Pub Date : 2026-01-20DOI: 10.1016/j.prp.2026.156375
Yaoxiong Xia, Jiazhu Wang, Dongmei Zhao, Yanli Li, Songqin Li, Man Li, Renyi Dong, Li Wang
Objective: This study aimed to investigate the function of KLF11 in regulating radiosensitivity (RT) in esophageal squamous cell carcinoma (ESCC) and to elucidate the underlying mechanisms.
Methods: A nude mouse ESCC xenograft model was established by injecting KYSE150 cells into the left dorsal flank. Cell proliferation was assessed using cell counting kit-8 (CCK-8) and colony formation assays, while DNA damage was evaluated via a neutral comet assay. Key gene and protein expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry. Additionally, coimmunoprecipitation and immunofluorescence were employed to validate proteinprotein interactions.
Results: KLF11 expression was upregulated in both ESCC and RT-resistant tissues. At the cellular level, KLF11 expression was higher in ESCC cell lines than in the normal esophageal epithelial cell line HET-1A, with the most pronounced upregulation in KYSE150 cells and the least in TE1 cells. Notably, KLF11 knockdown under ionizing radiation exposure suppressed proliferation and colony formation, promoted apoptosis, and increased the expression of the DNA damage marker γ-H2AX as well as overall DNA damage levels in KYSE150 cells. Conversely, KLF11 overexpression in TE1 cells led to the opposite phenotype, suggesting that KLF11 confers RT resistance in ESCC by mitigating DNA damage. Further investigations revealed that KLF11 primarily repairs RT-induced DNA damage through the homologous recombination (HR) pathway rather than through nonhomologous end joining (NHEJ). Additionally, the expression of MDM2, E2F1, and RAD51 was significantly elevated in ESCC and RT-resistant ESCC tissues. Mechanistically, KLF11 promotes MDM2 expression, which inhibits E2F1 ubiquitination, thereby stabilizing E2F1 protein levels and enhancing RAD51-mediated HR repair, ultimately leading to RT resistance in ESCC.
Conclusion: This study elucidates the critical role and molecular mechanism through which KLF11 drives radiotherapy resistance in ESCC by regulating the MDM2/E2F1 axis and enhancing HR repair, thereby providing a solid theoretical foundation and potential target for the development of KLF11-targeted radiosensitization therapies for ESCC.
{"title":"KLF11 interacts with MDM2 to stabilize E2F1 and promotes DNA damage repair to induce radioresistance in esophageal cancer cells.","authors":"Yaoxiong Xia, Jiazhu Wang, Dongmei Zhao, Yanli Li, Songqin Li, Man Li, Renyi Dong, Li Wang","doi":"10.1016/j.prp.2026.156375","DOIUrl":"https://doi.org/10.1016/j.prp.2026.156375","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the function of KLF11 in regulating radiosensitivity (RT) in esophageal squamous cell carcinoma (ESCC) and to elucidate the underlying mechanisms.</p><p><strong>Methods: </strong>A nude mouse ESCC xenograft model was established by injecting KYSE150 cells into the left dorsal flank. Cell proliferation was assessed using cell counting kit-8 (CCK-8) and colony formation assays, while DNA damage was evaluated via a neutral comet assay. Key gene and protein expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry. Additionally, coimmunoprecipitation and immunofluorescence were employed to validate proteinprotein interactions.</p><p><strong>Results: </strong>KLF11 expression was upregulated in both ESCC and RT-resistant tissues. At the cellular level, KLF11 expression was higher in ESCC cell lines than in the normal esophageal epithelial cell line HET-1A, with the most pronounced upregulation in KYSE150 cells and the least in TE1 cells. Notably, KLF11 knockdown under ionizing radiation exposure suppressed proliferation and colony formation, promoted apoptosis, and increased the expression of the DNA damage marker γ-H2AX as well as overall DNA damage levels in KYSE150 cells. Conversely, KLF11 overexpression in TE1 cells led to the opposite phenotype, suggesting that KLF11 confers RT resistance in ESCC by mitigating DNA damage. Further investigations revealed that KLF11 primarily repairs RT-induced DNA damage through the homologous recombination (HR) pathway rather than through nonhomologous end joining (NHEJ). Additionally, the expression of MDM2, E2F1, and RAD51 was significantly elevated in ESCC and RT-resistant ESCC tissues. Mechanistically, KLF11 promotes MDM2 expression, which inhibits E2F1 ubiquitination, thereby stabilizing E2F1 protein levels and enhancing RAD51-mediated HR repair, ultimately leading to RT resistance in ESCC.</p><p><strong>Conclusion: </strong>This study elucidates the critical role and molecular mechanism through which KLF11 drives radiotherapy resistance in ESCC by regulating the MDM2/E2F1 axis and enhancing HR repair, thereby providing a solid theoretical foundation and potential target for the development of KLF11-targeted radiosensitization therapies for ESCC.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"156375"},"PeriodicalIF":3.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143245","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 : 2026-01-20DOI: 10.1016/j.prp.2026.156377
