central role in energy homeostasis and its pharmacological tractability. Western-style diets high in fat and sugar exacerbate metabolic liver disease, highlighting the need for effective interventions. Here, we investigated the therapeutic potential of cannabinoid combinations targeting the eCB–liver axis in a Western diet-induced model of metabolic dysfunction. Two weeks of treatment reduced body weight, improved glycaemic control, and ameliorated liver pathology. These effects were accompanied by decreased liver weight, improved liver enzyme profiles, and reduced histological features of steatosis and injury. Overall, these findings suggest that modulation of the eCB system can induce acute improvements in metabolic and hepatic parameters under conditions of diet-induced metabolic stress. These results support further investigation into the eCB system as a therapeutic target, particularly to elucidate underlying mechanisms and longer-term effects. Full article

Hepatic ischemia–reperfusion injury (HIRI) is an unavoidable clinical challenge in liver transplantation, major hepatectomy and trauma resuscitation, with no approved specific therapeutics to date. As core innate immune effector cells, neutrophils are the central driver of the sterile inflammatory cascade in HIRI. Centered on the Mac-1-Syk core regulatory axis, this review systematically elaborates the neutrophil recruitment cascade and intracellular signaling network in HIRI, focuses on the sequential formation pathways of neutrophil extracellular traps (NETs) and their multi-dimensional injury mechanisms, and dissects the inflammation–thrombosis amplification crosstalk between neutrophils and multiple hepatic non-parenchymal cells. Furthermore, this review clarifies research controversies of core therapeutic targets, analyzes key translational bottlenecks, and proposes a NETs-centered sequential multi-target combination strategy, providing a solid theoretical basis and clear translational direction for the precise targeted therapy of HIRI. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized during adolescence and exhibits sex-specific characteristics. Its prevalence in late adolescent females is around 10% in the general population and exceeds 30% in obesity. Genetic variants in PNPLA3, MBOAT7, and MARC1 modulate hepatic fat accumulation and liver injury in adults, but evidence in adolescent females remains limited. This study examined MASLD-related variants (PNPLA3 rs738409, MBOAT7 rs641738, MARC1 rs2642438) in relation to metabolic and immune-inflammation indices in a late-adolescent female cohort. A cross-sectional analysis was performed in a prospectively assembled female cohort (n = 150; age 16–19 years). Ultrasound-defined MASLD prevalence was 16.7%. Although genotype-wise differences did not reach statistical significance, MASLD prevalence was directionally higher among PNPLA3 G- and MBOAT7 T-allele carriers, while a non-uniform, directionally favorable pattern was observed for the MARC1 A allele. Nominal, unadjusted differences were observed for low-density lipoprotein cholesterol (LDL-c) and systemic immune-inflammation index (SII) across MBOAT7 genotypes. Cumulative risk-allele burden analyses identified nominal trends for triglycerides (K-W p = 0.05; J-T p = 0.014) and triglyceride-glucose (TyG) index (K-W p = 0.034; J-T p = 0.008), which were not retained after adjustment for age and body mass index. Overall, these findings indicate modest, exploratory genotype-related patterns in metabolic and hematological immune-inflammation indices within a relatively healthy, late-adolescent female population. TyG and SII exhibited substantial inter-individual variability but did not demonstrate independent predictive value. Larger, longitudinal studies with advanced imaging are required to clarify the role of genetic variation and simple hematological metabolic-inflammation indices in early MASLD risk assessment in adolescent females. Full article

Background: Recruitment and activation of monocyte-derived macrophages (MoMFs) sustain cholangitis in primary biliary cholangitis (PBC), but whether MoMFs amplify inflammation through ferroptosis remains unclear. We defined ferroptotic programs in MoMFs and evaluated the calpain/ACSL4 axis as a regulatory and therapeutic node. Methods: We analysed a public human liver single-cell RNA sequencing (scRNA-seq) dataset and examined MoMF-associated ACSL4 and 4-hydroxynonenal (4-HNE) signals in CD11b⁺CD68⁺ cells by multiplex immunofluorescence. We used a 2OA–BSA-induced PBC-like mouse model to assess liver injury, inflammation and ferroptosis-related markers and tested Liproxstatin-1 (Lip-1), rosiglitazone (ROSI) or the calpain inhibitor PD150606. Bone marrow-derived macrophages (BMDMs) from control and PBC mice were profiled and challenged with RSL3, with or without Ferrostatin-1 (Fer-1), ROSI or PD150606. Results: MoMFs were expanded in PBC livers and showed the strongest induction of ferroptosis signatures, centered on ACSL4, with enhanced inflammatory crosstalk with cholangiocytes. Human PBC tissues showed increased CD11b⁺CD68⁺ cells positive for ACSL4 or 4-HNE. In PBC-like mice, malondialdehyde (MDA) increased and glutathione (GSH) decreased, and macrophages showed greater colocalization with ferroptosis markers; Lip-1, ROSI or PD150606 improved liver biochemistry, reduced inflammation scores and limited macrophage infiltration. PBC-derived BMDMs upregulated ACSL4 and CAPN1/2 and were more sensitive to RSL3; Fer-1, ROSI or PD150606 attenuated ferroptosis-associated molecular changes. Conclusions: MoMF ferroptosis is prominently engaged in PBC, and our findings implicate a pharmacologically tractable calpain/ACSL4 axis that may contribute to macrophage ferroptotic susceptibility and inflammatory liver injury. Full article

