Pathology, research and practice最新文献

{"title":"HER2 immunoreactivity in advanced non-p53abn endometrial carcinoma: Association with clinical features, prognosis, and molecular characteristics","authors":"Yining Zhen,&nbsp;Yinbo Xiao,&nbsp;Yang Zhou,&nbsp;Longyun Chen,&nbsp;Junyi Pang,&nbsp;Xiaohua Shi,&nbsp;Zhiyong Liang","doi":"10.1016/j.prp.2025.156304","DOIUrl":"10.1016/j.prp.2025.156304","url":null,"abstract":"<div><h3>Background</h3><div>Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in endometrial carcinoma (EC). Current guidelines recommend routine HER2 testing for p53 abnormal (p53abn) tumors, potentially underestimating its value in non-p53abn cases. This study aimed to assess the incidence and clinical relevance of HER2 immunoreactivity in advanced non-p53abn EC.</div></div><div><h3>Methods</h3><div>HER2 immunohistochemistry and next-generation sequencing were performed in 128 advanced EC patients. Clinicopathological features, survival, and molecular alterations were compared according to HER2 immunoreactivity.</div></div><div><h3>Results</h3><div>Of all patients, 18.8 % were HER2 2 + /3 + , 28.9 % were HER2 1 + , and 52.3 % were HER2 0. Molecular classification included 1.6 % <em>POLE</em> mutant, 35.2 % mismatch repair-deficient/ microsatellite instability-high, 29.7 % p53abn, and 33.6 % no specific molecular profile (NSMP). In the non-p53abn group, HER2 3 + was less frequent than in the p53abn group, whereas the frequencies of HER2 2 + and 1 + did not differ significantly between the two groups. In non-p53abn patients, HER2 2 + /3 + occurred most frequently in clear cell carcinoma (CCC, 6/11, 54.5 %) and was associated with adnexal metastasis (2 +/3 + vs. 1 +, 66.7 % vs. 15.4 %, <em>P</em> &lt; 0.05). No survival differences were observed among non-p53abn patients by HER2 immunoreactivity, however, within the NSMP subgroup, both overall and progression-free survival were worse in HER2 2 + /3 + compared with 1 + (log-rank <em>P</em> &lt; 0.05). In non-p53abn ECs, <em>KRAS</em> mutations were significantly less frequent in HER2 2 + /3 + group (2 +/3 + vs. 1 +, 6.7 % vs. 46.2 %, <em>P</em> &lt; 0.05).</div></div><div><h3>Conclusions</h3><div>HER2 2 + /3 + immunoreactivity was detected in 16.7 % of advanced non-p53abn EC, particularly enriched in CCC. These findings highlight the potential clinical significance of HER2 testing in non-p53abn patients.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156304"},"PeriodicalIF":3.2,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pitfalls in MLH1 promoter methylation assessment, including POLEmut/MLH1meth endometrial adenocarcinoma","authors":"Amelia Flaus ,&nbsp;Zhi Cui ,&nbsp;Mirko Miladinovic ,&nbsp;Ju-Yoon Yoon","doi":"10.1016/j.prp.2025.156303","DOIUrl":"10.1016/j.prp.2025.156303","url":null,"abstract":"<div><div><em>MLH1</em> promoter methylation status may serve as an important diagnostic, prognostic, and predictive biomarker in management of mismatch repair (MMR)-deficient cancers. A new commercial assay for detection of <em>MLH1</em> promoter hyper-methylation (EntroGen), which interrogates regions C and D, was assessed for its performance characteristics. False positive results were obtained in 5/21 non-lesional cases, with signals limited to region C. Three were explained by overloaded reactions. Two unexplained cases were both muscle samples (2/6 muscle samples, one each of skeletal and smooth). The assay was 100 % concordant (52/52) for lesional samples with expected <em>MLH1</em> promoter methylation status. These included two exceptional cases—one Lynch-associated, and one <em>POLE</em>-mutated endometrial carcinoma; thus expanding the spectrum of extreme cases, and demonstrate neither germline or somatic NGS results completely rule out <em>MLH1</em> promoter methylation, and vice versa. The <em>POLE</em>^mut/<em>MLH1</em>^meth carcinoma was notable for molecular features in keeping with POLE dysfunction, accompanied by multiple, additional genetic lesions in the MMR pathway. Exploring the TCGA dataset, 1/8 cases of POLE (ultramutated) endometrial carcinoma was notable for <em>MLH1</em> silencing. Comprehensive genomic profiling assay was informative, allowing for correlation of <em>MLH1</em> methylation and <em>POLE</em> genotype results with tumor mutation burden and mutational signature. Taken together, our data highlight the need for integrated approach in endometrial carcinoma biomarker testing, integrating NGS and <em>MLH1</em> promoter methylation status, the latter of which benefits from assessing both regions C and D. Finding of <em>MLH1</em> promoter methylation does not rule out either Lynch syndrome or ultramutated (POLE) carcinoma.