Lijun Lou , Jing Li , Yan Li , Jiaming Feng , Jun Yu , Zeyu Wang , Chao Zhang , Liyu Chen , Yuanhang Zhao , Yongzhan Nie , Liyan Li , Yanglin Pan
Acute pancreatitis (AP) remains a significant clinical challenge lacking early, targeted pharmacological interventions to prevent disease progression. Dysfunctional autophagy is a central pathogenic mechanism in AP. While indomethacin (IND), a nonsteroidal anti-inflammatory drug, is known to prevent post-ERCP pancreatitis, its broader therapeutic potential and underlying mechanisms in other forms of AP are unclear. Emerging evidence suggests that IND has the potential to activate autophagy. This study aimed to investigate whether IND protects against AP by regulating autophagy. We established cerulein (CER)-induced AP models both in vivo and in AR42J cells to evaluate the protective effects of IND. Transcriptomic and pathway analyses were conducted to identify underlying signaling mechanisms. Our results demonstrate that IND alleviated CER-induced pancreatic injury, as indicated by improved histopathological scores, reduced serum amylase and lipase levels, diminished inflammatory cell infiltration, and attenuated acinar cell cytotoxicity. Mechanistically, transcriptomic and experimental data revealed that IND restored autophagy via activation of the AMP-activated protein kinase (AMPK) signaling pathway. Critically, the protective effects of IND were abolished by either the autophagy inhibitor chloroquine or the AMPK inhibitor Compound C (CC). In conclusion, our findings suggest that IND may serve as a promising therapeutic candidate for the treatment of AP.
{"title":"Indomethacin alleviates acute pancreatitis by restoring autophagic flux via the AMPK signaling pathway","authors":"Lijun Lou , Jing Li , Yan Li , Jiaming Feng , Jun Yu , Zeyu Wang , Chao Zhang , Liyu Chen , Yuanhang Zhao , Yongzhan Nie , Liyan Li , Yanglin Pan","doi":"10.1016/j.prp.2026.156377","DOIUrl":"10.1016/j.prp.2026.156377","url":null,"abstract":"<div><div>Acute pancreatitis (AP) remains a significant clinical challenge lacking early, targeted pharmacological interventions to prevent disease progression. Dysfunctional autophagy is a central pathogenic mechanism in AP. While indomethacin (IND), a nonsteroidal anti-inflammatory drug, is known to prevent post-ERCP pancreatitis, its broader therapeutic potential and underlying mechanisms in other forms of AP are unclear. Emerging evidence suggests that IND has the potential to activate autophagy. This study aimed to investigate whether IND protects against AP by regulating autophagy. We established cerulein (CER)-induced AP models both in vivo and in AR42J cells to evaluate the protective effects of IND. Transcriptomic and pathway analyses were conducted to identify underlying signaling mechanisms. Our results demonstrate that IND alleviated CER-induced pancreatic injury, as indicated by improved histopathological scores, reduced serum amylase and lipase levels, diminished inflammatory cell infiltration, and attenuated acinar cell cytotoxicity. Mechanistically, transcriptomic and experimental data revealed that IND restored autophagy via activation of the AMP-activated protein kinase (AMPK) signaling pathway. Critically, the protective effects of IND were abolished by either the autophagy inhibitor chloroquine or the AMPK inhibitor Compound C (CC). In conclusion, our findings suggest that IND may serve as a promising therapeutic candidate for the treatment of AP.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156377"},"PeriodicalIF":3.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078735","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 : 2026-01-20DOI: 10.1016/j.prp.2026.156376
Hui Zhou , Yayun Cui , Lailing Li
