Liver transplantation, the only curative option for end-stage liver disease, is limited by ischemia-reperfusion injury, with hepatocyte ferroptosis as a key pathogenic mechanism. CD36, a fatty acid translocase, drives the progression of multiple liver diseases. Yet, its role in hepatic ischemia-reperfusion injury (HIRI) and ferroptosis remains unclear. In this study, we generated full and hepatocyte-specific CD36 knockout mice to investigate its impact on HIRI. A significant upregulation of CD36 was observed in livers following ischemia-reperfusion (I/R) injury and in primary hepatocytes after hypoxia-reoxygenation (H/R). CD36 knockout alleviated liver injury and ferroptosis in HIRI models. In vitro, CD36 silencing suppressed H/R induced ferroptosis. Furthermore, our results establish rutin, a flavonoid derived from Gardenia, as a novel inhibitor of hepatocyte CD36 that alleviates HIRI. Mechanistically, CD36 regulates fatty acid binding protein 5 (FABP5) to reprogram lipid metabolism and drive ferroptosis in HIRI. Additionally, Rutin suppresses CD36 transcription through the stabilization of hepatocyte nuclear factor 4 α (HNF4α). Our findings demonstrate that CD36 exacerbates HIRI by regulating FABP5-mediated lipid metabolism and ferroptosis, while rutin exerts protective effects via CD36 inhibition. These results highlight the therapeutic potential of rutin for HIRI and identify the CD36/FABP5 axis as a novel target for intervention.

Liver Fibrosis (LFib) represents a significant global health burden as a chronic progressive disease. Emerging evidence has established a critical link between macrophage extracellular traps (METs) and LFib; however, the precise triggers of METs formation and their mechanistic contributions to fibrosis remain poorly understood. Substantial evidence indicates that interleukin-25 (IL-25) potently regulates macrophage metabolism and LFib progression. A carbon tetrachloride (CCl₄)-induced mouse model of liver fibrosis spanning distinct stages (2 to 8 weeks) was established. In vitro studies utilized co-culture systems and conditioned medium treatment to assess METs-mediated activation of hepatic stellate cells (HSCs). To elucidate the specific role of IL-25, hepatocyte-specific IL-25 conditional knockout (IL-25CKO) mice were generated using CRISPR/Cas9 technology and subjected to the LFib model. Mechanistic investigations involved stimulating RAW 264.7 macrophages with rmIl-25 and specific inhibitors. Techniques such as scanning/transmission electron microscopy, immunofluorescence, Western blot and ELISA were employed to analyze MET formation, ROS production, lysosomal activation, mitophagy, and related signaling pathways. Fibrotic livers exhibited strong early co-localization of IL-25 with hepatocytes, which preceded METs formation. This demonstrates that early production of IL-25 by hepatocytes acts as a triggering factor for METs formation. In vitro co-culture systems revealed METs-mediated activation of HSCs, while mechanistic studies showed that IL-25 promotes IL-17RB receptor activation, triggering downstream reactive oxygen species (ROS) bursts, lysosomal activation, and METs formation. This work identifies a pathogenic hepatocyte–macrophage–HSC axis and supports IL-25 early blockade as a promising clinical strategy for LFib. Hepatocyte-derived IL-25 drives macrophage extracellular trap formation and liver fibrosis. IL-25 induces METosis through IL-17RB, triggering oxidative stress and organelle dysfunction. METs activate HSCs and promote fibrogenesis. Hepatocyte IL-25 knockout or anti-Ly6g-DNase I therapy inhibits MET-driven fibrosis in vivo. Targeting the IL-25–MET axis represents a promising therapeutic strategy for liver fibrosis.