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156303"},"PeriodicalIF":3.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the NR4A3-RNF139-ATF6 pathway as a therapeutic and diagnostic strategy in bladder cancer","authors":"Haiyang Cui ,&nbsp;Xuejiao Fan","doi":"10.1016/j.prp.2025.156301","DOIUrl":"10.1016/j.prp.2025.156301","url":null,"abstract":"<div><h3>Background</h3><div>Bladder cancer (BCa) is a prevalent malignancy with high recurrence and metastasis rates. Nuclear receptor subfamily 4 group A member 3 (NR4A3), a member of the orphan nuclear receptor superfamily, is implicated in various cancers, but its functional role and mechanisms in BCa have not been well understood. This study aimed to explore the functional significance and diagnostic value of NR4A3 in BCa, with a focus on its regulation of endoplasmic reticulum (ER) stress and anoikis sensitivity via ATF6 and RNF139.</div></div><div><h3>Methods</h3><div>NR4A3 expression in BCa cell lines was assessed by qRT-PCR and Western blot. Gain-of-function assays were performed to evaluate cell proliferation, apoptosis, and anoikis sensitivity <em>in vitro</em>. ER stress markers and ATF6 degradation were examined by immunoblotting, cycloheximide chase, and ubiquitination assays. The role of RNF139 and its regulation by NR4A3 via KLF2 and KLF4 were determined via various biological assays. <em>In vivo</em> tumorigenesis was assessed using a xenograft mouse model. Additionally, the diagnostic performance of NR4A3 was evaluated in 100 clinical patients using serum ELISA and color Doppler ultrasound.</div></div><div><h3>Results</h3><div>NR4A3 was downregulated in BCa cells, and its overexpression suppressed cell proliferation, colony formation and promoted apoptosis and anoikis sensitivity. Mechanistically, NR4A3 inhibited ER stress by promoting ATF6 ubiquitination and degradation via transcriptional activation of RNF139 through KLF2 and KLF4. RNF139 directly interacted with ATF6 and mediated its ubiquitination at lysine 152. <em>In vivo</em>, NR4A3 overexpression inhibited tumor growth. Clinically, combining color Doppler ultrasound with serum NR4A3 levels significantly improved diagnostic accuracy for BCa (AUC = 0.986).</div></div><div><h3>Conclusion</h3><div>NR4A3 suppresses BCa progression via the KLF2/4-RNF139-ATF6 axis and enhances diagnostic efficacy when combined with ultrasound imaging.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156301"},"PeriodicalIF":3.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular landscape and biomarker discovery in adrenocortical carcinoma: An integrative review of bioinformatics and translational insights","authors":"Javad Omidi","doi":"10.1016/j.prp.2025.156295","DOIUrl":"10.1016/j.prp.2025.156295","url":null,"abstract":"<div><div>Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with limited therapeutic options and poor prognosis. Recent advances in high-throughput sequencing and integrative bioinformatics have unraveled the complex molecular landscape of ACC, highlighting critical genomic, epigenomic, transcriptomic, and immune-related alterations. This review synthesizes current evidence to provide a comprehensive overview of the key molecular mechanisms driving ACC pathogenesis. The role of recurrent mutations (e.g., TP53, CTNNB1), dysregulated cell cycle genes (e.g., CDK1, CCNB1, AURKA), non-coding RNAs, and epigenetic modifications in shaping tumor behavior is discussed. Multi-omics integration and systems biology approaches have enabled the identification of robust prognostic gene signatures and protein biomarkers, offering novel tools for risk stratification. Furthermore, the tumor immune microenvironment is examined, with hypoxia, immune suppression, and checkpoint pathways highlighted as emerging targets. Finally, computational drug repositioning strategies that nominate repurposed agents such as IGF1R inhibitors and BCLAF1 modulators for therapeutic intervention are explored. Together, these insights pave the way for precision oncology in ACC, while emphasizing the need for rigorous multi-layered validation and standardized clinical integration to enable real-world translational impact.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156295"},"PeriodicalIF":3.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical pathological significance of TLSs in HER2-low breast cancer","authors":"Zhixing Zhang ,&nbsp;Wei Kang ,&nbsp;Chunjun Li ,&nbsp;Dongdong Zhang ,&nbsp;Xiaoyu Chen ,&nbsp;Dan Lu ,&nbsp;Yuzhen Huang ,&nbsp;Lixia Zeng","doi":"10.1016/j.prp.2025.156300","DOIUrl":"10.1016/j.prp.2025.156300","url":null,"abstract":"<div><h3>Purpose</h3><div>To investigate the presence and clinical significance of tertiary lymphoid structures (TLSs) in HER2-low breast cancer, by focusing on their associations with clinicopathological features and prognosis.