Pathology, research and practice最新文献

{"title":"Sphingolipid metabolism patterns reveal distinct prognostic and immune landscapes in head and neck squamous cell carcinoma","authors":"Bingtong Yue ,&nbsp;Huiqian Zhang ,&nbsp;Zhuoran Li ,&nbsp;Ruihua Bai ,&nbsp;Yueli Ma ,&nbsp;Jing Lu","doi":"10.1016/j.prp.2025.156233","DOIUrl":"10.1016/j.prp.2025.156233","url":null,"abstract":"<div><h3>Background</h3><div>Head and neck squamous cell carcinoma (HNSCC) remains a global public health concern due to its poor prognosis and high mortality. Sphingolipids, integral components of cell membranes, are emerging as potential therapeutic targets in cancer because of their critical roles in oncogenic signaling. However, a prognostic model based on sphingolipid metabolism in HNSCC with immune implications is still lacking.</div></div><div><h3>Methods</h3><div>We obtained transcriptomic and clinical data for HNSCC from TCGA and GEO databases, and retrieved sphingolipid metabolism–related genes from MSigDB. Qualitatively, HNSCC patients were categorized via unsupervised consensus clustering. Quantitatively, a risk model was constructed using Lasso regression. In addition, single-cell RNA sequencing analysis was performed for further investigation. Finally, the core gene of the risk model was identified by WGCNA analysis, and then validated by qRT-PCR and IHC in clinical specimens.</div></div><div><h3>Results</h3><div>We developed a novel five-gene prognostic signature (<em>SPNS2</em>, <em>NEU1</em>, <em>B4GALNT1</em>, <em>CSNK1G2</em>, and <em>ARSI</em>) to predict outcomes in HNSCC. Furthermore, the high-risk group exhibited a decreased immune infiltration level and a suppressive microenvironment. Immunotherapy response analysis further demonstrated the clinical utility of this risk stratification in guiding treatment decisions. Moreover, the core gene B4GALNT1 was confirmed to be highly expressed in clinical HNSCC samples.</div></div><div><h3>Conclusions</h3><div>This study is the first to establish a sphingolipid metabolism–based five-gene signature in HNSCC. Its superior reliability and accuracy in predicting prognosis and immune response offer new clinical perspectives.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156233"},"PeriodicalIF":3.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096139","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":"Apoptosis, ferroptosis, and the autophagy paradox in peritoneal metastasis","authors":"Jinfeng Qi ,&nbsp;Junliang Li ,&nbsp;Ruipeng Wang ,&nbsp;Yuanyuan Deng","doi":"10.1016/j.prp.2025.156225","DOIUrl":"10.1016/j.prp.2025.156225","url":null,"abstract":"<div><div>Peritoneal metastasis (PM) correlates with a diminished prognosis. Throughout the progression of PM, programmed cell death (PCD) often functions as the body's defense mechanism to eliminate aberrant malignant cells. Paradoxically, PCD within tumor cell populations also holds the potential to exert a pro-cancer effect by modulating the tumor microenvironment (TME). Apoptosis-mediated innate immune cells may orchestrate the pro-cancer TME and could potentially evade cancer therapy. This discussion delineates the impacts of PCD in PM, particularly focusing on apoptosis, ferroptosis, and autophagy, constituting a \"double paradox\" process. On one hand, PM is restrained through the removal of cancer cells, while on the other hand, it is propelled by the stimulation of repair and regenerative responses in the TME. Furthermore, the interplay of various PCDs such as cell apoptosis, autophagy, and ferroptosis in PM is explored, alongside a summary of PCD-based anticancer strategies. These insights aim to provide a theoretical basis for the prevention and treatment of PM.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156225"},"PeriodicalIF":3.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096101","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":"Heparanase and MMP-9 synergistically induce endothelial-mesenchymal transition in portal vein microvessels to promote hepatocellular carcinoma metastasis","authors":"Meng Pan ,&nbsp;Peng Chen ,&nbsp;Junlu Peng ,&nbsp;Dafei Dai ,&nbsp;Ruiqi Wu ,&nbsp;Peng Wang ,&nbsp;Jun Zhao ,&nbsp;Xiaopeng Chen","doi":"10.1016/j.prp.2025.156229","DOIUrl":"10.1016/j.prp.2025.156229","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Both heparanase (HPSE) and matrix metalloproteinase-9 (MMP-9) can promote metastasis of hepatocellular carcinoma (HCC), but it is not clear whether they co-induce endothelial-mesenchymal transition (EndoMT) in portal vein endothelial cells (PVECs) to facilitate HCC metastasis. This study aimed to investigate the combined effect of HPSE and MMP-9 on EndoMT in PVECs and subsequent intrahepatic metastasis of HCC and to explore the underlying mechanism.