Hepatocellular carcinoma (HCC) is characterized by high mortality, frequent recurrence, and limited long-term benefit from systemic therapy and radiotherapy. Circular RNAs (circRNAs), a class of covalently closed non-coding RNAs with high molecular stability and tissue-specific expression, have emerged as important regulators of HCC biology and treatment response. We searched PubMed from database inception to May 2, 2026 and manually screened the reference lists of eligible studies and relevant reviews for studies investigating circRNA-related molecular mechanisms, tumor progression, therapeutic resistance, radiotherapy response, or translational applications in HCC. A total of 694 records were identified in PubMed, 694 records were screened after duplicate removal, and 42 studies were included in the qualitative synthesis. Original studies involving human tissues, clinical cohorts, cell lines, or animal models were eligible. Title/abstract screening, full-text assessment, and data extraction were performed independently by two reviewers, with disagreements resolved by consensus or senior-author adjudication. Given substantial heterogeneity in study design, model systems, molecular endpoints, and reported outcomes, findings were synthesized qualitatively rather than by meta-analysis, and a structured qualitative evidence appraisal was used to weight mechanistic and translational conclusions. The included evidence indicates that circRNAs participate in HCC progression through miRNA sponging, RNA-binding protein interactions, transcriptional regulation, epigenetic modulation, and, in selected contexts, translational activity. Distinct oncogenic and tumor-suppressive circRNAs converge on pathways related to proliferation, epithelial-mesenchymal transition, metastasis, ferroptosis, stemness, and DNA-damage repair. CircRNAs were also associated with sorafenib and lenvatinib response, radioresistance, and radiosensitivity. Emerging translational applications include tissue and liquid-biopsy biomarkers, especially exosomal circRNAs, as well as junction-targeted oligonucleotide strategies. Current evidence supports circRNAs as mechanistically relevant regulators and promising translational candidates in HCC. However, progress toward clinical application is constrained by etiologic heterogeneity, limited standardization, incomplete specificity validation for therapeutic targeting, and the lack of multicenter prospective validation studies.

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a highly prevalent condition, yet its molecular mechanisms remain incompletely understood. We explored circulating protein signatures and their causal relationships with MAFLD using large-scale proteomic and genomic data from the UK Biobank. Baseline plasma levels of 2923 circulating proteins were quantified in 49,206 participants (744 MAFLD outcomes). Protein-MAFLD associations were evaluated using multivariable Cox regression, followed by cis-Mendelian randomization (cis-MR) to infer causal effects based on protein quantitative trait loci. Among 215 proteins associated with MAFLD risk, four proteins (FURIN, LILRB4, NFASC, and PRAP1) showed causal evidence by cis-MR. FURIN, a proprotein convertase that activates transforming growth factor-β (TGF-β), emerged as the strongest causal effector. Downstream TGF-β signaling molecules (TGFB1, TGFBR2, SMAD1, and SMAD5) were significantly elevated in MAFLD cases, supporting activation of the FURIN/TGF-β axis. Additionally, 30 TNF-α-related proteins, including TNF, TNFRSF1A, TNFRSF1B, JUN, FOS, MAPK9, and MAPK13, were significantly upregulated in MAFLD, suggesting upstream regulation of FURIN by inflammatory TNF-α signaling. Our integrative cohort and genetic analyses reveal FURIN as a causal mediator in MAFLD pathogenesis through activation of TGF-β signaling, potentially modulated by inflammatory TNF-α signaling. These findings highlight the TNF-α/FURIN/TGF-β cascade as a potential molecular target for early prediction and therapeutic intervention in MAFLD.

