Drug-induced liver injury (DILI) is a leading cause of acute liver failure, posing a significant public health burden. Emerging evidence underscores the gut microbiota as a critical environmental factor that profoundly influences liver function and DILI progression, yet the underlying mechanisms remain poorly understood. Here, we identify hepatic long non-coding RNA SNHG9 as a key mediator linking the gut microbiota to acetaminophen (APAP)-induced liver injury. Upregulation of hepatic SNHG9 protects against hepatotoxicity by activating MAS, a G protein-coupled receptor that facilitates the clearance of cellular damage via enhanced autophagy. Mechanistically, SNHG9 binds to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2), enhancing its interaction with MYC mRNA and suppressing MYC translation. Since MYC acts as a transcriptional repressor of the MAS1 gene, this suppression leads to upregulated MAS expression. Notably, hepatic SNHG9 expression is modulated by the gut microbiota, particularly through the metabolite 2-hydroxy 2-methylbutyric acid (HMB). Supplementation with HMB or HMB-producing microbes robustly induces hepatic SNHG9 expression and attenuates APAP-induced liver injury. Our findings unveil a previously unrecognized gut-liver axis and provide mechanistic insight into how gut microbiota regulate hepatic stress responses, suggesting potential avenues for modulating this pathway in drug-induced liver injury.

OBJECTIVES:To investigate the optimal dose ratio and mechanisms of the primary active components in Yinchenhao decoction (geniposide, chlorogenic acid, and rhubarb polysaccharides) for ameliorating metabolic associated fatty liver disease (MAFLD). METHODS:C57BL/6 mice were randomly divided into the normal control group, model control group, uniform design groups 1-6, and Yinchenhao decoction group; except for the normal control group, mice in all other groups were fed Western diets to establish MAFLD models, and after eight weeks of modeling, mice in the uniform design groups 1-6 and Yinchenhao decoction group were given the corresponding drugs by gavage. At 12 weeks, all mice were sacrificed: their body weight and liver weight were measured, hematoxylin-eosin staining was used to observe the histopathological changes of liver tissues, the plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST) were measured, and the levels of total cholesterol (TC) and triglycerides (TG) in plasma and liver were measured. Based on these results, the optimal uniform design group was identified; subsequently, with plasma AST, plasma TG, and liver TC levels as screening indicators, the optimal dose ratio was obtained via a regression equation, which was further verified from functional indicators and tissue morphology. Meanwhile, glucose tolerance test and insulin tolerance test were conducted to evaluate glucose metabolic homeostasis and insulin sensitivity in mice, periodic acid-Schiff staining was used to observe glycogen accumulation, quantitative reverse transcription-polymerase chain reaction was employed to detect the mRNA expression of genes related to glycolipid metabolism and bile acid metabolism, Western blotting was performed to measure the protein expression of molecules involved in bile acid metabolism, and commercial kits were used to determine the plasma levels of total bilirubin (TBIL), direct bilirubin (DBIL), and total bile acid (TBA). RESULTS:Combinations of geniposide, chlorogenic acid, and rhubarb polysaccharide all reduced the liver-to-body weight ratio, alleviated liver injury, and decreased lipid accumulation, among which the uniform design group 6 (200 mg/kg geniposide+160 mg/kg chlorogenic acid+340 mg/kg rhubarb polysac-charide) exhibited the optimal efficacy. Meanwhile, regression analysis indicated that the dosage ratio of uniform design group 6 was the optimal one for MAFLD intervention. Validation experiments showed that, compared with single-drug intervention, the optimal dosage ratio resulted in significantly lower body weight, as well as lower plasma levels of ALT, AST and TC in mice (all P<0.05), along with a more pronounced reduction in the area of hepatic lipid accumulation. Mechanistic investigation experiments demonstrated that intervention with the optimal dosage ratio significantly improved glucose tolerance and insulin sensitivity in mice (all P<0.05), reduced hepatic glycogen accumulation, and downregulated the mRNA expression of glycolipid metabolism-related genes such as Gsk3, G6pc, Pck1, Fbp1, Fasn, Srebp-1c, Scd1, Slc27a2, and Slc27a5 (all P<0.05); it also decreased plasma levels of TBIL, DBIL, and TBA (all P<0.05), restored the dysregulated protein expression of bile salt export pump (BSEP), farnesoid X receptor (FXR), and cytochrome P450 family 7 subfamily A member 1 (CYP7A1) in the liver (all P<0.05), and reversed the abnormal mRNA expression of bile acid metabolism-related genes including Nr1h4, Cyp7a1, Cyp27a1, Slc10a1, and Slco1a1 (all P<0.05). CONCLUSIONS:The combination of geniposide (200 mg/kg), chlorogenic acid (160 mg/kg), and rhubarb polysaccharide (340 mg/kg) exerts the optimal ameliorative effect on MAFLD in mice. This superior efficacy is presumably achieved by synergistically regulating the key nodes of glucose, lipid and bile acid metabolism.