</div></div><div><h3>Methods</h3><div>Hematoxylin and eosin staining and immunohistochemical markers were used in combination with whole-slide imaging (WSI) to delineate invasive carcinoma and adjacent TLSs. WSI-based tools were subsequently utilized to annotate the location, density, and maturity of TLSs.</div></div><div><h3>Results</h3><div>Among 560 patients with HER2-low breast cancer, the median age was 53 years and the age range was 28–85 years; 34 % (189/560) had TLSs-positive tumors. TLSs were associated with high histological grade, high-grade DCIS, absence of lymphovascular invasion, ER-negative, PR-negative, HER2 2 + , high K-i67, and triple-negative breast cancer subtypes (all P &lt; 0.05). In the low-age cohort, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with poorer DFS (all P &lt; 0.05).Conversely, TLSs (+), TLSs density, TLSs maturity, and peritumoral TLSs were significantly associated with better DFS in the high-age cohort (all P &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>In HER2-low breast cancer, TLSs were associated with higher histological grade, the presence of DCIS, absence of lymphovascular invasion, as well as expression of ER negative, PR negative, HER2 2 + , high K-i67, and triple-negative breast cancer. Additionally, the clinical prognosis value of TLSs (such as DFS) exhibited a correlation with the patient’s age.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156300"},"PeriodicalIF":3.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF4 transcriptional regulation of OMD and STC2 drives vascular calcification progression via the PI3K/AKT pathway","authors":"Zhang Yue ,&nbsp;Ming-Yan Wang ,&nbsp;Chun-Ze Yuan ,&nbsp;Jin-Wen Xu ,&nbsp;Ke-Ke Shao","doi":"10.1016/j.prp.2025.156296","DOIUrl":"10.1016/j.prp.2025.156296","url":null,"abstract":"<div><div>Vascular calcification (VC) is a pathological process characterized by the deposition of calcium phosphate crystals in blood vessels. Despite its clinical significance, the molecular mechanisms underlying VC remain poorly understood. This study integrated transcriptomic data from public datasets and experimental models to identify key regulators of VC. Human aortic smooth muscle cells (HASMCs) were induced to calcify using osteogenic medium (OM), followed by transcriptomic sequencing. Differential gene expression, functional enrichment, and machine learning-based hub gene identification, were performed. Experimental validation was conducted using in vitro and in vivo models. Transcriptomic analysis identified 278 differentially expressed genes (DEGs), 45 of which were associated with metabolism. Bioinformatic and machine learning approaches highlighted Osteomodulin (OMD), and Stanniocalcin 2 (STC2) as key regulators of VC. The iRegulon tool predicted that OMD and STC2 share a common transcription factor Activating Transcription Factor 4 (ATF4). In calcified human vascular tissues, ATF4, OMD, and STC2 expression levels were significantly upregulated, correlating with increased calcification markers such as RUNX2, ALP, and OCN. Functional studies demonstrated that ATF4 transcriptionally upregulates OMD and STC2 by binding to their promoter regions, then activated the PI3K/AKT signaling pathway, promoting osteogenic differentiation in HASMCs. In vivo experiments using AAV-SM22α-shATF4 confirmed that targeting ATF4 alleviates VC by suppressing OMD and STC2 expression and reducing calcium deposition. In conclusion, our study reveals that ATF4 promotes vascular calcification by transcriptionally upregulating OMD and STC2,which in turn activates the PI3K/AKT signaling pathway. These findings provides new evidence for the direct regulatory relationship between signaling nodes in the field of VC signaling network.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156296"},"PeriodicalIF":3.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EBF3 transcriptionally activates ACADL to block the Hippo/YAP signaling pathway and inhibits breast cancer progression","authors":"Caihong Cao ,&nbsp;Xing Feng","doi":"10.1016/j.prp.2025.156299","DOIUrl":"10.1016/j.prp.2025.156299","url":null,"abstract":"<div><h3>Objective</h3><div>Breast cancer (BC) is the chief cause of malignancy-related deaths in women. This paper investigates how the EBF3-ACADL axis inhibits BC progression through Hippo/YAP signaling.