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This study employed gene knockdown, gene overexpression and inhibitor strategies to manipulate HPSE/MMP-9 expression or activity within HCC cells, which were non-contact co-cultured with human umbilical vein endothelial cells (HUVECs). Quantitative real-time polymerase chain reaction and western blotting techniques were employed to assess the expression levels of endothelial and mesenchymal cell markers in the co-cultured HUVECs, while double immunofluorescent analysis was performed to determine the localization. Expression of syndecan 1 (SDC-1), transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and pSmad2/3 was determined simultaneously in HUVECs, with the first three proteins detected in the supernatant. Transendothelial migration assays were executed to detect the migration rate of HCC cells. A nude mouse model of liver cancer metastasis was established, and hematoxylin and eosin staining of the liver was performed to observe the liver metastasis and portal vein tumor thrombus (PVTT). Furthermore, immunohistochemical analyses of human HCC tissues around portal vein were performed to investigate the relationship between HPSE/MMP-9 and mesenchymal cell marker expression.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Compared with single knockdown of HPSE/MMP-9 in HCCLM3 cells, simultaneous knockdown was more effective in reducing the expression of mesenchymal markers and increasing the expression of endothelial markers in co-cultured HUVECs. The levels of SDC-1, TGF-β1, TNF-α and pSmad2/3 showed a coordinated downregulation pattern. The dual knockdown strategy suppressed the release of EndoMT activators from stimulated HUVECs, thereby suppressing EndoMT progression and significantly reducing HCC cell transendothelial migration in vitro. The application of HPSE/MMP-9 inhibitors and the TGF-β1-specific inhibitor in HCCLM3 cells, along with rescue experiments using HepG2 cells, yielded similar results. Nude mouse experiments showed that double knockdown HCCLM3 cells led to the lowest liver metastasis and PVTT rates. Immunohistochemical analyses displayed a gradual enhancement in the expression of mesenchymal cell markers with the increase in the expression or co-expression of HPSE/MMP-9.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;HPSE/MMP-9 may have a synergistic effect on inducing EndoMT in PVECs, ultimately promoting HCC metastasis through the SDC-1/TGF-β1 (TNF-α)/pSmad2/3 pathway. Our research expands the current understandin","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156229"},"PeriodicalIF":3.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081272","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 tumor microenvironment in triple-negative breast cancer: Biological insights and therapeutic opportunities","authors":"Teresa Maria Martorana ,&nbsp;Gabriele Ricciardi ,&nbsp;Pietro Tralongo ,&nbsp;Vincenzo Fiorentino ,&nbsp;Cristina Pizzimenti ,&nbsp;Mariausilia Franchina ,&nbsp;Maria Adele Marino ,&nbsp;Mariacarmela Santarpia ,&nbsp;Giovanni Tuccari ,&nbsp;Antonio Ieni ,&nbsp;Guido Fadda ,&nbsp;Maurizio Martini ,&nbsp;Valeria Zuccalà","doi":"10.1016/j.prp.2025.156226","DOIUrl":"10.1016/j.prp.2025.156226","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Despite initial chemosensitivity, TNBC often relapses, and nearly half of patients develop distant metastases, particularly to visceral organs and the brain. In recent years, growing attention has been given to the tumor microenvironment (TME) as a critical driver of disease progression, immune evasion, and therapeutic resistance. TME is composed of a dynamic network of immune and stromal cells, extracellular matrix components, and soluble mediators that influence tumor behavior and shape response to treatment. In this review, we provide a comprehensive overview of the cellular and molecular composition of the TME in TNBC, highlight key prognostic and predictive markers, and discuss emerging therapeutic strategies aimed at targeting TME components. Understanding the complex crosstalk between the tumor and its microenvironment is essential for developing effective, personalized approaches to managing TNBC in the future.