Introduction Sepsis is a major global health burden associated with high mortality and multiple organ dysfunction, among which liver injury is a key determinant of poor prognosis. However, effective therapeutic strategies for sepsis-associated liver injury (SALI) remain limited. Methods In this study, we investigated the protective effects of MAGL-18c, a novel monoacylglycerol lipase (MAGL) inhibitor, on lipopolysaccharide (LPS)-induced SALI. Hepatic inflammation, apoptosis, mitochondrial function, and lipid metabolism were assessed using liquid chromatography–mass spectrometry (LC-MS), Western blotting, real-time quantitative PCR (qPCR), immunohistochemistry, and other methods. Results MAGL-18c markedly attenuated hepatic inflammation by suppressing TGF-β/Smad signaling and reducing pro-inflammatory cytokine production. Moreover, MAGL-18c significantly improved liver histopathology, reduced neutrophil infiltration, modulated unsaturated fatty acid metabolism, and alleviated hepatocyte apoptosis and mitochondrial dysfunction. Discussion These findings indicate that MAGL-18c protects against LPS-induced SALI through coordinated regulation of inflammation, apoptosis, mitochondrial function, and lipid metabolism, highlighting its potential as a promising therapeutic candidate for sepsis-associated liver injury.

PCBP2 Inhibits Antiviral Innate Immune Responses via the MAVS-Mediated Signaling Pathway in Severe Fever with Thrombocytopenia Syndrome.

Integrated metabolomics and network pharmacology study on Si-miao-yong-an Decoction in regulating sphingolipid metabolism and improving vascular injury on thromboangiitis obliterans.

Colorectal cancer (CRC) is counted among the most widespread malignancies worldwide, characterised by elevated incidence and mortality rates. Conventional chemotherapy is frequently associated with severe toxic side effects and the development of drug resistance, which necessitates an urgent search for alternative therapeutic modalities. Traditional Chinese medicine (TCM), distinguished by its multi-component and multi-target synergistic actions, represents a promising prospect for the development of innovative anti-tumour therapies. Nitidine chloride (NC), a major bioactive component isolated from Zanthoxylum nitidum, has demonstrated notable anti-tumour activity in various cancer types. However, the specific molecular mechanisms underlying its anti-CRC effects remain unclear. Centromere-associated protein E (CENPE) exerts a pivotal function in the regulation of the cell cycle, and its aberrant expression has been documented in multiple malignancies. It may therefore serve as a potential therapeutic target. This study sought to clarify the interplay between NC and CENPE, with the aim of offering a scientific foundation for the advancement of precision therapeutic approaches for CRC utilising TCM-derived bioactive compounds. To comprehensively characterise the expression pattern of CENPE in CRC, we integrated a range of state-of-the-art technologies encompassing single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, large-scale mRNA cohort analyses and immunohistochemistry (IHC). The regulatory impact of NC on CENPE expression was verified through real-time quantitative polymerase chain reaction (RT-qPCR) and IHC. Additionally, molecular dynamics simulation (MDS) was employed to investigate the binding mode and stability of the NC-CENPE complex. Multi-dimensional analyses indicated that CENPE is significantly overexpressed in CRC tissues, with a standardised mean difference of 1.32, and its expression scores approach 1.0 in malignant regions. CRISPR screening data suggested that CENPE knockout is associated with markedly reduced proliferation of CRC cells. MDS data supported a plausible binding mode between NC and CENPE, with a predicted binding free energy of -8.2kcal/mol, in which van der Waals interactions constituted a major component of the calculated binding energy. Furthermore, treatment with NC was associated with significant downregulation of CENPE mRNA and protein levels in CRC cells and xenograft models in this study, although these findings require further validation in additional experimental systems. NC exerts anti-colorectal cancer activity through targeting CENPE. This discovery lays a mechanistic foundation for the development of precision therapies based on active TCM ingredients, offering a new direction for CRC treatment.