Metabolic-associated fatty liver disease (MAFLD) progresses via a vicious cycle of "lipid dysregulation-ceramide-inflammation-oxidative stress-ferroptosis," with sodium palmitate (PA) as a key mediator of hepatic lipotoxicity. To screen ameliorative natural compounds, we performed high-throughput screening of 236 traditional Chinese medicine-derived compounds using PA-induced AML-12 hepatocytes, identifying biochanin A (BCA)-a major isoflavone in chickpeas-as a potent protector against hepatocyte death. We validated BCA's effects in vitro (PA-induced AML-12 cells) and in vivo (high-fat diet-induced MAFLD mice, 25/50 mg/kg BCA), combined with IRE1α agonist IXA4 rescue experiments and multi-omics analyses. A novel finding is that BCA directly binds IRE1α (via LEU23/CYS91, validated by molecular docking and 100-ns MD simulations) and specifically inhibits the IRE1α-SPT-ceramide axis. This downregulates SPTLC1/SPTLC2 (ceramide synthesis rate-limiting enzymes), normalizes hepatic C16/C24 ceramide levels, suppresses IL-1β/IL-6 production, restores mitochondrial OXPHOS function, reduces ROS/lipid peroxidation, and inhibits ferroptosis. Concurrently, BCA treatment was associated with alterations in gut microbiota composition (enriching Bacilli, reducing pro-inflammatory Coriobacteriia), enhanced intestinal barrier function, and reduced LPS translocation, which may contribute to mitigating hepatic inflammation. Notably, IXA4 completely reversed BCA's protective effects. In conclusion, BCA ameliorates MAFLD by inhibiting the IRE1α-SPT-ceramide axis to block the pathological cascade. In parallel, BCA treatment is associated with alterations in gut microbiota composition, improved intestinal barrier integrity, and reduced systemic inflammation, suggesting that the gut-liver axis may be involved in its protective effects.