High-starch diets are increasingly used in aquafeeds to reduce feed costs, but carnivorous fish such as largemouth bass (Micropterus salmoides) have limited capacity to utilize dietary starch and are prone to hepatic metabolic disorders. In the present study, we evaluated whether dietary N-carbamylglutamate (NCG) could alleviate high-starch-induced hepatic oxidative stress and liver injury in largemouth bass. Fish were fed a control diet containing 11.50% starch, a high-starch diet containing 18.00% starch, or a high-starch diet supplemented with 0.15%, 0.20%, or 0.25% NCG for 8 weeks. Compared with the high-starch group, dietary NCG supplementation significantly reduced serum glucose and triglyceride levels, decreased hepatic glycogen and malondialdehyde contents, and increased hepatic superoxide dismutase and glutathione peroxidase activities. NCG also reduced serum alanine aminotransferase and aspartate aminotransferase activities and alleviated hepatic histopathological damage. At the transcriptional level, NCG upregulated genes related to insulin signaling, glycolysis, lipid catabolism, and antioxidant regulation, including insr, irs, gk, pk, atgl, hsl, ampk, and nrf2, while downregulating the expression of keap1, nf-κB, mtor, and multiple inflammation- and apoptosis-related genes. These changes were accompanied by increased serum nitric oxide levels and improved survival and growth performance under high-starch feeding conditions. Collectively, these results indicate that dietary NCG supplementation attenuates high-starch-induced hepatic oxidative stress and redox-associated liver injury in largemouth bass, which may be associated with the transcriptional modulation of genes related to the AMPK/Nrf2/Keap1 and mTOR/NF-κB signaling pathways. Full article

Fatty liver hemorrhagic syndrome (FLHS) is a common metabolic disorder in laying hens, leading to reduced egg production and economic losses. Aspirin eugenol ester (AEE) has lipid-lowering, anti-inflammatory, and antioxidant properties, but its effects on FLHS are unknown. This study evaluated the protective effects of AEE using an in vivo FLHS model induced by a high-energy low-protein diet in laying hens and an in vitro steatosis model established by free fatty acid treatment in LMH cells. AEE alleviated liver histopathological damage, reduced oxidative stress (decreased ROS and MDA; increased SOD, GSH, and CAT), and suppressed inflammatory responses. The hepatoprotective effects of AEE were tentatively associated with altered molecular expression of the Nrf2 antioxidant pathway and MAPK/NF-κB inflammatory signaling; however, this correlation was speculated based on molecular detection and incomplete in vitro pharmacological interventions, lacking rigorous causal validation. These findings suggest that AEE alleviates FLHS-related liver injury in laying hens, possibly in association with altered oxidative and inflammatory status. Collectively, these preliminary findings provide a limited theoretical reference for the potential application of AEE as a preventive agent against FLHS in laying hens. Full article

Gatifloxacin (GTFX), a fourth-generation fluoroquinolone, causes metabolic disturbances in mammals, but its hepatotoxic mechanisms in aquatic vertebrates remain unclear. This study investigated whether GTFX induces liver injury in zebrafish larvae through oxidative stress or alternative pathways. Larvae at 3 days post-fertilization were exposed to 0.2–2.3 mg/mL GTFX for 48 h. Liver morphology, histopathology, intracellular reactive oxygen species (ROS), and expression of lipid metabolism (pparg) and xenobiotic biotransformation genes (cyp1a, cyp1b1) were assessed. GTFX exposure caused concentration-dependent reductions in liver area, increased hepatic opacity, delayed yolk sac absorption, and hepatocyte swelling with cytoplasmic vacuolization. Despite these structural changes, ROS levels did not differ significantly from those of controls. In contrast, transcriptional analysis revealed significant upregulation of pparg, cyp1a, and cyp1b1, indicating disrupted lipid homeostasis and enhanced detoxification responses. Acute high-dose GTFX exposure induced a metabolism-associated hepatotoxic response in zebrafish larvae, which occurred without a statistically significant change in bulk ROS levels. Together, these findings offer mechanistic insight into fluoroquinolone-associated liver injury. Full article