Periodontitis is a common inflammatory disease that severely impairs oral health and may contribute to systemic complications such as cardiovascular diseases. Fibroblasts play a crucial role in the progression and repair processes of periodontitis. Exploring related biomarkers and pro-inflammatory fibroblast (PIF) subpopulations may offer potential therapeutic strategies for periodontitis. We integrated transcriptomic and single-cell RNA sequencing (scRNA-seq) data to identify hub fibroblast genes via Least Absolute Shrinkage and Selection Operator (LASSO) regression. Diagnostic models and nomograms were developed and validated based on these genes. Fibroblast molecular patterns were defined using ConsensusClusterPlus package, and pseudotime analysis was performed with Monocle package. Fibroblast-related genes (FRGs) and PIF subsets were confirmed by quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH). By integrating bulk transcriptomic and single-cell RNA sequencing data, six FRGs (XBP1, SELL, ST6GAL1, IGHG1, CD79A, and PIM2) were identified using LASSO regression to construct a diagnostic model. The area under the curve (AUC) values for the model were 0.894, 0.919, and 0.746 in the GSE10334, GSE16134, and GSE173078 datasets, respectively. A predictive nomogram was also developed and validated. Based on these FRGs, periodontitis samples were clustered into three groups. Enrichment analysis revealed involvement of classical inflammatory pathways such as KRAS/p53 and IL-6/JAK/STAT. Immune infiltration analysis showed that cluster 1 exhibited a pro-inflammatory microenvironment. CXCL13⁺ fibroblasts were significantly increased in periodontitis tissues. qRT-PCR confirmed significantly elevated expression of SELL, CD79A, and ST6GAL1 in periodontitis tissues. IHC demonstrated increased SELL expression in periodontitis samples, and FISH analysis revealed a marked increase of CXCL13⁺ fibroblasts in periodontitis tissues, consistent with the bioinformatics findings. This study not only confirms the critical role of fibroblasts in periodontitis but also identifies FRGs and a PIF subset, CXCL13⁺ fibroblasts. Our findings provide novel insights into the pathogenic mechanisms of fibroblasts in periodontitis and may inform the development of targeted diagnostic and therapeutic strategies.

Maternal diabetes increases the risk of neurodevelopmental alterations in the offspring, yet the molecular links to early corticogenesis remain unclear. During corticogenesis, radial migration is a coordinated process regulated by Reelin signaling and its disruption has been associated with abnormal cortical patterning. We reanalyze dorsal telencephalon transcriptomes from embryonic day 12 (E12) non-neural tube-defect rat embryos to identify canonical pathways perturbed by maternal hyperglycemia. Gene expression profiles from the dorsal prosencephalon at E12 from control and streptozotocin-treated dams (50 mg/kg at E5.5) were interrogated with Ingenuity Pathway Analysis (IPA). We then assessed Reelin pathway components using quantitative reverse transcription polymerase chain reaction (RT-qPCR), immunohistochemistry, and immunoblotting at E12 and E16, and examined postnatal cytoarchitecture/morphology in the primary motor cortex (M1) at postnatal day zero (P0) and P21 using hematoxylin-eosin and Golgi-Cox staining. All analyses excluded embryos with neural tube defects (NTD) to avoid cofounding by gross malformations. IPA revealed Reelin signaling in neurons as the only canonical pathway with a non-zero activation z-score, predicting inhibition in E12 embryos from diabetic rats. Concordantly, protein levels of Reelin (RELN), apolipoprotein E receptor 2/low-density lipoprotein receptor-related protein 8 (ApoER2/LRP8), very low-density lipoprotein receptor (VLDLR), and Disabled Homolog 1 (DAB1) were reduced at E12/E16 (all p < 0.05). N-cadherin (N-CAD) showed disrupted radial localization along the ventricular-pial axis despite unchanged total abundance, consistent with impaired neuron-radial glia adhesion/polarity. Postnatally, the M1 showed increased layer I cellularity, ectopic pyramidal neurons, and aberrant laminar organization. Maternal hyperglycemia is associated with attenuation of the Reelin signaling pathway and N-CAD mislocalization, providing a mechanistic framework for defective neuronal migration and abnormal lamination that persist into early postnatal life. Focusing on NTD-negative embryos isolates the pathway-specific effects of maternal hyperglycemia and nominates Reelin-pathway hypofunction as a candidate driver of altered fetal cortical patterning.