Background : Alcohol-induced liver injury (ALI) and subsequent hepatic fibrosis pose significant global health burdens, with limited effective therapeutic options. Traditional Chinese Medicine (TCM) formulas, such as Qing Hua Yu Du (QHYD) formula, have shown potential in treating alcoholic hepatic fibrosis in clinical, but their therapeutic effects, and underlying mechanisms remain incompletely characterized. Additionally, the interplay between hepatic inflammation, metabolic disorders, and gut-liver axis dysregulation in ALI-related fibrosis necessitates comprehensive validation across multiple models. Purpose : This study aimed to evaluate the therapeutic effects of QHYD formula on alcohol-CCl₄-induced alcoholic hepatic fibrosis in diverse models (alcohol-CCl₄, acute binge alcohol, and cell models), explore its mechanisms involving inflammatory signaling, hepatic metabolism, and gut microbiota, validate the key metabolite L-histidine’s role, and assess its safety profile. Methods : The QHYD formula's chemical composition was characterized using advanced high-performance liquid chromatography (HPLC) fingerprinting for quality control and ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) for constituent identification. Male C57BL/6 mice were assigned to normal, model, QHYD (2.7, 4.05, 5.4 g/kg/day), and fecal microbiota transplantation (FMT) groups. Acute binge alcohol and AML-12 cell models were used for supplementary validation. Liver injury was evaluated by plasma biochemical markers (ALT/AST/GGT/TC/TG) and histological staining (H&E/Masson). Inflammatory pathways (MAPK/TLR4-MyD88), metabolic changes, and gut microbiota were analyzed via Western blot, ELISA, transcriptomics, metabolomics, and 16S rRNA sequencing. L-histidine’s mechanism was validated in LX-2 cells using qRT-PCR and immunofluorescence. Acute/chronic toxicity assays were conducted to assess safety. Results : HPLC confirmed QHYD’s batch consistency, and UHPLC-Q/TOF-MS identified 82 constituents. QHYD significantly ameliorated liver injury and fibrosis in alcohol-CCl₄ and acute binge alcohol models, reduced plasma TC/TG, and inhibited Col1a1/α-SMA expression. It suppressed MAPK/TLR4-MyD88 signaling, restored protein digestion/absorption pathway (upregulating L-histidine), and modulated gut microbiota richness/composition. FMT experiments confirmed QHYD-modulated gut microbiota directly mediated anti-fibrotic effects. L-histidine dose-dependently inhibited HSC activation via the NF-κB-TIMP1 axis. Conclusion QHYD ameliorates alcoholic hepatic fibrosis through multi-targeted mechanisms: inhibiting MAPK/TLR4-MyD88 inflammatory pathways, restoring hepatic metabolism via L-histidine, and modulating gut microbiota. Its favorable safety profile and efficacy across diverse models support QHYD as a promising therapeutic candidate, with L-histidine serving as a key mediating metabolite.

IntroductionMetabolism-associated fatty liver disease (MAFLD) has emerged as a severe worldwide public health burden with insufficient available clinical therapeutic strategies, which underscores the urgent demand for safe, natural dietary interventions. Raspberry (Rubus idaeus L.), a typical food-medicine homologous fruit abundant in diverse bioactive components including anthocyanins, flavonoids and polysaccharides, possesses prominent nutritional and medicinal potential.MethodsIn this study, raspberry aqueous extract (RE) was prepared to comprehensively investigate its ameliorative effects and underlying molecular mechanisms against MAFLD. MAFLD animal model was established in C57BL/6 mice via 12-week high-fat diet (HFD) feeding. From the 9th week, model mice were intragastrically administered with RE at doses of 1 g/kg/d and 2 g/kg/d for continuous intervention. Integrated multi-omics analyses including 16S rRNA microbial sequencing, serum/hepatic biochemical detection, histopathological examination, in vivo microbial colonization assay, and in vitro cellular and metabolomic experiments were performed to systematically clarify the regulatory mechanism.ResultsRE treatment markedly improved the core pathological phenotypes of MAFLD mice, and significantly mitigated hepatic steatosis and hepatocellular injury. 16S rRNA sequencing demonstrated that RE remodeled the gut microbial dysbiosis, specifically elevating the abundance of beneficial genus Ileibacterium and suppressing pathogenic microbial taxa. Meanwhile, RE strengthened intestinal mucosal barrier integrity by upregulating tight junction protein expression, and activated hepatic purine metabolic reprogramming to boost the levels of critical metabolites including inosine and ADP. Spearman correlation analysis verified the significantly positive correlation between Ileibacterium abundance and hepatic inosine content, and both factors were closely correlated with the remission of MAFLD pathological indicators. In vivo colonization experiments further validated that Ileibacterium intervention alone remarkably alleviated hepatic lipid deposition and liver damage in MAFLD mice. In vitro strain metabolomics confirmed that Ileibacterium could directly biosynthesize and secrete inosine extracellularly. Furthermore, in vitro AML12 hepatocyte experiments revealed that 100 μM inosine remarkably relieved palmitic acid-induced lipotoxicity via reducing intracellular lipid overload, reactive oxygen species (ROS) accumulation and mitochondrial dysfunction, alongside modulating the expression of lipid metabolism, inflammatory and autophagy-related genes.DiscussionCollectively, our results elucidate that raspberry aqueous extract alleviates experimental MAFLD through the gut microbiota-purine metabolism-inosine regulatory axis, in which Ileibacterium and inosine act as the core synergistic mediators. This study provides solid preclinical experimental evidence for the development and application of raspberry as a promising functional food for the prevention and nutritional intervention of MAFLD.