</div></div><div><h3>Methods</h3><div>The differentially expressed gene ACADL in BC was screened by the bioinformatics databases, and ACADL expression in BC tumors and cells was verified by immunohistochemistry, RT-qPCR, and western blot analysis. BC cells were infected with an overexpressing-ACADL lentivirus to examine the effect of ACADL on BC cell growth. The <em>in vivo</em> impact of ACADL was investigated by constructing a xenograft tumor model. Cells were treated with XMU-MP-1, an inhibitor of MST1/2 kinase, to study the influence of ACADL on BC progression through the Hippo/YAP pathway. The upstream mechanism of abnormally elevated ACADL expression was analyzed by bioinformatics, and EBF3 expression in BC tumors and cells was verified. Regulatory assays were performed to confirm the binding relationship between ACADL and EBF3.</div></div><div><h3>Results</h3><div>ACADL and EBF3 were poorly expressed in BC tissues and cell lines. ACADL overexpression blocked p-YAP (Ser127), nuclear YAP localization, and canonical target genes (CTGF, CYR61, and ANKRD1), thereby suppressing BC cell growth and xenograft tumor development. XMU-MP-1 reversed the suppressive effect of ACADL overexpression on BC progression. EBF3 transcriptionally activated ACADL expression by binding to its promoter. EBF3 overexpression suppressed the malignant behavior of BC cells and xenograft tumor development in mice, which was reversed by ACADL knockdown.</div></div><div><h3>Conclusion</h3><div>EBF3 transcriptionally activates ACADL and blocks the Hippo/YAP pathway to inhibit BC progression.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156299"},"PeriodicalIF":3.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGCG inhibits hepatic stellate cell activity and liver fibrosis by targeting the MDM2/MUC5AC-mediated TGF-β1/Smad signaling pathway","authors":"Longbao Yang ,&nbsp;Fenrong Chen ,&nbsp;Xiong Li,&nbsp;Xiaoke Sun,&nbsp;Hong Li,&nbsp;Haitao Shi,&nbsp;Gang Zhao","doi":"10.1016/j.prp.2025.156298","DOIUrl":"10.1016/j.prp.2025.156298","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the intervention effect of epigallocatechin gallate (EGCG) on liver fibrosis and its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>A mouse model of liver fibrosis induced by a high-fat diet was established, with groups divided into normal control, high-fat diet (HF) group, and HF + EGCG groups (low, medium, and high doses). The therapeutic effect of EGCG on liver fibrosis was evaluated by liver pathological scoring, detection of serum biochemical indicators, analysis of fibrotic markers, and Western blot for fibrotic protein expression. LX-2 cells were cultured in vitro and activated by TGF-β1. Molecular biology experiments (RT-qPCR, Western blot, immunofluorescence, co-immunoprecipitation, etc.) were used to explore the effects of EGCG on LX-2 cell activation, proliferation, migration, and its regulation of the TGF-β/Smad signaling pathway. Ubiquitination assays, molecular docking, and enzyme inhibitor interventions were performed to clarify the regulatory mechanism of EGCG on MUC5AC stability and its interaction with MDM2. Gene silencing/overexpression techniques were used to verify the critical role of the MDM2/MUC5AC axis in EGCG’s anti-fibrotic effect.</div></div><div><h3>Results</h3><div>In vivo experiments showed that EGCG dose-dependently improved liver histological damage in high-fat diet-fed mice, reduced serum levels of ALT, AST, and TBil, increased albumin and prothrombin time, decreased the expression of fibrotic markers such as hyaluronic acid (HA) and laminin (LN), and inhibited the expression of fibrotic proteins including α-SMA and collagen I. In vitro experiments confirmed that EGCG reduced activation, proliferation, and migration of LX-2 cells by inhibiting the TGF-β1/Smad signaling pathway (downregulating Smad2/3 phosphorylation and upregulating Smad7). Mechanistically, EGCG targeted and bound to MDM2, inhibiting MDM2-mediated ubiquitination and degradation of MUC5AC, thereby increasing MUC5AC protein stability. MUC5AC directly interacted with TGF-β1, further inhibiting the activation of the TGF-β1/Smad pathway. Additionally, overexpression of MDM2 reversed the upregulation of MUC5AC and the anti-fibrotic effect of EGCG, while supplementation of MUC5AC restored the intervention effect of EGCG, confirming that EGCG exerts its function through the MDM2/MUC5AC axis.</div></div><div><h3>Conclusion</h3><div>EGCG targets MDM2 to prevent MUC5AC from ubiquitination and degradation. The upregulated MUC5AC binds to TGF-β1 and inhibits the TGF-β1/Smad signaling pathway, thereby suppressing hepatic stellate cell activation and liver fibrosis progression. This study provides new potential targets and experimental basis for the prevention and treatment of liver fibrosis.