The Calcitonin Related Polypeptide Alpha (Calca) gene is a source of four biologically active peptides with varied physiological roles. Alternative splicing of theCalcamessenger RNA generates either prepro calcitonin gene related peptide (CGRP) or preprocalcitonin encoding transcripts. Proteolytic processing of preprocalcitonin generates procalcitonin, calcitonin and katacalcin. Calcitonin is a ligand for the G-protein coupled receptor calcitonin receptor (CALCR) while CGRP is a ligand for the CGRP receptor (CGRP1R) formed by the calcitonin receptor like receptor (CALCRL)receptor activity modifying protein 1 (RAMP1) complex. Interestingly, procalcitonin too, is a ligand for the CGRP1R where it can antagonize CGRP. CGRP expression in taste neurons has been documented and is posited to regulate taste signaling. Single cell and bulk RNASeq of taste papillae revealed that the preprocalcitonin but not the CGRP transcript is expressed inTas1r3- expressing type II taste cells, whileCalcrl(but notCalcr) andRamp1are expressed in stem/progenitor and type I cells in the circumvallate papillae. The CGRP1R is also expressed by fibroblasts in the lingual mesenchyme. We confirmed this expression pattern using quantitative polymerase chain reaction (qPCR), RNAScope and immunohistochemistry. qPCR of geniculate and nodose-petrosal ganglia revealed that both expressCgrpand CGRP1R subunit mRNAs, but not procalcitonin andCalcr. This interesting expression patterns suggests that procalcitonin and CGRP might reciprocally regulate the CGRP1R in taste cells and lingual fibroblasts and thereby influence taste signaling, taste cell regeneration and the taste microbiome.

The interaction between FLOT1 and FOSL2 promotes EphA2 transcription, regulating microglial polarization and affecting neuroinflammation in Alzheimer's disease.

Multidrug resistance (MDR) remains a major obstacle in the treatment of epithelial ovarian cancer (EOC). This study aimed to elucidate the regulatory role of FBXW7 in modulating the HSF-1/P-glycoprotein (P-gp) signalling axis and its impact on MDR in ovarian cancer. Quantitative PCR, western blotting, immunohistochemistry, and immunofluorescence were employed to assess FBXW7, HSF-1, and P-gp expression in ovarian tissues and cell lines. Functional assays, including CCK-8 proliferation assays and lentiviral-mediated gene modulation, were conducted in SKOV3 and cisplatin-resistant SKOV3/DDP cells to evaluate the effects of FBXW7 on cell proliferation and drug resistance-associated pathways. FBXW7 expression was markedly reduced in ovarian cancer tissues compared to normal controls and positively correlated with patient progression-free survival. Overexpression of FBXW7 suppressed proliferation in both SKOV3 and SKOV3/DDP cells and led to decreased HSF-1 and P-gp expression. Conversely, FBXW7 knockdown enhanced cell proliferation and upregulated the HSF-1/P-gp axis. Immunohistochemical and immunofluorescence analyses confirmed an inverse expression pattern between FBXW7 and HSF-1 in patient tissues. The findings revealed FBXW7 to suppress multidrug resistance in ovarian cancer by downregulating the HSF-1/P-gp axis, thereby enhancing chemosensitivity. This study has highlighted a novel regulatory mechanism and suggested that restoring FBXW7 function may offer therapeutic benefit in overcoming chemoresistance. FBXW7 acts as a tumour suppressor that mitigates MDR in ovarian cancer by negatively regulating the HSF-1/P-gp pathway. The findings have offered mechanistic insights into chemoresistance and highlight the therapeutic potential of targeting FBXW7-HSF-1 signaling in EOC management.