Although dietary cholesterol is known to exacerbate liver disease progression, whether and how it contributes to hepatic steatosis, the hallmark early pathological feature of both MASLD and ALD, remains poorly understood. Here, we investigated how cholesterol disrupts hepatic triacylglycerol metabolism using both dietary and cellular cholesterol-loading models. Integrated transcriptomic, metabolomic, and biochemical analyses were performed, and causality was examined through genetic and pharmacologic modulation in multiple hepatocyte systems and mice. Our results demonstrate that cholesterol overload induces hepatocellular fat accumulation in a dose-dependent, cell-autonomous manner, primarily by suppressing fatty acid β-oxidation. Mechanistically, we identified PPARα inhibition as a key event underlying this effect. Cholesterol overload suppressed PPARα transactivation, thereby impairing fatty acid β-oxidation and promoting hepatocellular fat accumulation. This inhibition was mechanistically linked to reduced O-GlcNAcylation. Specifically, cholesterol overload downregulated OGT, leading to reduced protein O-GlcNAcylation and consequent PPARα inhibition; similarly, liver-specific OGT knockout mice exhibited suppressed PPARα activity and increased hepatic fat accumulation. RNA-sequencing and co-immunoprecipitation analyses identified PPARα as an O-GlcNAc-modified protein, and loss of this modification impaired its transactivity. Functionally, restoration of O-GlcNAcylation via genetic OGA knockdown or pharmacological activation of PPARα with WY14643 alleviated cholesterol-induced hepatic steatosis in mice without altering hepatic cholesterol levels. Lastly, we identified SREBP2 as the upstream transcriptional regulator linking cholesterol overload to OGT suppression. In conclusion, our findings in this study uncover a previously unrecognized cholesterol-OGT-PPARα axis that suppresses hepatic fatty acid β-oxidation and drives steatosis. Targeting O-GlcNAc cycling or activating PPARα represents a promising therapeutic strategy for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) lacks effective nutrition-based interventions. Hesperetin, a dietary citrus flavonoid, was evaluated for its hepatoprotective mechanism using high-fat diet-induced MASLD mice and free fatty acid-challenged hepatocytes. Hesperetin improved glucose and lipid metabolism, alleviated steatosis and inflammation, and restored hepatic function. Integrated transcriptomics and network analysis indicated activation of retinol metabolism and inhibition of MAPK signaling. Mechanistic studies showed that hesperetin suppressed aberrant MAPK activity, preserved retinoic acid receptor α (RARα) function, upregulated RARα-dependent metabolic genes, and reduced lipogenic gene expression. Pharmacological blockade or siRNA knockdown of RARα abrogated hesperetin's lipid-lowering effects, confirming RARα as an essential mediator. These findings identify hesperetin as a food-derived modulator of the MAPK-RARα axis that restores retinoid signaling and ameliorates hepatic lipid dysregulation, highlighting its potential as a targeted nutritional strategy for MASLD management.