Cisplatin (CP)-induced nephrotoxicity is a major clinical concern. Emerging evidence has revealed the critical role of PANoptosis, a coordinated cell death pathway, and neutrophil extracellular traps (NETs) in renal tubular damage. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has been recognized as a potential modulator of inflammation and cell survival; however, its regulatory function and mechanism in acute kidney injury (AKI), especially CP-induced AKI, particularly concerning NETs and PANoptosis, remain poorly understood. This study investigates the central role of PPARγ and explores the therapeutic potential of its novel activator, O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1L), in this context. Cultured renal tubular epithelial cells (mTECs) as well as a CP-induced AKI mouse model (20 mg/kg, 72 h) and renal ischemia–reperfusion injury (IRI) model​ were used. PPARγ heterozygous knockout mice, NET inhibitors (DNase I and GSK484), and pharmacological interventions (including the novel PPARγ agonist HD-1L and rosiglitazone [ROSI]) were used. The molecular mechanisms were assessed using western blotting, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and cellular thermal shift assays (CETSA). PPARγ activity, NET markers (MPO, Cit-H3, and dsDNA), PANoptosis-related proteins (p-MLKL, GSDMD-N, and cleaved caspase-3), and reactive oxygen species (ROS) levels were quantified. CP triggered robust PANoptosis in the renal tissues, accompanied by elevated NETs and ROS-dependent NETosis. PPARγ activation significantly suppressed ROS production in neutrophils, thereby reducing NET formation. Mechanistically, NETs facilitate the release of cytoplasmic dsDNA, activate the AIM2 inflammasome, and promote PANoptosome assembly. Genetic PPARγ heterozygous knockout exacerbated renal injury and abolished protective effects, confirming the central role of PPARγ. HD-1L-induced activation of PPARγ reduced markers of PANoptosis and improved renal function in CP-AKI models. Furthermore, PPARγ agonism similarly protected against renal injury and suppressed the NETosis-PANoptosis axis in the IRI model. PPARγ is a pivotal checkpoint in CP-AKI by inhibiting ROS-NETosis-driven AIM2-mediated PANoptosis. This protective mechanism is also applicable to IRI-induced AKI, highlighting its broad relevance. HD-1L confers renoprotection through PPARγ activation, providing a novel therapeutic strategy against AKI.

Vascular dementia (VaD), characterized by white matter damage and cognitive decline, currently lacks effective therapeutic options. Human umbilical cord blood mononuclear cells (hUCB-MNCs) have shown neuroprotective and immunomodulatory properties; however, their therapeutic efficacy and underlying mechanisms in VaD remain incompletely understood. In this study, we investigated the effects of hUCB-MNCs treatment in a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Behavioral assessments showed that hUCB-MNCs treatment improved cognitive performance, affective-like behaviors, and motor coordination in BCAS mice. Histopathological analyses demonstrated that hUCB-MNCs treatment attenuated white matter injury, preserved myelin integrity, and mitigated neuronal and synaptic damage. Integrated transcriptomic and proteomic analyses of corpus callosum (CC) tissues revealed enrichment of immune-regulatory, phagocytosis-related, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-associated pathways after hUCB-MNCs treatment. In vivo and in vitro analyses further indicated that hUCB-MNCs helped preserve microglial homeostatic features and improved myelin debris-handling responses. Collectively, these findings suggest that hUCB-MNCs ameliorate VaD-associated pathology, at least in part, by modulating microglial myelin debris-handling responses and PI3K/AKT-related signaling, highlighting hUCB-MNCs as a promising cell-based therapeutic candidate for VaD.

N6-methyladenosine (m6A), a well-known adenosine modification with newly recognized epigenetic functions, reportedly participates in the development of diverse liver diseases. Methyltransferases and demethylases, commonly referred to as "writers" and "erasers", respectively, play crucial roles in maintaining the balance of m6A modification. In liver disease research specifically, the functioning of these enzymes has piqued significant interest, revealing new perspectives on molecular pathogenic mechanisms. Writer proteins collaborate with co-factors to install m6A modification on RNA, while eraser proteins, exemplified by Fto and Alkbh5, remove modifications via different mechanisms. In liver diseases, the two are not simply antagonistic, but rather act jointly to affect disease progression. By focusing this review on the mechanisms of methyltransferases and demethylases in various liver diseases, we seek to enhance comprehension of m6A modification's role and support the advancement of related research and treatment strategies.

