The Journal of Pathology最新文献

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"268 S1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148085944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning-based H&E-derived risk scores in colorectal cancer: associations with tumour morphology, biology, and predicted drug response","authors":"Nic G Reitsam,&nbsp;Xiaofeng Jiang,&nbsp;Junhao Liang,&nbsp;Bianca Grosser,&nbsp;Veselin Grozdanov,&nbsp;Chiara ML Loeffler,&nbsp;Marco Gustav,&nbsp;Tim Lenz,&nbsp;Hannah S Muti,&nbsp;Zunamys I Carrero,&nbsp;Nicholas P West,&nbsp;Philip Quirke,&nbsp;Sebastian Foersch,&nbsp;Moritz Jesinghaus,&nbsp;Wolfram Müller,&nbsp;Tanwei Yuan,&nbsp;Michael Hoffmeister,&nbsp;Hermann Brenner,&nbsp;Jitendra Jonnagaddala,&nbsp;Nicholas J Hawkins,&nbsp;Robyn L Ward,&nbsp;Heike I Grabsch,&nbsp;Bruno Märkl,&nbsp;Jakob N Kather","doi":"10.1002/path.70039","DOIUrl":"10.1002/path.70039","url":null,"abstract":"<p>Over recent years, several deep learning (DL) models have been presented to predict colorectal cancer (CRC) patient survival directly from haematoxylin and eosin (H&amp;E)-stained routine whole-slide images (WSIs). Unlike traditional studies that rely on manually defined histopathological features, weakly supervised DL allows training directly on clinical endpoints without prior specification of the model's focus. This offers a unique opportunity to study the tissue morphology underlying these predictions, improving our understanding of disease biology. Here, we present a comprehensive analysis of the clinicopathological features, tumour morphology and biology, as well as gene expression-based predicted drug response of over 4,000 CRC patients derived from four different international cohorts with available H&amp;E-inferred DL-based risk scores (low- versus high-risk as well as absolute risk scores). The results from our study suggest that conventional clinicopathological risk factors, such as grade of differentiation, presence of lymph node metastasis, tumour budding, and percentage of tumour necrosis, are positively associated with DL-based risk scores. Moreover, CRCs with direct tumour–adipocyte interactions are enriched in the DL-based high-risk group. Through detailed morphologic review, we provide comprehensive evidence that direct tumour–adipocyte interaction, a high degree of tumour budding, and poorly differentiated morphology are linked to high DL-based risk scores. Transcriptomic and genetic subgroups show only limited association with H&amp;E-derived DL-based risk scores. Moreover, we present data suggesting that DL-based low- versus high-risk CRCs may be characterised by differential drug sensitivity. Our study highlights that DL-based risk scores derived from H&amp;E WSIs not only align with established clinicopathological features but also highlight morphological features, such as tumour–adipocyte interaction, that are not routinely captured by established clinicopathological scoring systems. Moreover, DL-based risk groups may be associated with a differential treatment response, underlining their potential to guide patient stratification in routine clinical practice. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"112-124"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xenium-based spatial transcriptomic analyses uncover prognosis-associated heterogeneity in the tumor microenvironment (TME) of angioimmunoblastic T-cell lymphoma (AITL)","authors":"Jiyan Dong,&nbsp;Xiaoyue Xiao,&nbsp;Lin Nong,&nbsp;Xuemin Xue,&nbsp;Long Wang,&nbsp;Xujie Sun,&nbsp;Kang Jiang,&nbsp;Xiaoli Feng","doi":"10.1002/path.70035","DOIUrl":"10.1002/path.70035","url":null,"abstract":"<p>Angioimmunoblastic T-cell lymphoma (AITL) exemplifies a neoplasm characterized by prominent inflammatory infiltration and robust immune responses in the tumor microenvironment (TME). The pathophysiology of refractory/recurrent (RR) AITL remains poorly understood due to profound intratumoral heterogeneity and complex TME features, contributing to limited