Abstract Background The diagnosis of prostate cancer (PCa) is limited by low specificity and invasiveness. This study aims to establish a highly accurate, noninvasive reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR)‐based urinary prostate cancer antigen 3 ( PCA3 ) assay system and explore the feasibility of using first‐morning urine instead of post‐digital rectal examination (DRE) samples. Methods Three prospective multicenter cohort studies were conducted on 643 Chinese men. Urine PCA3 expression was quantified by RT‐qPCR, using either the novel reference gene microseminoprotein‐beta ( MSMB ) or conventional kallikrein‐related peptidase 3 ( KLK3 , encoding prostate‐specific antigen, PSA). Diagnostic performance was evaluated through receiver operating characteristic (ROC) analysis in Cohort I ( n = 176), with validation in Cohort II ( n = 350). In Cohort III ( n = 117), the diagnostic accuracy of PCA3 / MSMB test was compared between DRE and non‐DRE urine samples. Results The PCA3 / MSMB RT‐qPCR system showed high precision and stability. In Cohort I, the PCA3 / MSMB test demonstrated superior diagnostic performance compared with the PCA3 / KLK3 test, with a significantly higher area under the receiver operating characteristic curve (AUC) (0.869 vs. 0.830, p = 0.0468), higher sensitivity (82.1% vs. 79.0%), and higher specificity (77.8% vs. 74.1%). Cohort II confirmed these results, yielding a sensitivity of 82.63% and a specificity of 77.50%. In Cohort III, no significant difference in diagnostic performance was observed between non‐DRE and DRE urine samples (AUC 0.859 vs. 0.850, p = 0.6262), suggesting the potential for simplified sample collection. Conclusion The PCA3 / MSMB urine test is a promising noninvasive diagnostic tool for PCa; it can reduce unnecessary biopsies and improve detection accuracy using non‐DRE urine samples.

This study aims to investigate the molecular mechanisms by which 4-hydroxynonenal (4-HNE) regulates hydrogen sulfide (H₂S)-producing enzymes, mediating the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) during pregnancy, thereby offering novel molecular targets for early diagnosis and intervention of related disorders. By establishing a MAFLD pregnant mouse model, we comprehensively examined the regulatory effects of 4-HNE on placental function and its interaction with the H₂S system. We found that MAFLD pregnant mice exhibited significant glucose metabolic disorders, hepatic steatosis, and placental damage. Mechanistically, 4-HNE disrupts H₂S biosynthesis, thereby impairing its inhibitory effect on the inflammasome pathway while simultaneously activating inflammatory cascades. This synergistic action exacerbates placental pathological damage, manifesting as abnormal vascular function and impaired materno-fetal exchange. Notably, exogenous H₂S intervention partially reversed 4-HNE-induced toxicity, suggesting the therapeutic potential of targeting this pathway. These findings demonstrate the pivotal role of the "4-HNE-H₂S-NLRP3" regulatory axis in MAFLD-associated placental injury, providing novel mechanistic insights and potential therapeutic targets for pregnancy complications.

Atractylenolide I (AO-I), a major pharmacological ingredient derived from Atractylodes macrocephala, has been reported to possess multiple bioactivities. This study aimed to investigate the potential protective effects of AO-I against lipotoxicity in both cultured hepatocytes and mice with non-alcoholic fatty liver disease (NAFLD). The NAFLD model was established by feeding C57BL/6 mice a high-fat diet (HFD) for 12 weeks. Oral administration of AO-I at doses of 20 or 50 mg/kg body weight per day was explored. Lipotoxicity in AML12 hepatocytes was induced by incubation with palmitate for in vitro investigations on the roles of AO-I. The results demonstrated that supplementation with AO-I improved alanine transaminase (ALT), aspartate transaminase (AST), and liver histology in NAFLD mice. Furthermore, AO-I directly alleviated palmitate-induced lipotoxicity by reducing hepatocyte death. Mechanistic studies revealed that AO-I significantly attenuated lipotoxicity through its potential resistance to endoplasmic reticulum (ER) stress and IRE1α-XBP1 splicing both in vivo and in vitro. We identified that AO-I substantially rescued HFD- and palmitate-induced SIRT1 decline in mouse livers and hepatocytes, respectively, thereby improving liver injury and hepatocyte cell death. Mechanistic studies demonstrated that the amelioration of ER stress and lipotoxicity by AO-I supplementation depended on SIRT1 activity. Moreover, AO-I also mitigated IRE1α activation-triggered JNK/p38 MAPK hyperphosphorylation. In conclusion, our findings suggest that AO-I exhibits significant therapeutic effects for improving lipotoxicity in the liver and may be considered as a candidate for NAFLD therapy.