Liver fibrosis is caused by liver injury resulting from the wound healing response. According to recent research, the primary factor responsible for liver fibrosis is the activation of hepatic stellate cells (HSCs). C-C motif chemokine ligand 1 (CCL1) is one of several chemokine genes clustered on chromosome 17, which is involved in immune regulation and inflammatory processes. However, the role of CCL1 in liver fibrosis has not been reported. We found that CCL1 secreted by macrophages can target and activate the receptor protein C-C motif chemokine receptor 8 (CCR8) of HSCs, accelerating liver fibrosis progression by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. This suggested that the CCL1-mediated regulation of CCR8 is an important event in liver fibrosis progression. In conclusion, this study identified a novel signalling axis, the CCL1/CCR8/JAK/STAT pathway, which regulates the activation and apoptosis of HSCs, thus providing a novel therapeutic strategy for liver fibrosis.

In the early stage of intracerebral hemorrhage (ICH), rebleeding occurs when blood from the initial hematoma permeates the surrounding brain parenchyma through the disrupted blood-brain barrier (BBB), exacerbating brain injury. Neuroinflammation is a critical driver of the pathological processes underlying this phenomenon. Research on microglia near early hematomas revealed that promoting the transition of microglia to the M2 phenotype could mitigate perihematomal inflammatory damage. Recent studies have shown that the nuclear receptor-related 1 protein (NR4A2) can regulate microglial function and inhibit inflammation. However, the functions of NR4A2 in the development of ICH are still unclear. In this study, we explored the potential protective effect and mechanism of NR4A2 in ICH models. Our results demonstrated that the expression of NR4A2 was significantly decreased in both ICH rats and cell models. Increasing NR4A2 activity could effectively decrease the hematoma volume, improve the neurological prognosis and alleviate perihematomal BBB damage. In vivo and in vitro experiments revealed that NR4A2 inhibited perihematomal inflammatory damage by driving microglial polarization toward the anti-inflammatory M2 phenotype. Mechanistically, NR4A2 targeted TLR4 and inhibited the TRAF6/NF-κB pathway, thereby promoting M2 microglial polarization, reducing inflammatory cell extravasation and maintaining the integrity of the BBB. Conversely, the protective effects of NR4A2 were negated when CRX-527 (a TLR4 agonist) was introduced. These findings suggest that NR4A2 represents a promising therapeutic target for ICH.

Splicing factor 3b subunit 4 (SF3b4) is closely associated with cancer development. As a core subunit of the SF3b complex, SF3b4 participates in regulating alternative splicing, and its abnormal expression is linked to the onset of malignant tumors. However, the role of SF3b4 in colorectal cancer (CRC) remains undefined. This study demonstrates that in CRC, E1A binding protein p300 (EP300) and CREB binding protein (CREBBP) regulate SF3b4 expression by activating Histone H3 lysine 27 acetylation (H3K27ac) on the SF3b4 promoter. Additionally, enhanced autophagy counteracts the proliferation-inhibitory effect of SF3b4 knockdown in CRC cells. Implications Statement: SF3b4 may promote CRC proliferation by enhancing cellular autophagy. SF3b4 acts as a potential oncogene in CRC tumorigenesis and progression. SF3b4 serves as a promising prognostic biomarker for CRC.