This study aimed to develop and validate a Cuproptosis-Related Gene (CRG) signature for predicting Biochemical Recurrence-Free Survival (BCRFS) and characterizing the Tumor Immune Microenvironment (TIME) in Prostate Cancer (PCa). Transcriptomic and clinical data were collected from TCGA (n=405) and GEO (GSE70770, n=203). Consensus clustering based on 10 CRGs defined molecular subtypes. Differentially expressed genes between clusters were subjected to LASSO Cox regression to construct a prognostic signature in the TCGA cohort, followed by validation in GEO and combined cohorts. Quantitative real-time polymerase chain reaction (qRT-PCR) and Immunohistochemistry (IHC) were conducted for experimental validation. Two CRG-based subtypes were identified, characterized by distinct clinicopathological features, immune checkpoint expression, and BCRFS. A six-gene signature (CALML5, MMP11, UBE2C, ANPEP, TMEM59L, COMP) stratified patients into high- and low-risk groups with significantly different BCRFS (log-rank P<0.001). The model showed good predictive accuracy (AUCs 0.717-0.837 at 1 year, 0.728-0.771 at 3 years, 0.683-0.695 at 5 years) and remained independent of clinicopathological factors. High-risk patients exhibited elevated immune/stromal scores, altered immune infiltration, and higher immune checkpoint expression. qRT-PCR confirmed upregulation of CALML5, MMP11, UBE2C, and COMP in PCa cell lines, while IHC validated differential protein expression of all six genes between PCa and BPH tissues (all P<0.05). This six-gene CRG signature predicts BCRFS and reflects immune heterogeneity in PCa. Its integration into prognostic models may guide personalized management and inform immunotherapy strategies, warranting further validation in prospective clinical studies. This study initially identified two cuproptosis-related molecules based on the expression patterns of cuproptosis-related genes. In addition, we developed a new cuproptosisrelated molecular signature with great predictive performance for BCRFS and tumor immune environment using six DERRGs (including CALML5, MMP11, UBE2C, ANPEP, TMEM59L, COMP). These findings would be conducive to a deeper cognition of the potential mechanism of cuproptosis of PCa.

From chronic gastritis to gastric cancer: Mendelian randomisation and multi-omics interrogation of leukaemia inhibitory factor receptor (LIFR), hepatocyte growth factor (HGF), serine protease inhibitor E1 (SERPINE1) and interleukin-10 receptor subunit beta (IL10RB).

SLC22A17 affects the development of urethral stricture by promoting ferroptosis and inhibiting the activation of fibroblasts.

Mechanic exploration of Yin Jia tablet against chronic salpingitis via the miR-34a-5p-mediated ceRNA network.

This study aimed to investigate the molecular mechanism by which tripartite motif-containing 24 (TRIM24) regulates the ubiquitination of sirtuin 1 (SIRT1) and to explore the protective effect of paeoniflorin (PF) on pulmonary arterial hypertension (PAH). Bioinformatics analysis identified TRIM24 and SIRT1 as key targets of PF. A PAH rat model was established by SU5416 (Su) injection combined with chronic hypoxia (Hx). These model rats were then treated with PF and/or subjected to overexpression of TRIM24 or SIRT1. TRIM24 and SIRT1 expression were assessed by reverse transcription quantitative PCR (RT-qPCR) and immunohistochemistry. Lung vascular remodeling was evaluated by hemodynamic analysis and hematoxylin-eosin (HE) staining. Inflammatory cytokine levels (interleukin-1β, interleukin-6, tumor necrosis factor-α) in lung tissues were measured. Invitro, hypoxia-exposed human pulmonary artery endothelial cells (HPAECs) were used to evaluate PF effects on cell viability (CCK-8), migration (scratch assay), and protein expression (Western blot). Ubiquitination and protein stability assays demonstrated that TRIM24 promoted SIRT1 protein degradation. TRIM24 inhibited SIRT1-mediated autophagy, thereby activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Conversely, SIRT1 upregulation enhanced autophagy and suppressed NLRP3 activation. PF alleviated PAH and endothelial dysfunction by downregulating TRIM24 and preserving SIRT1 function. These findings reveal a novel mechanism by which PF protects against PAH via the TRIM24/SIRT1/NLRP3 axis.