Background Salidroside (SAL), the primary active compound extracted from Rhodiola rosea, has demonstrated potential efficacy against MASH-induced fibrosis; however, its precise pharmacological mechanisms and molecular targets remain incompletely elucidated. Purpose The aim of this study was to explore the protective effects of against MASH-induced liver fibrosis and its underlying pharmacological mechanisms. Methods In this work, a MASH-induced fibrosis model was established using the high-fat diet (HFD) and choline-deficient, L-amino acid-defined (CDAHFD) diet-fed in vivo and palmitic acid/oleic acid-stimulated hepatocytes in vitro. By comprehensively conducting biochemical index measurements, pathological analysis, Western blot, PCR detection, RNA sequencing, 4D-DIA proteomic analyses, molecular docking, and validation experiments, the study revealed the critical association of PI3K/AKT/mTOR-mediated autophagy-associated mitochondrial quality control with the treatment of MASH-related liver fibrosis. Results Sal treatment significantly ameliorates hepatic steatosis, inflammatory infiltration, and liver fibrosis induced by CDAHFD and HFD. Integrated RNA sequencing and 4D-DIA proteomics analysis revealed that the anti-fibrotic effect of Sal on MASH-induced liver fibrosis may be associated with regulation of the PI3K/AKT/mTOR signaling pathway, thereby enhancing autophagy-associated mitochondrial quality control in hepatocytes, preventing cytoplasmic accumulation of mitochondrial DNA (mtDNA), and ultimately blocking the activation of the cGAS-STING pathway and subsequent production of pro-inflammatory cytokines, including TNF-α and IL-1β. Further in vivo and in vitro andvalidation experiments demonstrated that the anti-fibrotic effects of Sal could be reversed by combined treatment with PI3K or mTOR agonists, specifically manifested as activation of the PI3K/AKT/mTOR signaling pathway, reduced hepatocyte mitochondrial autophagy, restoration of cGAS-STING pathway activity, and increased production of pro-inflammatory cytokines. Conclusion In summary, Our findings demonstrate that SAL mitigates MASH-induced liver fibrosis by targeting hepatocyte autophagy-associated mitochondrial quality control to suppress the mtDNA-dependent cGAS-STING inflammatory pathway, thereby revealing a novel therapeutic strategy.

To explore the protective effect of vitexin-4 ″-O-glucoside (VOG) against acetaminophen-induced acute liver injury in mice and its underlying mechanism. C57BL/6 mice were randomly divided into 4 groups: normal control group, model control group, low-dose group of VOG (30 mg/kg), and high-dose group of VOG (60 mg/kg). Acute liver injury was induced by intraperitoneal injection of acetaminophen (500 mg/kg). VOG was administrated by gavage 2 h before acetaminophen treatment in VOG groups. The protective effect of VOG against acute liver injury was evaluated by detecting alanine transaminase (ALT), aspartate transaminase (AST) levels and hematoxylin and eosin staining. The malondialdehyde (MDA) content, superoxide dismutase (SOD) and catalase (CAT) activity in liver were detected to evaluate the hepatic oxidative stress. The expression levels of tumor necrosis factor (TNF)-α, Il-1β, and Il-6 in liver were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression levels of phosphorylated c-jun N-terminal kinase (JNK)/JNK, phosphorylated p38/p38, inositol-requiring enzyme 1 alpha (IRE-1α), X-box binding protein 1s (XBP1s), and glucose-regulated protein 78 (GRP78) in liver were detected by Western blotting. An endoplasmic reticulum stress model was established in AML-12 cells using tunicamycin. Cell viability was assessed using the CCK-8 assay, and the degree of cell damage was detected by lactate dehydrogenase (LDH) assay. The gene expression levels of Ire-1α, Xbp1s, and Grp78 in the cells were detected using qRT-PCR. In the animal experiments, compared with the model control group, VOG significantly improved plasma