Pub Date : 2026-02-01Epub Date: 2025-12-08DOI: 10.1016/j.prp.2025.156328
Maxime Golias , Zuzana Krupova , Pierre Defrenaix , Marie-Françoise Heymann , Dominique Heymann
Intratumoral heterogeneity is a real challenge for understanding the key mechanisms involved in cancer progression, but also for pathologists to make a reliable diagnosis. The development of precision medicine in oncology allows each treatment to be tailored to the specific characteristics of the tumours. However, the ability to isolate pure cell populations is a very difficult task and makes accurate analysis difficult. The development since the 90’s of precise dissection techniques, known as microdissection, has helped to overcome problems associated with tumor heterogeneity. Since then, a few techniques have been developed that provide dissection accuracy down to the sub-cellular level. These technologies have enabled key principles to be understood in basic research but handling difficulties have prevented their use in pathology laboratories. Working with microquantities can also be a difficult task and requires several technical adaptations. This review provides an overview of all microdissection techniques currently available. In addition to their main advantages, examples of applications and adaptations of molecular biology techniques to microquantities are proposed to illustrate the interest of these technical approaches in both basic research and clinical applications.
{"title":"Microdissection: Insights and progress in the era of precision medicine","authors":"Maxime Golias , Zuzana Krupova , Pierre Defrenaix , Marie-Françoise Heymann , Dominique Heymann","doi":"10.1016/j.prp.2025.156328","DOIUrl":"10.1016/j.prp.2025.156328","url":null,"abstract":"<div><div>Intratumoral heterogeneity is a real challenge for understanding the key mechanisms involved in cancer progression, but also for pathologists to make a reliable diagnosis. The development of precision medicine in oncology allows each treatment to be tailored to the specific characteristics of the tumours. However, the ability to isolate pure cell populations is a very difficult task and makes accurate analysis difficult. The development since the 90’s of precise dissection techniques, known as microdissection, has helped to overcome problems associated with tumor heterogeneity. Since then, a few techniques have been developed that provide dissection accuracy down to the sub-cellular level. These technologies have enabled key principles to be understood in basic research but handling difficulties have prevented their use in pathology laboratories. Working with microquantities can also be a difficult task and requires several technical adaptations. This review provides an overview of all microdissection techniques currently available. In addition to their main advantages, examples of applications and adaptations of molecular biology techniques to microquantities are proposed to illustrate the interest of these technical approaches in both basic research and clinical applications.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156328"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743735","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}
Pub Date : 2026-01-01Epub Date: 2025-11-07DOI: 10.1016/j.prp.2025.156284
Naglaa F. Khedr , Hend M. Selim , Gamal A. Abourayya
Chronic diseases like neurodegenerative disorders, musculoskeletal issues, metabolic diseases, cancer, liver and kidney disorders are increasingly linked to mitochondrial dysfunction. PINK1-Parkin-mediated mitophagy, a vital autophagic process, plays a central role in maintaining cellular homeostasis by selectively eliminating damaged mitochondria, which is crucial for preserving mitochondrial integrity and preventing reactive oxygen species accumulation. Activation of the PINK1-Parkin signaling pathway has emerged as a promising therapeutic strategy to restore mitochondrial function and attenuate disease progression. Recent studies have demonstrated that natural PINK1-Parkin activators offer significant therapeutic potential for treating a wide range of chronic diseases by modulating mitochondrial dynamics, alleviating cellular inflammation, and preventing mitochondrial damage. This review provides an in-depth analysis of the molecular mechanisms underlying PINK1-Parkin signaling, discusses the therapeutic benefits of natural activators, and presents them as a compelling strategy for addressing mitochondrial dysfunction and mitigating the progression of chronic diseases.