therapeutic efficacy. Using Xenium-based spatial transcriptomics on 10 clinical samples, we compared RR AITL with treatment-responsive [non-refractory/recurrent event in 3 years (NR)] cases to map the TME architecture. We identified a novel cluster of <i>NEIL3</i>+ (Nei Like DNA Glycosylase 3) T-follicular helper (Tfh) cells, which exhibited stem-like characteristics at the transcriptional level, featuring self-renewal and multilineage differentiation capacity, and were highly enriched in RR tumors. Furthermore, we found major differences in immune cell organization between NR and RR microenvironments: RR cases were dominated by B cells primed for adaptive immunity and myeloid cells driving angiogenesis, whereas NR cases exhibited a chemokine-mediated regulatory landscape. These findings provide comprehensive characterization of the TME ecosystem in AITL and reveal potential therapeutic targets for high-risk RR AITL patients. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"71-85"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146217883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological significance of loss of Y chromosome in male meningiomas","authors":"Maki Sakaguchi,&nbsp;Masafumi Horie,&nbsp;Yukinobu Ito,&nbsp;Shingo Tanaka,&nbsp;Hiroko Ikeda,&nbsp;Mitsutoshi Nakada,&nbsp;Akihiko Yoshizawa,&nbsp;Daichi Maeda","doi":"10.1002/path.70040","DOIUrl":"10.1002/path.70040","url":null,"abstract":"<p>Male meningiomas, comprising approximately 30% of all meningiomas, are more frequently high-grade and associated with poorer clinical outcomes compared to their female counterparts. Although Y chromosome alterations have been studied in various male-predominant tumors, a limited number of studies have evaluated their role in meningiomas. To evaluate the clinicopathological significance of Y chromosome loss in male meningiomas, we assessed the frequency of loss of the Y chromosome (LOY) using droplet digital polymerase chain reaction in combination with multiplex ligation-dependent probe amplification on tumor DNA from 93 male meningioma samples. LOY, detected in nine cases (9.7%), was significantly associated with a higher World Health Organization tumor grade (grade 2: 55.6% versus 14.3%; grade 1: 44.4% versus 85.7%; <i>p</i> = 0.009) and loss of the NF2 gene-encoded protein, moesin-ezrin-radixin-like protein (merlin) (loss: 88.9% versus 50.0%; retained: 11.1% versus 50.0%; <i>p</i> = 0.035). RNA <i>in situ</i> hybridization targeting <i>KDM5D</i> on formalin-fixed paraffin-embedded tissue sections demonstrated a sensitivity of 100% (9/9) and a specificity of 76.2% (64/84) for LOY detection, supporting its utility as a screening modality. Moreover, spatial transcriptomic analysis revealed significant differences in the expression of genes associated with epithelial–mesenchymal transition and extracellular matrix organization between LOY and non-LOY meningioma tumor cells. Our findings emphasize the presence of atypical pathological features and distinct transcriptional profiles in LOY-associated meningiomas. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"125-137"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13050807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"E1-E4"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148065085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular matrix remodeling as a unique mechanism of expansion of periprostatic adipose tissue: implication for prostate cancer aggressiveness","authors":"David Estève,&nbsp;Aurélie Toulet,&nbsp;Mathieu Roumiguié,&nbsp;Dawei Bu,&nbsp;Mathilde Lacombe,&nbsp;Sarah Péricart,&nbsp;Chloé Belles,&nbsp;Cécile Manceau,&nbsp;Cynthia Houël,&nbsp;Manuelle Ducoux-Petit,&nbsp;Nathalie Van Acker,&nbsp;Stéphanie Dauvillier,&nbsp;Yiyue Jia,&nbsp;Marine Hernandez,&nbsp;Mohammed Moutahir,&nbsp;Camille Franchet,&nbsp;Nicolas Doumerc,&nbsp;Mathieu Thoulouzan,&nbsp;Sophie Le Gonidec,&nbsp;Philippe Valet,&nbsp;Bernard Malavaud,&nbsp;Odile Burlet-Schiltz,&nbsp;Anne Bouloumié,&nbsp;Philipp