TWF1 promotes tumor progression in head and neck squamous cell carcinoma via AKT phosphorylation.

Colon cancer (CC) is a malignant cancer with high incidence and poor prognosis.Ferroptosis could induce iron-dependent accumulation of lipid peroxidation and oxidative death of cancer cells. This work aimed to elucidate the role of KAT6A, a lysine acetyltransferase, in CC development. We collected tumor and paired non-tumor samples from patients with CC and analyzed the RNA and protein level of KAT6A using quantitative real-time PCR and immunohistochemistry (IHC) staining. We conducted KAT6A knockdown in CC cells and determined cell proliferation and ferroptosis. Cell proliferation was measured by cell counting kit-8 (CCK-8) and colony formation assay. Ferroptosis was identified by measuring the levels of lipid ROS, intracellular iron and Fe2+, malondialdehyde (MDA), and glutathione (GSH). The in vivo effects of KAT6A were assessed by xenograft mouse model. Protein levels of KAT6A and glutathione peroxidase 4 (GPX4) were checked by western blotting assay. The enticement of acetylation on lysine 9 of histone3 (H3K9ac) and RNA polymerase II on GPX4 gene was analyzed by chromatin immunoprecipitation (ChIP) assay. The RNA and protein level of KAT6A is notably higher in tumor tissues compared with the non-tumor sections. Depletion of KAT6A suppressed in vitro and in vivo CC cell growth. Overexpression of KAT6A reversed the erastin-induced CC cell death. knockdown of KAT6A significantly elevated the intracellular level of MDA, induced accumulation of total iron, Fe2+ and lipid ROS, and suppressed the level of GSH. The knockdown of KAT6A caused a decrease in the expression of GPX4 and enrichment of H3K9ac on GPX4 gene. KAT6A promotes the proliferation of CC cells and suppresses ferroptosis via epigenetic regulation of GPX4. Our work presented KAT6A as a potential diagnostic and therapeutic target for treatment CC.

BackgroundDiabetic retinopathy (DR) is the leading cause of blindness-related eye diseases in adults. The pathogenesis of DR is attributed to the excessive proliferation of microvessels, which leads to vitreous haemorrhage and retinal traction, thereby significantly damaging the patient’s vision. In this study, we investigated the role and molecular mechanism of Peroxidasin (PXDN) and the active ingredient baicalin (BAI) of traditional Chinese medicine in regulating the senescence and pathological angiogenesis of human retinal microvascular endothelial cells (HRMECs) to identify the key genes and signalling pathways involved in the progression of DR.MethodsIn this study, key hub genes were screened using relevant datasets. The expression levels of PXDN, fibronectin (FN1), and PI3K/AKT pathway-related proteins were verified in clinical specimens, animal models, and DR cell models using enzyme-linked immunosorbent assays (ELISA), quantitative real-time PCR, Western blot, and immunohistochemistry (IHC). The binding ability of BAI to the receptor for advanced glycation end products (RAGE) was verified by molecular docking technology analysis and Western blot. Moreover, the direct binding relationship between PXDN and FN1 was verified by protein–protein interaction (PPI) and western blot. By further applying gene knockdown and overexpression techniques in combination with Western blot analysis, the molecular pathways through which BAI affects RAGE/PXDN(FN1)/PI3K/AKT signalling were investigated.ResultsIn the DR model, the expression level of PXDN significantly increased. Direct protein interactions between PXDN and FN1 were verified through PPI and coimmunoprecipitation (Co-IP) experiments. Moreover, knockdown of PXDN in vivo and in vitro significantly reduced the formation of lesions. BAI inhibited the expression of PXDN and FN1 by binding to RAGE, thereby effectively alleviating the senescence and pathological angiogenesis of HRMECs induced by high glucose (HG) conditions through regulation of the PI3K/AKT signalling pathway.ConclusionsThis study revealed that BAI regulates the progression of DR by regulating the RAGE/PXDN (FN1)/PI3K/AKT signalling pathway. These findings not only provide new molecular insights into the pathogenesis of DR but also lay an important theoretical foundation for the development of new therapeutic strategies.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07590-0.