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156226"},"PeriodicalIF":3.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060795","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":"METTL3/IGF2BP2 stabilizes IQGAP3 via m6A modification to drive HCC metastasis through TGF-β/Smad signaling and EMT","authors":"Debiao Pan ,&nbsp;Haiyuan Zhang ,&nbsp;Junbin Zhou ,&nbsp;Songqing He ,&nbsp;Guandou Yuan","doi":"10.1016/j.prp.2025.156228","DOIUrl":"10.1016/j.prp.2025.156228","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) metastasis is a leading cause of mortality, yet its molecular drivers remain poorly defined. In this study, we identify methyltransferase-like 3 (METTL3), an N6-methyladenosine (m6A) RNA methyltransferase frequently upregulated in HCC, as a critical promoter of metastasis through m6A-mediated post-transcriptional upregulation of the oncogenic protein IQ motif-containing GTPase-activating protein 3 (IQGAP3). Using HCC cell lines in vitro and a nude mouse lung metastasis model in vivo, we demonstrate that METTL3-catalyzed m6A modification of IQGAP3 mRNA enhances IQGAP3 stability and expression, which in turn drives HCC cell migration, invasion, and lung colonization. METTL3 knockdown reduces m6A marks on IQGAP3 transcripts and decreases IQGAP3 levels and metastatic capacity, whereas ectopic IQGAP3 expression rescues the invasive phenotype. Mechanistically, RNA immunoprecipitation assays reveal that Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m6A reader protein, binds m6A-modified IQGAP3 transcripts to prolong their half-life. Consequently, the METTL3-IQGAP3 axis activates TGF-β/Smad signaling and drives an epithelial-mesenchymal transition, thereby promoting a metastatic phenotype. Concordantly, METTL3 depletion or IGF2BP2 knockdown significantly suppresses these pathways and impedes metastasis in vitro and in vivo. Overall, our findings uncover a novel m6A-dependent mechanism driving HCC metastasis. This m6A-dependent METTL3-IGF2BP2-IQGAP3 axis represents a promising therapeutic target for metastatic HCC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156228"},"PeriodicalIF":3.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044820","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":"LRPPRC promotes the progression of colorectal cancer via HIF-1ꭤ/VEGF-meditated angiogenesis","authors":"Yanhua Mo ,&nbsp;Shujing Wu ,&nbsp;Yuanmeng Liu ,&nbsp;Yezhi Liang ,&nbsp;Zhengwen Cai ,&nbsp;Li Liang","doi":"10.1016/j.prp.2025.156223","DOIUrl":"10.1016/j.prp.2025.156223","url":null,"abstract":"<div><h3>Background</h3><div>Distant metastasis is the primary cause of mortality in patients with colorectal cancer (CRC). Angiogenesis plays a critical role in cancer development, invasion, and metastasis. However, the signaling mechanisms driving angiogenesis were not fully elucidated. This study investigated the role of leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) in CRC metastasis.</div></div><div><h3>Methods</h3><div>The impact of LRPPRC was assessed in CRC cells and a mouse xenograft model. The correlation between LRPPRC expression level and clinicopathological features was analyzed through immunohistochemical (IHC) staining on CRC tissue microarrays. LRPPRC-induced proliferation and angiogenesis were evaluated using immunoblotting, immunofluorescence, HUVEC-based tube formation, co-immunoprecipitation, and invasion assays. Gain-of-function experiments were performed to assess the function of LRPPRC in cell proliferation and angiogenesis.</div></div><div><h3>Results</h3><div>LRPPRC expression level was significantly upregulated in CRC tissues, and a higher LRPPRC expression level was associated with a progressive prognosis and poorer survival in CRC patients. The mouse xenograft model indicated that overexpression of LRPPRC significantly promoted CRC development via angiogenesis. Additionally, LRPPRC induced vascular endothelial growth factor (VEGF) expression level, and the restoration of VEGF rescued the angiogenesis suppression caused by LRPPRC knockdown. LRPPRC promoted the activation of hypoxia-inducible factor 1-alpha (HIF-1α) by interacting with it in CRC cells.