E Scherer,&nbsp;Delphine Milhas,&nbsp;Catherine Muller","doi":"10.1002/path.70033","DOIUrl":"10.1002/path.70033","url":null,"abstract":"<p>One of the most striking features of the adipose depot surrounding the prostate [periprostatic adipose tissue (PPAT)] is that its accumulation is independent of body mass index. Its volume varies considerably between individuals, with some patients exhibiting abundant PPATs, which have been correlated to the occurrence of aggressive prostate cancer (PCa). However, abundant PPAT is not well defined at the biological level. We used a new statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of 351 patients using a linear regression model. Applying this definition, we confirmed the link between abundant PPAT and PCa aggressiveness, thereby validating our approach. At the biological level, we showed that abundant PPAT exhibited extensive extracellular matrix remodeling, notably of the collagen network, decreasing the mechanical constraints in hypertrophic adipocytes, leading to inflammation-free expansion. Degradation of the most abundant collagen in adipose tissue (AT), collagen VI, was associated with increased production of endotrophin, a signaling peptide derived from AT that was also elevated in the urine of patients with abundant PPAT confirming the clinical relevance of our results. These results highlight a unique mechanism of expansion of an adipose depot and open new mechanistic avenues to explain its role in prostate-related disorders. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"55-70"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-grade endometrial stromal sarcoma is closely related to BCOR-altered sarcomas of the soft tissue and kidney rather than to other uterine sarcomas: implications for uterine sarcoma classification","authors":"Damiano Arciuolo,&nbsp;Sara Patrizi,&nbsp;Rita Alaggio,&nbsp;Antonio Travaglino,&nbsp;Giulia Scaglione,&nbsp;Silvia Vallese,&nbsp;Angela Santoro,&nbsp;Lucia Pedace,&nbsp;Claudia Nardini,&nbsp;Giuseppe Maria Milano,&nbsp;Franco Locatelli,&nbsp;Isabella Giovannoni,&nbsp;Sabina Barresi,&nbsp;Luigi Pedone Anchora,&nbsp;Camilla Fedeli,&nbsp;Francesca Ciccarone,&nbsp;Frediano Inzani,&nbsp;Evelina Miele,&nbsp;Gian Franco Zannoni","doi":"10.1002/path.70024","DOIUrl":"10.1002/path.70024","url":null,"abstract":"<p>High-grade endometrial stromal sarcoma (HGESS), which was not recognized as a distinct entity in the third edition of the World Health Organization (WHO) classification and was therefore included in the undifferentiated uterine sarcoma (UUS) category, was reestablished as a separate entity in the fourth edition. HGESS shares BCL-6 corepressor (BCOR) alterations with undifferentiated small round-cell sarcoma (USRCS) of the soft tissue and clear cell sarcoma of the kidney (CCSK). This study aims to perform a comparative morphological, immunohistochemical, and molecular analysis of HGESS, UUS, USRCS, and CCSK. Consecutive uterine sarcomas diagnosed as HGESS or UUS were reviewed and compared to BCOR<i>-</i>altered USRCS (<i>n</i> = 28) and CCSK (<i>n</i> = 10) (including both previously published and new cases). Molecular, DNA methylome (DNAm), and copy number variation (CNV) analyses were performed. DNAm data of 93 previously analyzed uterine and round-cell tumors of several different types were used for clustering analysis. Twenty-five uterine sarcomas (six HGESS and 19 UUS) were included; five of six HGESS cases showed fusions associated with <i>BCOR</i> alterations (<i>YWHAE</i>::<i>NUTM2A/B, EPC1</i>::<i>KDM2B, ZC3H7B</i>::<i>BCOR</i>); UUS showed no fusions (<i>n</i> = 15) or fusions unrelated to BCOR alterations (<i>n</i> = 4). All USRCS and CCSK cases showed either BCOR-ITD or BCOR alteration-related fusions. BCOR-altered HGESS showed broad morphological and immunophenotypic overlap with USRCS and CCSK. DNAm analysis showed that <i>BCOR</i>-altered HGESS, USRCS, and CCSK clustered together, separately from all other tumor types. The non-BCOR-altered HGESS showed a <i>JAZF1</i>::<i>SUZ12</i> fusion and arose from a low-grade endometrial stromal sarcoma component. CNVs were found in 15/16 uterine sarcomas and in 16/36 USRCS/CCSK cases. BCOR-altered HGESS appeared to be closely related to BCOR-altered USRCS and CCSK rather than to other uterine sarcomas. We suggest that HGESS with BCOR alterations may warrant reclassification as ‘BCOR-altered uterine sarcomas’. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"24-33"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146217915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile duct tumor thrombus (intraductal polypoid growth)–positive intrahepatic cholangiocarcinoma: clinicopathologic and genomic analysis","authors":"Ayaka Mitsui,&nbsp;Minoru Esaki,&nbsp;Satoshi Nara,&nbsp;Yasuhito Arai,&nbsp;Hiromi Nakamura,&nbsp;Tatsuhiro Shibata,&nbsp;Daisuke Ban,&nbsp;Takahiro Mizui,&nbsp;Nobuyoshi Hiraoka","doi":"10.1002/path.70038","DOIUrl":"10.1002/path.70038","url":null,"abstract":"<p>Bile duct tumor thrombus (BDTT), a tumor cluster occupying the luminal space in the large bile duct, is rare in intrahepatic cholangiocarcinoma (iCCA). Most studies on BDTT in iCCA to date are case reports, and the clinicopathological characteristics remain unknown. This study aimed to characterize iCCA with BDTT clinicopathologically and genetically. We analyzed 223 surgically resected iCCA cases, including 102 small duct type (SDT) and 121 large duct type (LDT) cases. BDTT was found in 19.6% (20/102) of SDT cases. Histological and immunohistochemical features of BDTT-positive SDT were comparable with those of conventional SDT (MUC1⁺MUC2⁻MUC5AC⁻MUC6^+/−CDX-2⁻). BDTT-positive SDT showed female predominance and higher T factors compared with conventional SDT. SDT was associated with a significantly longer survival in iCCA. SDT patients with BDTT had significantly shorter survival than those without BDTT and survival rates similar to those of LDT patients; the presence of BDTT in SDT was an independent unfavorable prognostic factor (HR = 2.601, <i>p</i> = 0.006). Whole-exome sequencing analysis revealed recurrent altered gene expression: those more frequent in SDT compared with LDT (<i>BAP1</i>, <i>IDH1/2</i>, <i>ZNF717</i>, <i>FGFR2</i>, <i>NRAS</i>); those more frequent in LDT (<i>KRAS</i>, <i>TP53</i>, <i>SMAD4</i>, <i>MUC6</i>, <i>CACNA1A</i>, <i>MLL2</i>, <i>MDM2</i>, <i>TGFBR1/2)</i>; and those found comparably in both SDT and LDT (<i>MUC4</i>, <i>ARID1A</i>, <i>EPHA2</i>, <i>PIK3CA</i>, <i>MUC17</i>, <i>MAP3K4</i>, <i>MUC2</i>, <i>BRAF</i>, <i>NF1</i>). Genetic landscapes were similar in SDT iCCA with and without BDTT; recurrent mutations in <i>MUC2</i> and <i>MUC17</i> and <i>FGFR2</i> fusion genes were more frequent in BDTT-positive SDTs. <i>PTPRK</i>::<i>RSPO3</i> fusion gene was found in one LDT case. Intraglandular papillary and tubular proliferation is a unique and rare histology of SDT. BDTT was frequently found in SDT with this pattern, and <i>FGFR2</i> gene rearrangement was frequent. These results highlight the importance of evaluating BDTT in SDT, as it may be the main route of hilar extension in aggressive cases. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"100-111"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The immune-metabolism interactome in efferocytosis: a new paradigm for the central nervous system diseases revealed by single-cell sequencing analysis","authors":"Huiyi Zhang,&nbsp;Wenbin Li,&nbsp;Peilun Xiao,&nbsp;Zeyao Lu,&nbsp;Ye Tian,&nbsp;Ying Xu","doi":"10.1002/path.70031","DOIUrl":"10.1002/path.70031","url":null,"abstract":"<p>Efferocytosis is a process that maintains tissue homeostasis by removing apoptotic cells (ACs) by professional or non-professional phagocytes. The intricate process can be categorized into recognition of ACs, engulfment of ACs, and degradation of efferosomes. Aberrations in efferocytosis result in inadequate clearance of ACs, leading to prolonged inflammation that is implicated in the development and progression of