{"title":"Therapeutic potential of natural compounds in the management of chronic diseases: Targeting PINK1–Parkin pathway","authors":"Naglaa F. Khedr , Hend M. Selim , Gamal A. Abourayya","doi":"10.1016/j.prp.2025.156284","DOIUrl":"10.1016/j.prp.2025.156284","url":null,"abstract":"<div><div>Chronic diseases like neurodegenerative disorders, musculoskeletal issues, metabolic diseases, cancer, liver and kidney disorders are increasingly linked to mitochondrial dysfunction. PINK1-Parkin-mediated mitophagy, a vital autophagic process, plays a central role in maintaining cellular homeostasis by selectively eliminating damaged mitochondria, which is crucial for preserving mitochondrial integrity and preventing reactive oxygen species accumulation. Activation of the PINK1-Parkin signaling pathway has emerged as a promising therapeutic strategy to restore mitochondrial function and attenuate disease progression. Recent studies have demonstrated that natural PINK1-Parkin activators offer significant therapeutic potential for treating a wide range of chronic diseases by modulating mitochondrial dynamics, alleviating cellular inflammation, and preventing mitochondrial damage. This review provides an in-depth analysis of the molecular mechanisms underlying PINK1-Parkin signaling, discusses the therapeutic benefits of natural activators, and presents them as a compelling strategy for addressing mitochondrial dysfunction and mitigating the progression of chronic diseases.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156284"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506307","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}
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.
{"title":"ATF4 transcriptional regulation of OMD and STC2 drives vascular calcification progression via the PI3K/AKT pathway","authors":"Zhang Yue , Ming-Yan Wang , Chun-Ze Yuan , Jin-Wen Xu , 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":"2026-01-01","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}
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder identified by persistent synovial inflammation, joint destruction, and systemic complications. Affecting approximately 0.5–1 % of the global population, RA poses a considerable burden in terms of disability and healthcare costs. Over the past century, insights into RA pathogenesis—driven by immune dysregulation, genetic predisposition, and environmental triggers—have revolutionized therapeutic strategies. This review provides a detailed overview of the evolving landscape of RA drug development, tracing the progression from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate and sulfasalazine, to targeted synthetic DMARDs (tsDMARDs) like JAK inhibitors, and biologic DMARDs (bDMARDs) including TNF and IL-6 antagonists. We explore the molecular underpinnings of RA, discuss the mechanisms of action and clinical applications of current therapies, and highlight emerging drug candidates under clinical investigation. Despite significant advances, challenges such as incomplete remission rates, variable patient responses, and long-term safety concerns underscore the need for precision medicine and novel therapeutic approaches. This review emphasizes the critical role of immunopathology in guiding RA drug development and the ongoing efforts to achieve personalized, sustained disease control.
{"title":"New frontiers in rheumatoid arthritis therapy: From classic DMARDs to biologics and beyond","authors":"Vanshika , Puja Gulati , Ritika Thakur , Deeksha Bala , Richa Bajaj , Priya , Chetan Bansal , Tamanna Dhiman , Inderjeet Verma , Shivani Pannu","doi":"10.1016/j.prp.2025.156307","DOIUrl":"10.1016/j.prp.2025.156307","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder identified by persistent synovial inflammation, joint destruction, and systemic complications. Affecting approximately 0.5–1 % of the global population, RA poses a considerable burden in terms of disability and healthcare costs. Over the past century, insights into RA pathogenesis—driven by immune dysregulation, genetic predisposition, and environmental triggers—have revolutionized therapeutic strategies. This review provides a detailed overview of the evolving landscape of RA drug development, tracing the progression from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate and sulfasalazine, to targeted synthetic DMARDs (tsDMARDs) like JAK inhibitors, and biologic DMARDs (bDMARDs) including TNF and IL-6 antagonists. We explore the molecular underpinnings of RA, discuss the mechanisms of action and clinical applications of current therapies, and highlight emerging drug candidates under clinical investigation. Despite significant advances, challenges such as incomplete remission rates, variable patient responses, and long-term safety concerns underscore the need for precision medicine and novel therapeutic approaches. This review emphasizes the critical role of immunopathology in guiding RA drug development and the ongoing efforts to achieve personalized, sustained disease control.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156307"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615961","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}
Pub Date : 2026-01-01Epub Date: 2025-11-10DOI: 10.1016/j.prp.2025.156287
Yanping Zhang , Shazhou Ye , Suying Wang , Qi Ding , Jing Jin , Ming Zhao
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.