</div></div><div><h3>Conclusion</h3><div>It was revealed that LRPPRC effectively promoted CRC growth and angiogenesis by activation of the HIF-1α/VEGF signaling pathway. The findings may provide a new treatment target and a potential prognostic biomarker for CRC development.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156223"},"PeriodicalIF":3.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060842","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":"Mechanistic signaling pathways of flavonoid-induced oral squamous cell carcinoma therapy: Clinical evidence and therapeutic application","authors":"Md. Zamshed Alam Begh ,&nbsp;Mehrukh Zehravi ,&nbsp;Jeetendra Kumar Gupta ,&nbsp;P. Balaji ,&nbsp;Ramana Gangireddy ,&nbsp;Venkata Ramana Singamaneni ,&nbsp;Patibandla Jahnavi ,&nbsp;Aditya Kumar ,&nbsp;I. Somasundaram ,&nbsp;Rajeshwar Vodeti ,&nbsp;Prem Shankar Gupta ,&nbsp;Rajasekhar Sreerama ,&nbsp;Abdullah D. Alotaibi ,&nbsp;Safia Obaidur Rab ,&nbsp;Talha Bin Emran","doi":"10.1016/j.prp.2025.156227","DOIUrl":"10.1016/j.prp.2025.156227","url":null,"abstract":"<div><div>Flavonoids, a class of plant-derived polyphenolic chemicals, are being explored as potential candidates for oral squamous cell carcinoma (OSCC) therapy due to their anti-cancer properties. The review explores flavonoids' potential therapeutic applications and their impact on OSCC, evaluating clinical evidence and investigating flavonoid-induced therapy mechanisms. Recent research focusing on experimental and clinical investigations has been thoroughly analyzed to understand the flavonoid mechanisms of action in OSCC. The review also evaluated the efficacy and safety of flavonoid therapy in treating angiogenesis, invasion, apoptosis, and cell proliferation through clinical trials and case studies. Flavonoids exhibit anti-cancer actions in OSCC by modulating essential cell growth and survival signaling pathways like PI3K/Akt, MAPK, and NF-κB. Furthermore, the study suggests that targeting matrix metalloproteinases and other factors can prevent cancer cell invasion and metastasis and induce apoptosis through intrinsic and extrinsic pathways. Flavonoids are promising therapies for treating OSCC due to their diverse modes of action, safety profile, and ability to impact critical cancer pathways. They can reduce side effects and improve patient outcomes. However, clinical trials reveal varied outcomes, necessitating further research to enhance patient selection, dosage, and formulation. Further mechanistic studies and clinical trials are needed to enhance their therapeutic efficacy.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156227"},"PeriodicalIF":3.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044818","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":"Peptidyl-prolyl isomerase PIN1 as a pivotal regulator of cancer progression and therapy","authors":"Ousman Bajinka ,&nbsp;Anastasia Rosebud Aikins ,&nbsp;Lamarana Jallow","doi":"10.1016/j.prp.2025.156221","DOIUrl":"10.1016/j.prp.2025.156221","url":null,"abstract":"<div><div>PIN1, a unique phosphorylation-dependent peptidyl-prolyl <em>cis-trans</em> isomerase, serves as a pivotal regulator of oncogenic signaling by catalyzing conformational changes in proteins phosphorylated at Ser/Thr-Pro motifs. Its overexpression across diverse cancers drives tumorigenesis by simultaneously inactivating tumor suppressors and activating oncogenes, thereby promoting uncontrolled proliferation, apoptosis evasion, genomic instability, epithelial-mesenchymal transition (EMT), metastasis, and therapy resistance. PIN1 critically regulates multiple cancer hallmarks via interactions with key pathways, including PI3K/Akt/mTOR, Wnt/β-catenin, NF-κB, and DNA repair machinery. Clinically, PIN1 overexpression correlates with advanced disease stage, poor prognosis, and therapeutic failure, underscoring its value as a prognostic biomarker. Recent breakthroughs in PIN1-targeted therapies demonstrate significant promise. This review aimed to explain PIN1's oncogenic roles and therapeutic targeting in cancer. Direct inhibitors and repurposed agents destabilize oncoproteins, induce \"BRCAness\" to sensitize tumors to PARP inhibitors, and reverse chemoresistance. Novel strategies, including peptide-based inhibitors and natural compounds, show enhanced selectivity and efficacy in preclinical models. However, challenges persist, including cancer-type heterogeneity in PIN1-driven mechanisms, on-target toxicity risks, and the need for bioavailable inhibitors. Future research must prioritize delineating common core pathways, structure-guided drug design, and biomarker-driven combination therapies. PIN1 inhibition represents a transformative approach to overcome resistance and improve outcomes across malignancies.