As the global average temperature increases, heat stress (HS) caused by high temperatures has become a key constraint to the development of the poultry industry. As the primary metabolic organ, HS can induce liver injury in chickens, thereby compromising feed safety. However, the precise mechanisms underlying HS-induced liver injury remain to be elucidated. The objective of this study is to explore the impact of HS on liver damage, oxidative stress, the Keap1-Nrf2 pathway, ferroptosis and cuproptosis in chickens. A total of 70 chickens were selected for this experiment and divided into a CON group and a HS group: the CON group was reared in a normal-temperature environment (24 ± 1°C), whilst the chronic HS group was reared in a high-temperature environment (33 ± 1°C). The findings of the study suggested that HS has the potential to induce liver dysfunction, oxidative stress, and disruption of the Keap1-Nrf2 pathway. HS has been demonstrated to induce Fe²⁺ accumulation in chicken livers, inhibit the expression of FTH1, FSP1, SLC7A11 and Gpx4, and simultaneously upregulate the expression of CD71, PTGS2 and ACSL4, thereby promoting ferroptosis. Furthermore, Cu²⁺ accumulation in the liver upregulates HSP70, DLAT and Lip-DLAT levels and downregulates the expression of ATP7B, PDH1A, PDHB, PDK4, DLST and FDX1, thereby inducing cuproptosis. Subsequent correlation analysis revealed that HS can induce ferroptosis and cuproptosis via the HO-1/FDX1/Gpx4 pathway. This finding provides new insights into the mechanisms underlying HS-induced liver injury. Full article

Chronic kidney disease (CKD) is characterized by the progressive accumulation of uremic toxins (UTs), which contribute to systemic complications, increased cardiovascular risk, and disease progression. Epidemiological and experimental evidence demonstrate pronounced sex differences in CKD progression and outcomes, yet the mechanisms underlying sex-specific uremic toxicity remain unclear. This review synthesizes current knowledge on sex differences in the origin, metabolism, transport, and biological effects of UTs, with a focus on sex-dependent regulatory mechanisms along the gut–liver–kidney axis. Sex hormones influence key determinants of toxin handling, including gut microbiota composition, hepatic enzyme activity, plasma protein binding, membrane transporter expression, and intracellular signaling pathways. Together, these factors regulate systemic toxin exposure and tissue susceptibility to injury. CKD also disrupts endocrine homeostasis, creating bidirectional interactions between hormonal regulation and toxin accumulation. Experimental and limited clinical evidence suggest that sex may influence circulating toxin profiles and susceptibility to toxin-associated complications. Collectively, sex is an important modulator of uremic toxicity, with sex hormones mediating at least part of the sex differences. A sex-informed framework may improve fundamental understanding through mechanistic studies and future clinical research may help clarify its relevance for biomarker development and support the development of personalized therapeutic strategies for CKD. Full article

Glyphosate, the most widely used herbicide worldwide, is now ubiquitous in the environment, posing a growing threat to human health. While accumulating evidence has linked glyphosate exposure to liver injury, the underlying mechanisms remain unclear. In this study, based on data from NHANES 2013–2018, we identified significant associations between glyphosate exposure and abnormal liver function parameters in the general US population. A glyphosate-exposed mouse model was further established, and the results showed that hepatic accumulation of glyphosate induced direct histopathological damage and increased serum AST, ALT, and ALP levels in mice. Combined network toxicology and gene set analyses revealed that glyphosate activated liver macrophages, upregulating genes related to lipid metabolism, inflammation, and pyroptosis. The activation of the pyroptosis pathway was further confirmed by Western blot analysis of NLRP3 inflammasome-associated proteins. Mechanistically, glyphosate disrupted mitochondrial membranes and compromised mitochondrial function, leading to the release of mtDNA, which subsequently activated the cGAS-STING pathway in mouse livers and RAW264.7 macrophages. Moreover, glyphosate-induced NLRP3 activation in RAW264.7 cells was attenuated by the cGAS inhibitor. These findings provide a novel mechanistic insight into glyphosate-induced hepatotoxicity and reinforce the growing concern over its association with liver injury in humans. Full article