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality globally. Transcobalamin 1 (TCN1) is a driver associated with the progression of various cancers. However, the role of TCN1 in NSCLC remains elusive. The current research aimed to disclose the biological function and regulatory mechanisms of TCN1 in NSCLC. The expression pattern of TCN1 in NSCLC was first identified via qRT-PCR and western blotting. Functional assays including CCK-8, Transwell, Epithelial-mesenchymal transition (EMT), and glycolysis detection were performed to evaluate the effects of TCN1 on the malignant phenotype of NSCLC cells. Then LinkedOmics database and KEGG pathway analysis were employed to explore TCN1-mediated molecular pathways. Finally, the rescue tests were conducted to validated the underlying molecular mechanisms. Here, we observed that TCN1 was apparently overexpressed in NSCLC and predicted poor prognosis. TCN1 knockdown restrained the proliferation, metastasis, EMT, and glycolysis of NSCLC cells. Mechanism studies demonstrated that TCN1 positively regulated B3GNT3 level via activating the EGFR pathway. Knockdown of B3GNT3 also suppressed the malignant progression and glycolysis of NSCLC cells, and its overexpression partially rescued the effects of TCN1 knockdown. In vivo experiments presented that TCN1 knockdown attenuated tumor growth in the xenograft mouse model and downregulated B3GNT3 expression. Collectively, TCN1 overexpression aggravated NSCLC progression by regulating the expression of B3GNT3. The TCN1-B3GNT3 axis served a key part in the growth, migration, invasion, and glycolysis of NSCLC cells, making it a potential therapeutic target for NSCLC treatment.
{"title":"TCN1 knockdown inhibits the progression and glycolysis of non-small cell lung cancer via regulating B3GNT3","authors":"Hui Zhou , Yayun Cui , Lailing Li","doi":"10.1016/j.prp.2026.156376","DOIUrl":"10.1016/j.prp.2026.156376","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality globally. Transcobalamin 1 (TCN1) is a driver associated with the progression of various cancers. However, the role of TCN1 in NSCLC remains elusive. The current research aimed to disclose the biological function and regulatory mechanisms of TCN1 in NSCLC. The expression pattern of TCN1 in NSCLC was first identified via qRT-PCR and western blotting. Functional assays including CCK-8, Transwell, Epithelial-mesenchymal transition (EMT), and glycolysis detection were performed to evaluate the effects of TCN1 on the malignant phenotype of NSCLC cells. Then LinkedOmics database and KEGG pathway analysis were employed to explore TCN1-mediated molecular pathways. Finally, the rescue tests were conducted to validated the underlying molecular mechanisms. Here, we observed that TCN1 was apparently overexpressed in NSCLC and predicted poor prognosis. TCN1 knockdown restrained the proliferation, metastasis, EMT, and glycolysis of NSCLC cells. Mechanism studies demonstrated that TCN1 positively regulated B3GNT3 level via activating the EGFR pathway. Knockdown of B3GNT3 also suppressed the malignant progression and glycolysis of NSCLC cells, and its overexpression partially rescued the effects of TCN1 knockdown. In vivo experiments presented that TCN1 knockdown attenuated tumor growth in the xenograft mouse model and downregulated B3GNT3 expression. Collectively, TCN1 overexpression aggravated NSCLC progression by regulating the expression of B3GNT3. The TCN1-B3GNT3 axis served a key part in the growth, migration, invasion, and glycolysis of NSCLC cells, making it a potential therapeutic target for NSCLC treatment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156376"},"PeriodicalIF":3.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023921","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}
Tongue squamous cell carcinoma (SCC), the most common type of oral cancer, remains a major clinical challenge due to its aggressive behavior and poor prognosis in advanced stages. Standard treatments, including surgery, radiation therapy, and chemotherapy, provide limited benefit highlighting the need for novel therapeutic strategies. Recently, immunotherapy has emerged as a promising approach, largely through its ability to reshape the tumor microenvironment (TME). Increasing evidence indicates that chemokine signaling plays a critical role in tongue SCC by orchestrating the recruitment and function of immune regulatory cells. In particular, CC chemokine ligand 22 (CCL22), mainly produced by tumor-associated macrophages and dendritic cells, promotes the accumulation of CC chemokine receptor 4 (CCR4)–expressing regulatory T cells, consequently establishing an immunosuppressive TME and facilitating tumor progression and immune evasion. Furthermore, emerging studies suggest that histamine-related pathways within the TME can induce CCL22 expression, subsequently amplifying immunosuppressive feedback loops and further modulate tumor–immune interactions, although their precise roles in tongue SCC remain incompletely understood. A deeper understanding of these intertwined networks may uncover new therapeutic targets and enhance the efficacy of existing immunotherapies, including immune checkpoint inhibitors. This review provides an updated overview of the immune landscape of tongue SCC, with special emphasis on the CCL22–CCR4 axis and its interaction with histamine signaling. A deeper understanding of CCL22- and histamine-mediated pathways may contribute to the development of more effective and personalized immunotherapy strategies for tongue SCC.