BACKGROUND:Chronic liver disease (CLD), mainly non-alcoholic fatty liver disease (NAFLD), is a significant public health concern worldwide. This study aims to quantify the burden of NAFLD in CLD globally and within China, using data from the Global Burden of Disease (GBD) Study 2021, providing crucial insights for global and local health policies. METHODS:The study used comprehensive data from the GBD study 2021. It included estimates of prevalence, incidence, mortality, and disability-adjusted life years (DALYs). Age-standardized rates and average annual percent change (AAPC) from 2011 to 2021 were reported. A meticulous decomposition analysis was conducted. RESULTS:In 2021, there were 1582.5 million prevalent cases, 47.6 million incident cases, 1.4 million deaths, and 44.4 million DALYs attributable to CLD, globally. Among these, NAFLD has emerged as the predominant cause, accounting for 78.0% of all prevalent CLD cases (1234.7 million) and 87.2% of incident cases (41.5 million). Correspondingly, NAFLD had the highest age-standardized prevalence (15,017.5 per 100,000 population) and incidence (876.5 per 100,000 population) rates among CLDs. In addition, China's CLD age-standardized prevalence rate was 21,659.5 per 100,000 population, and the age-standardized incidence rate was 752.6 per 100,000 population, higher than the global average. From 2011 to 2021, the global prevalence rate of CLD increased slowly (AAPC = 0.17), consistent with the trend in China (AAPC = 0.23). Furthermore, the prevalence rate of NAFLD rose significantly in China (AAPC = 1.30) compared with the global average (AAPC = 0.91). Decomposition analysis also showed the worldwide increase in deaths and DALYs for NAFLD, which were primarily attributable to population growth and aging. CONCLUSIONS:The burden of CLD and NAFLD remains substantial globally and within China in terms of high prevalence and incidence. As such, this underscores the need for targeted prevention and treatment strategies. These findings emphasize the importance of continued surveillance and research to mitigate the growing impact of liver diseases on global and Chinese health systems.

Renal clear cell carcinoma (KIRC), the most common subtype of renal cell carcinoma, is characterized by high metastatic potential and heterogeneity.The expression pattern of the ARHGAP26 gene in KIRC, its link to patient prognosis, and its role in the TME immunoregulatory network are not well understood, with significant research gaps. We will analyze ARHGAP26 expression using TCGA and GSCALite databases and assess its association with the tumor microenvironment using the ESTIMATE algorithm. Additionally, we will use the GEO database to examine ARHGAP26 expression across different cell subsets in KIRC and evaluate its correlation with immune cell infiltration using TIMER 2.0. Immunohistochemistry (IHC) will be used to confirm differences in ARHGAP26 expression between renal clear cell carcinoma (KIRC) and adjacent normal tissues. ARHGAP26 expression is higher in KIRC, with a significant difference from normal tissues (p < 0.001). In KIRC patients, high ARHGAP26 expression is linked to longer overall, progression-free, and disease-specific survival, suggesting a tumor suppressor role, though it does not affect the disease-free interval. High ARHGAP26 expression may remodel the tumor stroma and alter the tumor microenvironment by changing the tumor-to-non-tumor cell ratio.

BACKGROUND AND AIMS:Hepatic fibrosis presents a major global health challenge, yet effective preventive and therapeutic strategies remain limited. Hepatic macrophages, which play a dual role in fibrosis progression, are central to understanding its pathogenesis. This study aimed to elucidate how macrophage lipid metabolism mediated by CD36 regulates immune function and fibrosis development. APPROACH AND RESULTS:We demonstrated that macrophages engulf lipids secreted by hepatic stellate cells (HSCs) via the CD36 receptor, resulting in enhanced lipid peroxidation, ferroptosis, and diminished antigen-presenting capacity, thereby impairing CD8 + T cell function. Conversely, CD36 deficiency restored antigen presentation through activation of the cGAS-STING pathway. Single-cell RNA sequencing further revealed that loss of CD36 in myeloid cells upregulated MHC-I-related gene expression in macrophages and promoted CD8 + T cell activation within the fibrotic liver microenvironment. Macrophage-specific CD36 knockout protected mice from fibrosis progression. In patients with liver cirrhosis, histological and serological analyses showed elevated CD36 expression, underscoring its clinical relevance. CONCLUSIONS:CD36-driven lipid uptake induces macrophage ferroptosis and impairs adaptive immunity. Targeting CD36 restores macrophage antigen-presenting function and enhances CD8 + T cell activation, identifying CD36 as a potential therapeutic target for hepatic fibrosis. The clinical trial was registered in the Research Registry (researchregistry10830).