The chromatin remodelling proteins DAXX and ATRX are key regulators of genome stability and epigenetic processes. Alterations in their expression have been associated with tumour stage and prognostic outcomes in various human cancer types, whereas their role in veterinary oncology has received little investigation to date. We analysed canine prostate and urinary bladder samples, including 18 prostate carcinomas (12 adenocarcinomas and 6 prostatic urothelial carcinomas), 10 non-malignant prostate tissues, 22 urinary bladder carcinomas, and 6 non-malignant bladder tissues. Nuclear expression of DAXX and ATRX was assessed using fully quantitative digital immunohistochemistry. Overall, DAXX exhibited consistently higher expression than ATRX across benign and malignant samples from the prostate and bladder. DAXX and ATRX expression demonstrated a positive correlation across all samples (ρ = 0.553, p < 0.05), suggesting coordinated regulation. They displayed organ-specific expression patterns: prostate carcinomas showed increased expression of DAXX compared with non-malignant prostate tissues (p < 0.05). In contrast, in the bladder, expression of DAXX and ATRX declined with increasing tumour grade (p < 0.05). Our findings provide new insights into the potential of DAXX and ATRX as biomarkers, offering new insights into their clinical relevance in dogs.

KCMF1 regulates HRI ubiquitination to inhibit the integrated stress response in ovarian cancer.

PurposeRetinoblastoma is the most common intraocular cancer in infants and children, with a significant potential for metastasis. The mini-peptide ribosomal protein L41 (RPL41) has demonstrated extensive antitumor effects in vitro by promoting the degradation of activating transcription factor 4 (ATF4). This study aims to evaluate the therapeutic effect of RPL41 on retinoblastoma and elucidate its potential mechanisms.MethodsA xenografted retinoblastoma model was constructed in nude mice. The effects of xenografted RPL41 on tumor proliferation, invasion and metastasis were evaluated by local injection. Mass spectrometry identified differentially expressed genes in Y79 and Weri-RB1 retinoblastoma cells pre- and post-treatment. We utilized quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry to assess the expression levels of ARL5B(ADP ribosylation factor like GTPase 5B) in retinoblastoma cell lines and tissues. We also explored ATF4’s regulatory role on ARL5B expression through chromatin immunoprecipitation (ChIP) experiments and luciferase reporter gene assays.ResultsRPL41 inhibits the growth of subcutaneous retinoblastoma xenografts. ARL5B expression was significantly downregulated in treated Y79 and Weri-RB1 cells. ARL5B was upregulated in retinoblastoma cells and clinicopathological tissues. RPL41 treatment led to ATF4 degradation, reducing the expression levels of ARL5B and lysotransfer-related molecules. Knocking down ATF4 decreased ARL5B protein levels. ChIP experiments and dual-luciferase assays confirmed ATF4 positively regulates ARL5B. Rescue experiments indicated that ARL5B overexpression partially reversed the effects of RPL41 therapy or ATF4 knockdown on lysosomal pathways and cell migration.ConclusionsRPL41 down-regulates the expression of ARL5B by degrading ATF4 and the impaired ARL5B-related lysosomal trafficking is a mechanism to inhibit the metastasis of retinoblastoma.