{"title":"The role of CCL22 and its histamine-associated modulation in the tumor microenvironment of tongue squamous cell carcinoma","authors":"Satoshi Kimura , Shohei Shimajiri , Ayumi Nitta , Hiroaki Sato , Hirotsugu Noguchi , Toshiyuki Nakayama","doi":"10.1016/j.prp.2026.156373","DOIUrl":"10.1016/j.prp.2026.156373","url":null,"abstract":"<div><div>Tongue squamous cell carcinoma (SCC), the most common type of oral cancer, remains a major clinical challenge due to its aggressive behavior and poor prognosis in advanced stages. Standard treatments, including surgery, radiation therapy, and chemotherapy, provide limited benefit highlighting the need for novel therapeutic strategies. Recently, immunotherapy has emerged as a promising approach, largely through its ability to reshape the tumor microenvironment (TME). Increasing evidence indicates that chemokine signaling plays a critical role in tongue SCC by orchestrating the recruitment and function of immune regulatory cells. In particular, CC chemokine ligand 22 (CCL22), mainly produced by tumor-associated macrophages and dendritic cells, promotes the accumulation of CC chemokine receptor 4 (CCR4)–expressing regulatory T cells, consequently establishing an immunosuppressive TME and facilitating tumor progression and immune evasion. Furthermore, emerging studies suggest that histamine-related pathways within the TME can induce CCL22 expression, subsequently amplifying immunosuppressive feedback loops and further modulate tumor–immune interactions, although their precise roles in tongue SCC remain incompletely understood. A deeper understanding of these intertwined networks may uncover new therapeutic targets and enhance the efficacy of existing immunotherapies, including immune checkpoint inhibitors. This review provides an updated overview of the immune landscape of tongue SCC, with special emphasis on the CCL22–CCR4 axis and its interaction with histamine signaling. A deeper understanding of CCL22- and histamine-mediated pathways may contribute to the development of more effective and personalized immunotherapy strategies for tongue SCC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156373"},"PeriodicalIF":3.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023830","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}
Mucinous adenocarcinoma (MAC) of the colorectum is increasingly recognized as a subtype characterized by an immunosuppressive tumor microenvironment and poor response to immunotherapy, yet its immune and stromal landscape remains incompletely defined. In this study, we integrated three publicly available single-cell RNA sequencing datasets to comprehensively profile the cellular ecosystem of microsatellite-stable (MSS) MAC. Compared to classical adenocarcinoma (AC), MAC exhibited a distinct tumor microenvironment marked by elevated infiltration of myeloid and fibroblast populations, along with reduced lymphocyte and epithelial cell proportions. Notably, MAC harbored abundant immunosuppressive neutrophils that interacted intensively with interstitial resident tissue macrophage-like tumor-associated macrophages (RTM-TAMs) through IL1B–IL1R2 and CXCL8–CXCR2 signaling pathways, related to a pro-tumor myeloid network. Fibroblast analysis revealed a significant enrichment of VEGFA⁺ myofibroblastic cancer-associated fibroblasts (myCAFs), particularly in hypoxic, mucin-rich tumor regions, which were spatially associated with RTM-TAMs via SPP1–CD44/ITGA5/ITGB1 interactions. Leveraging cell-type-specific genes and key ligand–receptor pairs, we developed a Mucinous Colorectal cancer Immune Module (MCIM) comprising 18 genes, which stratified patient prognosis and was associated with overall survival in colorectal cancer cohorts. Together, these findings provide a detailed map of the immune-stromal architecture in MAC with MSS status, reveal macrophage-associated immunosuppressive features, and propose MCIM as a potential biomarker for prognostication in mucinous colorectal cancer.