Alcohol-associated steatohepatitis (ASH) represents a critical stage in the progression of Alcohol-associated liver disease (ALD), characterized by extensive hepatocellular steatosis, immune cell infiltration, and a poor therapeutic response. Neutrophils play a central role in the inflammatory landscape of ASH, with their hepatic accumulation strongly correlating with disease severity. Although studies have demonstrated that neutrophil depletion attenuates liver injury, the precise mechanisms underlying neutrophil-mediated hepatocellular damage remain poorly defined. Neutrophil extracellular traps (NETs), web-like DNA structures released during NETosis, have emerged as key effectors in sterile inflammation and may exacerbate liver injury beyond their antimicrobial functions. In this study, we employed the Binge-Gao mouse model to explore the involvement of NETs in ethanol-induced liver injury. Our findings revealed that ethanol exposure led to significant hepatic neutrophil infiltration and NET formation. Stressed hepatocytes released damage-associated molecular patterns (DAMPs), particularly interleukin-1 alpha (IL-1α), which activated Toll-like receptor 9 (TLR9) on neutrophils, thereby enhancing NET generation. NET components subsequently activated the cytosolic DNA sensor AIM2 (absent in melanoma 2) in hepatocytes, triggering apoptosis. This cascade illustrates a previously unrecognized immune axis linking ethanol-damaged hepatocytes, NET-producing neutrophils, and DNA-sensing death pathways.

Our previous research demonstrated that growth differentiation factor 15 (GDF15) exhibited superior predictive capability for metabolic dysfunction-associated steatohepatitis (MASH) development with an AUC of 0.86 at 10 years before disease diagnosis. However, the specific pathways and molecular mechanisms associated with GDF15 expression during MASH development remain to be fully investigated in humans. A nested case–control study comprising a MASH group of 78 individuals and three age- and sex-matched control groups (156 metabolic dysfunction-associated steatosis, 78 viral hepatitis, and 156 normal liver controls) was conducted. The baseline levels of GDF15-related transcription factors and upstream signaling pathways associated with the identified transcription factors were analysed prospectively. The significantly higher level of nuclear factor of activated T cells 3 (NFATC3), a transcription factor for GDF15, was identified in the circulation in MASH patients compared to controls. Expression of the non-canonical Wnt signaling pathway that is upstream of NFATC3, and its related proteins CTHRC1, FRZB, SFRP1, and SFRP4, were highest in the MASH group, suggesting a non-canonical Wnt signaling/NFATC3/GDF-15 cascade in MASH disease pathogenesis. A predictive model for MASH development based on four biomarkers (CTHRC1, FRZB, NFATC3, and GDF15) showed an AUC of 0.90 at 10 years. A protein-clinical model that included these four circulating proteins and BMI yielded an AUC of 0.93 at 10 years. Non-canonical Wnt signaling pathway may activate NFATC3 to promote GDF15 expression in MASH disease pathogenesis. These molecular mechanisms provide novel insights for developing targeted therapies that could modulate the non-canonical Wnt/NFATC3/GDF15 cascade to prevent/treat MASH.

AIMS:This study aims to determine the predictive capability for metabolic dysfunction-associated steatohepatitis (MASH) long before its diagnosis by using six previously identified diagnostic biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) with proteomic data from the UK Biobank. MATERIALS AND METHODS:A nested case-control study comprising a MASH group and three age- and sex-matched control groups (metabolic dysfunction-associated steatosis, viral hepatitis and normal liver controls) was conducted. Olink proteomics, anthropometric and biochemical data at baseline levels were obtained from the UK Biobank. The baseline levels of CDCP1, FABP4, FGF21, GDF15, IL-6 and THBS2 were analysed prospectively to determine their predictive accuracy for subsequent diagnosis with a mean lag time of over 10 years. RESULTS:At baseline, GDF15 demonstrated the best performance for predicting MASH occurrence at 5 and 10 years later, with AUCs of 0.90 at 5 years and 0.86 at 10 years. A predictive model based on four biomarkers (GDF15, FGF21, IL-6 and THBS2) showed AUCs of 0.88 at both 5 and 10 years. Furthermore, a protein-clinical model that included these four circulating protein biomarkers along with three clinical factors (BMI, ALT and TC) yielded AUCs of 0.92 at 5 years and 0.89 at 10 years. CONCLUSIONS:GDF15 at baseline levels outperformed other individual circulating protein biomarkers for the early prediction of MASH. Our data suggest that GDF15 and the GDF15-based model may be used as easy-to-implement tools to identify patients with high risks of developing MASH at a mean lag time of over 10 years.