{"title":"SCD1 drives bladder cancer progression and trametinib sensitivity","authors":"Yanping Zhang , Shazhou Ye , Suying Wang , Qi Ding , Jing Jin , 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-11-26DOI: 10.1016/j.prp.2025.156311
Yi Shi, Yajuan Song, Tong Wang, Yan Jiao, Juanli Dang, Yufei Zhang, Shu’ao Xiao, Baoqiang Song, Zhou Yu
Background
Hypertrophic scar (HS) is a severe fibrotic disease characterized by excessive fibroblast activation and extracellular matrix deposition. While previous studies have revealed the involvement of Aortic Carboxypeptidase Like Protein (ACLP) in other fibrotic diseases, the role of ACLP in HS has not been investigated.
Methods
Quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence were applied to investigate the expression and subcellular location of ACLP. Wound healing and Transwell assays were employed to evaluate the impact of ACLP on HSF migration after ACLP siRNA transfection or recombinant human ACLP protein (rACLP) stimulation. The protein expression levels of VIM, MMP2, MMP9, α-SMA, COL I, and COL III in HSFs were also analyzed. A collagen gel contraction assay was harnessed to assess the contractile ability of HSFs after ACLP siRNA transfection or rACLP treatment. Lastly, RNA-Seq was utilized to reveal the gene expression profile of HSFs following ACLP knock-down.
Results
ACLP expression was increased in both HS tissues and human hypertrophic scar fibroblasts (HSFs). ACLP knock-down attenuated the horizontal and vertical migration of HSFs, collagen gel contraction activity, fibroblast to myofibroblast transition (FMT), and VIM, MMP2, MMP9, α-SMA, and COL III protein expression. Conversely, rACLP stimulation promoted HSF migration, gel contraction, FMT, and associated protein expression. Additionally, ACLP knock-down downregulated the expression of two cholesterol synthesis-related genes comprising HMGCS1 and HMGCR.
Conclusions
Here, for the first time, we reveal that ACLP expression is upregulated during HS and that it promotes HSF migration and myofibroblast activation. Hence, ACLP may serve as a candidate biomarker for HS pathogenesis and as an intervention target for HS prevention and treatment.
{"title":"ACLP promotes hypertrophic scar pathogenesis by enhancing myofibroblast activation and cholesterol synthesis-related gene expression","authors":"Yi Shi, Yajuan Song, Tong Wang, Yan Jiao, Juanli Dang, Yufei Zhang, Shu’ao Xiao, Baoqiang Song, Zhou Yu","doi":"10.1016/j.prp.2025.156311","DOIUrl":"10.1016/j.prp.2025.156311","url":null,"abstract":"<div><h3>Background</h3><div>Hypertrophic scar (HS) is a severe fibrotic disease characterized by excessive fibroblast activation and extracellular matrix deposition. While previous studies have revealed the involvement of Aortic Carboxypeptidase Like Protein (ACLP) in other fibrotic diseases, the role of ACLP in HS has not been investigated.</div></div><div><h3>Methods</h3><div>Quantitative real-time PCR (qRT-PCR), Western blotting, and immunofluorescence were applied to investigate the expression and subcellular location of ACLP. Wound healing and Transwell assays were employed to evaluate the impact of ACLP on HSF migration after ACLP siRNA transfection or recombinant human ACLP protein (rACLP) stimulation. The protein expression levels of VIM, MMP2, MMP9, α-SMA, COL I, and COL III in HSFs were also analyzed. A collagen gel contraction assay was harnessed to assess the contractile ability of HSFs after ACLP siRNA transfection or rACLP treatment. Lastly, RNA-Seq was utilized to reveal the gene expression profile of HSFs following ACLP knock-down.</div></div><div><h3>Results</h3><div>ACLP expression was increased in both HS tissues and human hypertrophic scar fibroblasts (HSFs). ACLP knock-down attenuated the horizontal and vertical migration of HSFs, collagen gel contraction activity, fibroblast to myofibroblast transition (FMT), and VIM, MMP2, MMP9, α-SMA, and COL III protein expression. Conversely, rACLP stimulation promoted HSF migration, gel contraction, FMT, and associated protein expression. Additionally, ACLP knock-down downregulated the expression of two cholesterol synthesis-related genes comprising HMGCS1 and HMGCR.</div></div><div><h3>Conclusions</h3><div>Here, for the first time, we reveal that ACLP expression is upregulated during HS and that it promotes HSF migration and myofibroblast activation. Hence, ACLP may serve as a candidate biomarker for HS pathogenesis and as an intervention target for HS prevention and treatment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156311"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615959","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}
Pub Date : 2026-01-01Epub Date: 2025-11-13DOI: 10.1016/j.prp.2025.156297
Lijuan Yang, Dongli Wang, Nan Yu, Caixia Zhu
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 Fe2 + , 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. In vivo 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.