{"title":"Macrophage-associated immune-stromal crosstalks correlate with the tumor microenvironment in microsatellite-stable mucinous colorectal cancer","authors":"Yinjun He , Tianneng Zhu , Mingyu Zheng , Qingxin Yu , Siqin Lei , Chaoyi Chen , Dianhe Yu , Zhiyong Liang , Honghe Zhang","doi":"10.1016/j.prp.2026.156371","DOIUrl":"10.1016/j.prp.2026.156371","url":null,"abstract":"<div><div>Mucinous adenocarcinoma (MAC) of the colorectum is increasingly recognized as a subtype characterized by an immunosuppressive tumor microenvironment and poor response to immunotherapy, yet its immune and stromal landscape remains incompletely defined. In this study, we integrated three publicly available single-cell RNA sequencing datasets to comprehensively profile the cellular ecosystem of microsatellite-stable (MSS) MAC. Compared to classical adenocarcinoma (AC), MAC exhibited a distinct tumor microenvironment marked by elevated infiltration of myeloid and fibroblast populations, along with reduced lymphocyte and epithelial cell proportions. Notably, MAC harbored abundant immunosuppressive neutrophils that interacted intensively with interstitial resident tissue macrophage-like tumor-associated macrophages (RTM-TAMs) through IL1B–IL1R2 and CXCL8–CXCR2 signaling pathways, related to a pro-tumor myeloid network. Fibroblast analysis revealed a significant enrichment of VEGFA⁺ myofibroblastic cancer-associated fibroblasts (myCAFs), particularly in hypoxic, mucin-rich tumor regions, which were spatially associated with RTM-TAMs via SPP1–CD44/ITGA5/ITGB1 interactions. Leveraging cell-type-specific genes and key ligand–receptor pairs, we developed a Mucinous Colorectal cancer Immune Module (MCIM) comprising 18 genes, which stratified patient prognosis and was associated with overall survival in colorectal cancer cohorts. Together, these findings provide a detailed map of the immune-stromal architecture in MAC with MSS status, reveal macrophage-associated immunosuppressive features, and propose MCIM as a potential biomarker for prognostication in mucinous colorectal cancer.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156371"},"PeriodicalIF":3.2,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011538","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 : 2026-01-16DOI: 10.1016/j.prp.2026.156370
Yuanhang Gong , Weilan Hu , Min Li
Proliferating cell nuclear antigen (PCNA) orchestrates DNA replication, repair, stress responses, and cell-cycle control. Because tumors are hyperproliferative and genomically unstable, they are highly dependent on PCNA, creating a therapeutic vulnerability. Strategies under evaluation include direct inhibition of PCNA, disruption of PCNA–partner interactions that govern DNA metabolism and cell-cycle progression, and combination regimens with DNA-damaging agents to enhance chemo- and radiosensitivity. Several agents—most notably the APIM peptide ATX-101 and the allosteric small molecule AOH1996—have progressed beyond preclinical testing and are being evaluated as monotherapies or in combination with radiotherapy and genotoxic chemotherapies in early clinical studies. This review synthesizes the mechanistic rationale, therapeutic modalities, and development landscape of PCNA-targeted interventions, highlighting their potential to improve anticancer efficacy while mitigating toxicity.