ALT and AST levels, liver MDA content, as well as SOD and CAT activities. VOG also reduced the expression levels of Tnf-α, Il-1β, and Il-6 in the liver, and improved protein phosphorylation levels of JNK and p38, as well as the protein expression levels of IRE-1α, XBP1s, and GRP78. In cell experiments, VOG pretreatment enhanced cell viability, reduced LDH release and decreased the mRNA expression of Ire-1α, Xbp1s, and Grp78. VOG can suppress inflammation and oxidative stress, and alleviate acetaminophen-induced acute liver injury in mice by suppressing endoplasmic reticulum stress and modulating the MAPK signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) accounts for remarkable burden of death and costs worldwide with no recommended pharmacological intervention for the clinical management. This study aimed to investigate the efficacy and underlying mechanisms of rhubarb-derived polysaccharides (RP) in mitigating high-fat diet (HFD)-induced NAFLD and to analyze the primary monosaccharide components of RP. Forty male C57BL/6 mice were subjected to a dietary intervention consisting of either a high fat or chow diet for a duration of 12 weeks. RP (270, 540 mg·kg-1·d-1) was administered to the mice for 4 consecutive weeks from the 9th week. Various assessments were conducted, including histopathological examination, liver transcriptome analysis, non-targeted metabolomics analysis, and evaluation of protein expressions related to lipid and bile acid metabolism. This study found RP demonstrate a protective effect on the livers of NAFLD mice by inhibiting lipid accumulation and reducing hepatocyte inflammatory damage. The metabolomics analysis of multi-tissues revealed that the RP exert a hepatoprotective effect against NAFLD by restoring the altered bile acids (BAs) and fatty acids (FFAs) metabolism through the improvement of BA transporter, nucleus hormone receptor, lipogenesis protein, FFA transporter, and lipolysis proteins. Hence, RP may serve as a potential therapeutic agent for NAFLD.

Background:Ulcerative colitis (UC) has a complex etiology, and whether there are sex-related differences in its molecular mechanisms remains unclear. This study employed multi-omics analysis to explore sex-based differences in UC, aiming to provide support for personalized treatment. Methods:The GSE36807 and GSE206171 datasets from the GEO database were grouped by sex. Data were preprocessed using the R software, and DEGs identified using the limma package and key modules of WGCNA. LASSO regression was conducted to screen hub genes, ROC curves were used to evaluate diagnostic value, CIBERSORT was used to analyze immune cell proportions, and Spearman's correlation was performed to explore associations. The single-cell dataset GSE214695 was processed using Seurat to analyze immune cell proportion differences. Histological, immunohistochemical, and metabolomic analyses were performed on the colon tissues of DSS-induced colitis model mice. Results:Thirty-seven DEGs and 47 co-expression modules were identified. LASSO regression highlighted RPS4Y1 as the core gene, which was significantly upregulated in males. Females showed higher proportions of resting NK cells and M0 macrophages but a lower number of eosinophils. RPS4Y1 expression was positively correlated with resting memory CD4+ T cells and eosinophils and negatively with M0 macrophages and resting mast cells. Macrophage function exhibited sex-based disparities. Increased immune cell infiltration was observed in female colon tissues compared with that in male colon tissues. Metabolomic analysis identified 140 sex-dimorphic metabolites, with significant alterations in glutathione metabolism. Conclusion:RPS4Y1 exhibits sex-specific expression in UC and plays a key role in immunomodulation. Mitochondrial energy metabolism contributes to sex-based macrophage differences, highlighting the importance of considering sex-specific mechanisms in UC diagnosis and individualized treatment.