F-box和WD重复结构域7 （FBXW7）是一种泛素化酶，已被证实是骨关节炎（OA）病理中机械超载和软骨细胞衰老的关键因素。鉴于FBXW7对OA的调控机制缺乏深入的研究，阐明FBXW7在OA中的作用机制可以为OA的治疗提供理论依据。通过损伤前交叉韧带（ACL）建立骨关节炎模型。应用铁抑素-1 （fer1）分析铁下垂。FBXW7过表达或沉默后，通过CCK-8和TUNEL染色检测细胞活力和凋亡情况。采用铁测定试剂盒、ELISA、C11-BODIPY/DCFH-DA和JC-1染色法检测细胞内Fe2 +、GSH浓度、ROS水平和线粒体膜电位。Western blot和RT-qPCR检测凋亡相关因子（SLC7A11和GPX4）和ecm相关因子（collagen II （Col II）和ADAMTS5）。采用免疫荧光（IF）和免疫沉淀（IP）检测SLC7A11蛋白与FBXW7的相互作用。与对照组相比，OA组FBXW7表达上调，SLC7A11和GPX4表达下调。FBXW7过表达显著抑制细胞活力，损伤细胞形态，促进细胞凋亡，降低Col II蛋白水平，而fe -1处理可阻断FBXW7过表达在OA损伤中的作用。此外，FBXW7沉默显示相反的结果，同时OA软骨细胞中Fe2+水平降低，GSH释放增加，ROS含量降低，线粒体膜电位升高，SLC7A11和GPX4升高。此外，SLC7A11和FBXW7在软骨细胞中共定位，并表现出蛋白质相互作用。软骨细胞中的FBXW7加速了SLC7A11的泛素化降解，MG132阻断了FBXW7。体内实验结果进一步揭示了FBXW7敲低对OA模型铁下垂和软骨损伤的缓解作用。研究结果表明，FBXW7加重OA损伤和铁下沉，这可能与SLC7A11的泛素化降解有关。
{"title":"FBXW7 promotes osteoarthritis injury by regulating SLC7A11 ubiquitination degradation and chondrocyte ferroptosis","authors":"Lijuan Yang, Dongli Wang, Nan Yu, 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<sup>2 +</sup> , 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 Fe<sup>2+</sup> 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":"2026-01-01","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}
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality. Microsatellite instability-high (MSI-H) tumors, resulting from defective DNA mismatch repair (MMR), represent a well-defined subtype with distinctive biological behavior and immunogenicity. In contrast, tumors with elevated microsatellite alterations at tetranucleotide repeats (EMAST) are less well characterized. EMAST can manifest with MSI or arise as an isolated form of instability, delineating discrete phenotypes underpinned by distinct mechanisms. This study aimed to characterize MSI and EMAST status in CRCs. By integrating instability profiles with clinicopathological features and mutational profiles of key driver genes, we aimed to refine molecular classification and advance understanding of CRC tumorigenesis. A total of 332 CRCs were analyzed for MSI and EMAST using established panels. Clinicopathological characteristics were recorded, and mutational profiling of KRAS, BRAF, CTNNB1, PIK3CA, and TP53 was performed. MLH1 expression was assessed using immunohistochemistry. MSS/EMAST-S tumors displayed profiles typical of chromosomally stable CRC, dominated by KRAS and followed by TP53 and PIK3CA mutations. MSI-H/EMAST-H tumors were characterized by frequent BRAF mutations, right-sided location, female predominance, and lower TP53 mutation rate, consistent with the classical hypermutated, immunogenic subtype. In contrast, MSS/EMAST-H tumors exhibited unique features, including enrichment for PIK3CA and CTNNB1 mutations, larger tumor size, and poorer differentiation, suggesting an intermediate phenotype between MSS and MSI-H. MSS/EMAST-L tumors aligned with chromosomally stable, KRAS/Wnt-driven CRC. In conclusion, MSS/EMAST-H tumors represent an underrecognized CRC subtype with intermediate genomic instability and a distinctive molecular profile, with potential implications for prognostic assessment and personalized therapeutic strategies.