Background:Renal cell carcinoma (RCC) is a prevalent malignancy characterized by a rising incidence and significant mortality. Interleukins (ILs) are crucial in regulating immune cell trafficking and exhibit anti-tumor properties. However, limited research has explored the expression levels and prognostic significance of interleukins in RCC. Methods:In this comprehensive study, we performed a detailed analysis of interleukins in RCC patients using multiple bioinformatics tools, including Oncomine, UALCAN, GEPIA, Kaplan-Meier plotter, cBioPortal, GeneMANIA, TRRUST, STRING, and Linked Omics. Results:Our analysis demonstrated a significant upregulation in the transcriptional levels of IL4, IL7, IL15, IL16, IL23A, IL26, and IL32 were significantly upregulated in RCC tissues, indicating their potential involvement in the pathogenesis of this malignancy. In contrast, IL1A, IL11, and IL27 were downregulated, indicating their potential function as tumor suppressors. Significant correlations were identified between the expression levels of IL11, IL23A, IL27, IL32, and the pathological stage of RCC patients. The expression levels of IL1A, IL4, IL11, IL15, IL16, IL23A, IL26, IL27, and IL32 were significantly correlated with improved prognosis. The differentially expressed interleukins primarily function in cytokine-cytokine receptor interactions and immune response-regulating signaling pathways. homeobox A10 (HOXA10), v-myb myeloblastosis viral oncogene homolog (avian) (MYB), v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA), and nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NFKB1) are key transcription factors for ILs, while LCK proto-oncogene (LCK), LYN proto-oncogene (LYN), spleen associated tyrosine kinase (SYK), Janus kinase 3 (JAK3), and FER tyrosine kinase (FER) are IL targets. IL expression significantly correlated with the infiltration of six distinct immune cell types. IL1A potentially exerts an anti-tumor effect in RCC prognosis by inducing neutrophil extracellular traps (NETs). Additionally, NFKB1 may positively regulate IL1A, providing a rationale for further in vivo and clinical studies. Conclusion:In conclusion, our study demonstrates the potential role of IL 1A in the prognosis of RCC and establishes a theoretical foundation for subsequent in vivo and clinical investigations.

IntroductionAlcoholic fatty liver disease (AFLD) is a common consequence of chronic alcohol consumption, characterized by lipid accumulation and oxidative stress in the liver. Cytochrome P450 (CYP450) enzymes play essential roles in metabolizing alcohol and other compounds. However, the specific long-term effects of alcohol on these enzymes remain unclear.MethodsThis study the examines influence of prolonged ethanol exposure on CYP450 activity and expression in AFLD using a rat model. Key enzymes such as CYP2E1, CYP2D6, and CYP3A1 were assessed in relation to lipid accumulation and oxidative stress.ResultsSignificant alterations were identified in the expression and activity of CYP2E1, CYP2D6, and CYP3A1, which were associated with increased lipid accumulation and oxidative stress in the liver. Additionally, the expression of P-glycoprotein (P-gp) was elevated, suggesting that chronic alcohol intake may impact drug transport and excretion.DiscussionThese findings provide new insights into the molecular mechanisms of AFLD and highlight the potential of CYP450 modulation as a therapeutic target. By elucidating how long-term ethanol exposure disrupts hepatic CYP450 enzyme profiles, this research lays the groundwork for developing personalized therapeutic strategies to improve outcomes for patients with AFLD.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 μM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.