The increasing prevalence of brain injuries resulting in cognitive and motor function impairments poses a substantial global medical challenge. Nerve repair therapies offer promise for addressing brain injury-related disorders. Ferroptosis, as a cell death mechanism associated with oxidative stress and inflammation. Certain ferroptosis inhibitors, such as iron chelators and antioxidants, exhibit therapeutic potential for brain injury-related conditions. This review explores the fundamental processes and associated mechanisms that regulate neural repair by inhibiting ferroptosis, thereby alleviating brain injury and promoting neuroregeneration. Furthermore, it examines the action mechanisms and potential therapeutic applications of ferroptosis inhibitors in neural repair, aiming to provide novel insights for treating brain injuries.

This study aimed to explore the efficacy and mechanisms of raspberry (Rubus idaeus L. fruit) aqueous extract (RE) in alleviating high-fat diet (HFD)-induced metabolic-associated fatty liver disease (MAFLD). The MAFLD mouse model was established to examine the effects of RE through liver transcriptome and metabolomics analysis. In this study, RE supplementation significantly alleviated HFD-induced liver injury, hepatosteatosis, inflammation, and insulin resistance. Liver transcriptome analysis demonstrated that RE supplementation favorably regulated signaling pathways involved in fatty acid metabolism and inflammation, including the AMPK signaling pathway, PPAR signaling pathway, apoptosis, etc. Furthermore, the injection of compound C, an antagonist of AMPK, notably reversed the hepatoprotective effects of RE, evidenced by increased lipid profile levels, accelerated fatty acid-related gene disorder, and increased positive tunnel staining area. Furthermore, liver metabolomics analysis demonstrated that RE treatment led to substantial enrichment of the liver tissue metabolite umbelliferone (UMB), which has the potential to ameliorate lipid accumulation and hepatocyte injury through the AMPK signaling pathway. In summary, RE intervention mitigated HFD-induced liver dysfunction in mice, with UMB likely being the primary component responsible for its therapeutic efficacy in the liver. In addition, this study provided new insights, suggesting that RE could be used as a promising therapeutic approach for modulating MAFLD via apoptosis and the AMPK/PPARα signaling pathway.

Pharmacologically-induced liver injury from N-acetyl-p-aminophenol (APAP) overdose has become a leading cause of acute liver failure. Extensive research has elucidated the relationship between the intestinal microbiota and the pathophysiology of liver diseases. The growing body of evidence supporting the beneficial effects of probiotics, coupled with their established safety profile, has led to their widespread adoption in clinical practice. Among these, Bifidobacterium bifidum has garnered substantial attention due to its potential hepatoprotective properties, particularly in APAP-induced acute liver injury (AILI). However, the precise therapeutic effects and underlying mechanisms of its potential to alleviate drug-induced liver toxicity remain largely unexplored. To address this knowledge gap, the present study aimed to investigate the role of a new Bifidobacterium bifidum strain CGMCC No. 29,545 isolated from faeces on AILI. A mouse model was constructed through the administration of heat-killed or active B. bifidum CGMCC No. 29,545 preparations via gavage, followed by an intraperitoneal overdose of APAP. The results showed that the active B. bifidum could significantly reverse the increase in plasma transaminase levels and reduce the necrotic area of liver cells in AILI mice. A reduction in oxidative stress accompanied a reduction in this effect. Furthermore, B. bifidum attenuated plasma endotoxin levels and improved colonic inflammation, reducing hepatocyte apoptosis. The 16 S rRNA diversity of intestinal contents suggests that the involvement of B. bifidum in the regulation of the intestinal microbiota also plays a crucial role in the protection against AILI. The above results suggest that the amelioration of multiple injuries due to APAP overprocessing is closely related to active B. bifidum, which was confirmed by heat-killed B. bifidum preparations. Heat-killed B. bifidum preparations did not attenuate the degree of liver injury and oxidative stress caused by APAP treatment. The effects of two different active B. bifidum preparations provide new insights into the protective strategies of active B. bifidum as a probiotic against AILI.