{"title":"Clinicopathological features and mutational landscape of colorectal cancer subgroups defined by MSI and EMAST status","authors":"Tamara Cacev , Kristina Vuković Đerfi , Anamarija Salar , Sonja Marinović , Emilija Zapletal , Vesna Musani , Anita Škrtić , Arijana Pačić , Sanja Kapitanović","doi":"10.1016/j.prp.2025.156302","DOIUrl":"10.1016/j.prp.2025.156302","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality. Microsatellite instability-high (MSI-H) tumors, resulting from defective DNA mismatch repair (MMR), represent a well-defined subtype with distinctive biological behavior and immunogenicity. In contrast, tumors with elevated microsatellite alterations at tetranucleotide repeats (EMAST) are less well characterized. EMAST can manifest with MSI or arise as an isolated form of instability, delineating discrete phenotypes underpinned by distinct mechanisms. This study aimed to characterize MSI and EMAST status in CRCs. By integrating instability profiles with clinicopathological features and mutational profiles of key driver genes, we aimed to refine molecular classification and advance understanding of CRC tumorigenesis. A total of 332 CRCs were analyzed for MSI and EMAST using established panels. Clinicopathological characteristics were recorded, and mutational profiling of <em>KRAS</em>, <em>BRAF</em>, <em>CTNNB1</em>, <em>PIK3CA</em>, and <em>TP53</em> was performed. MLH1 expression was assessed using immunohistochemistry. MSS/EMAST-S tumors displayed profiles typical of chromosomally stable CRC, dominated by <em>KRAS</em> and followed by <em>TP53</em> and <em>PIK3CA</em> mutations. MSI-H/EMAST-H tumors were characterized by frequent <em>BRAF</em> mutations, right-sided location, female predominance, and lower <em>TP53</em> mutation rate, consistent with the classical hypermutated, immunogenic subtype. In contrast, MSS/EMAST-H tumors exhibited unique features, including enrichment for <em>PIK3CA</em> and <em>CTNNB1</em> mutations, larger tumor size, and poorer differentiation, suggesting an intermediate phenotype between MSS and MSI-H. MSS/EMAST-L tumors aligned with chromosomally stable, KRAS/Wnt-driven CRC. In conclusion, MSS/EMAST-H tumors represent an underrecognized CRC subtype with intermediate genomic instability and a distinctive molecular profile, with potential implications for prognostic assessment and personalized therapeutic strategies.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"277 ","pages":"Article 156302"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615526","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}
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.
Methods
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.
Results
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 % POLE 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 %, P < 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 P < 0.05). In non-p53abn ECs, KRAS mutations were significantly less frequent in HER2 2 + /3 + group (2 +/3 + vs. 1 +, 6.7 % vs. 46.2 %, P < 0.05).
Conclusions
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.
{"title":"HER2 immunoreactivity in advanced non-p53abn endometrial carcinoma: Association with clinical features, prognosis, and molecular characteristics","authors":"Yining Zhen, Yinbo Xiao, Yang Zhou, Longyun Chen, Junyi Pang, Xiaohua Shi, 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> < 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> < 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> < 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-11-19DOI: 10.1016/j.prp.2025.156295
Javad Omidi
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.
{"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":"2026-01-01","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号