various human diseases. Most central nervous system (CNS) diseases are associated with dysregulation of inflammatory homeostasis. Microglia, the resident immune cells of the CNS, play a primary role in efferocytosis in the brain, which is essential for maintaining the homeostasis of the internal environment. In this review, we summarize the current knowledge of the basic processes of efferocytosis and its indispensable role in the developing and aging brain. Additionally, we discuss the regulatory role of immune-metabolism crosstalk and the insights from single-cell sequencing analysis in dissecting microglial heterogeneity during efferocytosis. We also focus on recent discoveries regarding the critical role of efferocytosis in several CNS diseases, including cerebral ischemia, intracerebral hemorrhage, traumatic brain injury, major depressive disorder, glioblastoma multiforme, Alzheimer's disease, and Parkinson's disease. Finally, we outline potential therapeutic strategies and existing challenges, emphasizing the need for context-specific targeting to improve CNS disease outcomes. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"1-23"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acid and cysteine metabolic interplay regulate ferroptosis and highlight xCT as a selenium-chrysin target in breast carcinoma","authors":"Ana Hipólito,&nbsp;Bruna Abreu,&nbsp;Joana Gonçalves,&nbsp;Fernanda Silva,&nbsp;Carmo Martins,&nbsp;Laura Gouveia,&nbsp;Sofia A Pereira,&nbsp;Vasco D B Bonifácio,&nbsp;Saudade André,&nbsp;Cindy Mendes,&nbsp;Jacinta Serpa","doi":"10.1002/path.70027","DOIUrl":"10.1002/path.70027","url":null,"abstract":"<p>Cancer metabolic remodeling impacts the entire network of metabolic pathways, and strategies that target various points within this system could contribute to successfully abrogating cancer cell survival. Fatty acids (FAs) are essential to cancer cells because they support membrane biosynthesis during proliferation and provide energy during metabolic stress. Fatty acid transport protein 1 (FATP1)has been shown to mediate FA uptake in breast carcinoma (BC). The light chain of cysteine/glutamate amino acid exchange transporter system Xc (xCT)is crucial for the uptake of cysteine serving as a carbon and sulfur source that contributes to redox control, bioenergetics, and biosynthesis. In this study, targeting of FA and cysteine metabolic pathways was shown to be a potential strategy for managing BC by inhibiting FATP1 and xCT with arylpiperazine 5k and selenium-chrysin (SeChry), respectively. In BC cell lines, FATP1 expression is controlled by estrogen receptor β (ER-β) and promotes the accumulation of lipid droplets (LDs), which is associated with triple-negative breast carcinoma (TNBC) cells showing increased rates of cell proliferation, two-dimensional directional cell migration, and higher chemoresistance. Expression of xCT was also associated with the TNBC molecular BC subtype. In BC specimens, an association between FATP1 and xCT expression was observed. <i>In vitro</i>, SeChry induced ferroptosis in BC cells by targeting xCT and cysteine reliance and ultimately inducing cell death. In xenograft BC tumors, arylpiperazine 5k abrogated the effects of SeChry encapsulated in polyurea dendrimers functionalized with folate (SeChry@PURE_G4-FA₂) by reducing intracellular FA and rescuing ferroptosis. <i>In vitro</i>, SeChry sensitized BC cells to cisplatin and may therefore serve as an alternative in combination therapy. Overall, our study confirmed FATP1 as a marker and xCT as both a marker and a target in BC, particularly in TNBC. Induction of ferroptosis by interfering with xCT function may provide an opportunity to improve BC treatment, and a therapeutic approach using SeChry@PURE_G4-FA₂ is a promising strategy. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"269 1","pages":"34-54"},"PeriodicalIF":5.2,"publicationDate":"2026-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146217891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}