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156221"},"PeriodicalIF":3.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041060","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":"Unraveling the gut-brain enigma: New frontiers in functional dyspepsia and gastroparesis","authors":"Huan Li ,&nbsp;Jianshe Chen ,&nbsp;Jianghong Hou","doi":"10.1016/j.prp.2025.156220","DOIUrl":"10.1016/j.prp.2025.156220","url":null,"abstract":"<div><div>Functional Dyspepsia and Gastroparesis present significant challenges in gastroenterology due to their overlapping symptoms and complex pathophysiology. This review explores recent advances in understanding these disorders, focusing on shared mechanisms involving gut-brain interactions, microbiome dysregulation, and immunological factors. We discuss evolving diagnostic techniques, including gastric emptying scintigraphy and novel approaches like wireless motility capsules. Management strategies encompass dietary modifications, pharmacological interventions targeting neuromodulation and motility, and emerging therapies such as microbiome modulation. Advanced interventions, including gastric electrical stimulation and endoscopic techniques, are examined for refractory cases. The review also highlights the potential of Traditional Chinese Medicine in addressing multiple aspects of Functional Dyspepsia and Gastroparesis. Despite progress, differentiating between these conditions remains challenging due to symptom overlap and variable gastric emptying patterns. We emphasize the need for a personalized, multidisciplinary approach to patient care and identify critical areas for future research, including standardization of diagnostic criteria and exploration of integrated gastroduodenal pathophysiology.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156220"},"PeriodicalIF":3.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060796","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":"METTL3 promotes ovarian cancer progression through YTHDF2-dependent degradation of GATA4","authors":"Di Zhao ,&nbsp;Mengya Li ,&nbsp;Peiling Li","doi":"10.1016/j.prp.2025.156224","DOIUrl":"10.1016/j.prp.2025.156224","url":null,"abstract":"<div><div>Ovarian cancer (OC) remains a highly lethal gynecological malignancy with limited therapeutic options due to its aggressive progression and therapeutic resistance. N6-methyladenosine (m6A) RNA modification has emerged as a critical regulator of tumorigenesis, but the specific mechanisms linking m6A regulators to OC progression require further clarification. Here, we report that METTL3 promotes OC progression by enhancing YTHDF2-dependent degradation of the tumor suppressor GATA4. Mechanistically, METTL3-mediated hypermethylation of GATA4 transcripts at nucleotides 1837 and 2432 promotes YTHDF2-dependent mRNA decay, thereby suppressing GATA4 expression. Pharmacological inhibition of METTL3 with STM2457 increases GATA4 abundance, and attenuates malignant phenotypes of OC. Single-cell RNA sequencing (scRNA-seq) revealed that GATA4 was markedly downregulated in granulosa cells, fibroblasts, and endothelial cells within the OC microenvironment, potentially linking its loss to aberrant epithelial-mesenchymal transition (EMT), abnormal proliferation, and stromal remodeling. In conclusion, our findings establish a METTL3-YTHDF2 regulatory axis that destabilizes GATA4 mRNA, providing novel insights into the epigenetic control of OC progression. Thus, targeting this axis may offer promising therapeutic strategies to improve outcomes for OC patients.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"275 ","pages":"Article 156224"},"PeriodicalIF":3.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044822","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}