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156298"},"PeriodicalIF":3.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FBXW7 promotes osteoarthritis injury by regulating SLC7A11 ubiquitination degradation and chondrocyte ferroptosis","authors":"Lijuan Yang,&nbsp;Dongli Wang,&nbsp;Nan Yu,&nbsp;Caixia Zhu","doi":"10.1016/j.prp.2025.156297","DOIUrl":"10.1016/j.prp.2025.156297","url":null,"abstract":"<div><div>F-box and WD repeat domain-containing 7 (FBXW7), a ubiquitinating enzyme, has been verified as a key factor linking to the mechanical overloading and chondrocyte senescence in the pathology of osteoarthritis (OA). Given the lack of deeply mechanism research on the regulation of OA by FBXW7, elucidation of the action mechanism of FBXW7 in OA could provide theoretical basis for the treatment of OA. OA model was established by injuring the anterior cruciate ligament (ACL). Ferrostatin-1 (Fer-1) was applied for analysis of ferroptosis. After overexpressed or silence of FBXW7, cell viability and apoptosis were determined via CCK-8 and TUNEL staining. The intracellular Fe^2 + , GSH concentration, ROS levels and mitochondrial membrane potential were assessed by iron determination kit, ELISA, C11-BODIPY/DCFH-DA and JC-1 staining methods. Western blot and RT-qPCR were carried out for determination of ferroptosis-correlated factors (SLC7A11 and GPX4) and ECM-related factors (collagen II (Col II) and ADAMTS5). The interaction between SLC7A11 protein and FBXW7 was detected by immunofluorescence (IF) and immunoprecipitation (IP). Up-regulation of FBXW7, and down-regulation of SLC7A11 and GPX4 were observed in OA groups, compared to that in Control group. Moreover, FBXW7 overexpression significantly hindered cell viability, injured cell morphology, promoted apoptosis and reduced Col II protein level, while Fer-1 treatment blocked the function of FBXW7 overexpression in OA injury. Additionally, silence of FBXW7 showcased the opposite results, meanwhile decreased Fe²⁺ level, increased GSH release, reduced ROS content, raised mitochondrial membrane potential and elevated SLC7A11 and GPX4 in OA chondrocytes. Furthermore, SLC7A11 and FBXW7 were co-localized in chondrocytes and exhibited protein interaction. The ubiquitination degradation of SLC7A11 was accelerated by FBXW7 in chondrocytes, which was intercepted by MG132 treatment. <em>In vivo</em> experimental results further uncovered the alleviated functions of FBXW7 knockdown in ferroptosis and cartilage damage in OA model. The finding demonstrated that FBXW7 aggravated OA injury and ferroptosis, which might be linked to the ubiquitination degradation of SLC7A11.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156297"},"PeriodicalIF":3.2,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SCD1 drives bladder cancer progression and trametinib sensitivity","authors":"Yanping Zhang ,&nbsp;Shazhou Ye ,&nbsp;Suying Wang ,&nbsp;Qi Ding ,&nbsp;Jing Jin ,&nbsp;Ming Zhao","doi":"10.1016/j.prp.2025.156287","DOIUrl":"10.1016/j.prp.2025.156287","url":null,"abstract":"<div><div>Bladder cancer (BCa) is the most common malignancy of the urinary system. Despite advancements in novel targeted therapies and immunotherapy, the majority of patients remain incurable, and disease progression frequently occurs after treatment. Therefore, identifying new therapeutic strategies is crucial. Fatty acids are essential components of cell structure, playing roles in energy storage and serving as signaling molecules. In tumor tissues, due to abnormal blood vessel development, cancer cells primarily rely on de novo fatty acid synthesis to meet the demands of growth and proliferation. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme, widely recognized as a potential therapeutic target in various cancers. SCD1 promotes the synthesis of cell membranes by converting saturated fatty acids into monounsaturated fatty acids, thus supporting tumor cell growth. In this study, we conducted bioinformatics analysis using public datasets (including bulk RNA-seq and single-cell RNA-seq) and immunohistochemical examination of BCa tissues. Our findings reveal that SCD1 is specifically expressed in BCa cells and is associated with poor tumor grade and prognosis. Furthermore, drug sensitivity predictions and validations suggest that SCD1 enhances the sensitivity of BCa cells to trametinib. Therefore, SCD1 offers a promising new avenue for the early diagnosis, prognostic assessment, and optimization of personalized treatment strategies for BCa.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156287"},"PeriodicalIF":3.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}