{"title":"Targeting the master of the replication fork—PCNA","authors":"Yuanhang Gong , Weilan Hu , Min Li","doi":"10.1016/j.prp.2026.156370","DOIUrl":"10.1016/j.prp.2026.156370","url":null,"abstract":"<div><div>Proliferating cell nuclear antigen (PCNA) orchestrates DNA replication, repair, stress responses, and cell-cycle control. Because tumors are hyperproliferative and genomically unstable, they are highly dependent on PCNA, creating a therapeutic vulnerability. Strategies under evaluation include direct inhibition of PCNA, disruption of PCNA–partner interactions that govern DNA metabolism and cell-cycle progression, and combination regimens with DNA-damaging agents to enhance chemo- and radiosensitivity. Several agents—most notably the APIM peptide ATX-101 and the allosteric small molecule AOH1996—have progressed beyond preclinical testing and are being evaluated as monotherapies or in combination with radiotherapy and genotoxic chemotherapies in early clinical studies. This review synthesizes the mechanistic rationale, therapeutic modalities, and development landscape of PCNA-targeted interventions, highlighting their potential to improve anticancer efficacy while mitigating toxicity.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156370"},"PeriodicalIF":3.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019283","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 : 2026-01-15DOI: 10.1016/j.prp.2026.156368
Jiuru Guo , Wenjian Zhao , Yaqin Hu , Chenchen Zhou , Haiyan Cao , Guolian Xue , Yueyang Mou , Zhicheng Fan , Yunpeng Kou , Peigang Ji , Min Chao , Liang Wang
Glioblastoma (GBM), the most prevalent primary brain tumor, is characterized by rapid proliferation, invasive growth patterns, and poor clinical outcomes. This study investigates the expression and clinical significance of DNA damage-binding protein 2(DDB2) in GBM, aiming to identify potential prognostic biomarkers and therapeutic targets. In this study, we demonstrated that DDB2 expression was negatively associated with patient prognosis in GBM patients. DDB2 knockdown inhibited the proliferation, invasion, and migration capacity of U87 and LN229 cells. In vivo, DDB2 knockdown inhibited the growth of xenograft tumors derived from inoculated GBM cells. DDB2 knockdown inhibited epithelial-mesenchymal transition (EMT) in U87 and LN229 cells. Mechanistically, DDB2 down-regulation led to the inhibition of nuclear translocation of P65 subunit, which inhibited the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and resulted in the reduced expression of EMT-related transcription factors. Taken together, the present study demonstrates that DDB2 promotes EMT by activating the NF-κB pathway in GBM. These findings provide new insights into the role of DDB2 in GBM, suggesting that DDB2 could serve as a potential therapeutic target and prognostic marker for this malignancy.
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，其特点是快速增殖、侵袭性生长模式和临床预后差。本研究探讨DNA损伤结合蛋白2（DNA damage-binding protein 2, DDB2）在GBM中的表达及其临床意义，旨在寻找潜在的预后生物标志物和治疗靶点。在本研究中，我们证明了DDB2的表达与GBM患者的预后呈负相关。DDB2敲低抑制了U87和LN229细胞的增殖、侵袭和迁移能力。在体内，DDB2敲低抑制了由接种的GBM细胞衍生的异种移植肿瘤的生长。DDB2敲低抑制了U87和LN229细胞的上皮-间质转化（EMT）。机制上，DDB2下调导致P65亚基核易位抑制，从而抑制活化B细胞核因子κB轻链增强子（NF-κB）信号通路的激活，导致emt相关转录因子的表达减少。综上所述，本研究表明DDB2通过激活GBM中的NF-κB通路来促进EMT。这些发现为DDB2在GBM中的作用提供了新的见解，表明DDB2可以作为这种恶性肿瘤的潜在治疗靶点和预后标志物。
{"title":"DDB2 promotes epithelial-mesenchymal transition through activating NF-κB pathway in glioma","authors":"Jiuru Guo , Wenjian Zhao , Yaqin Hu , Chenchen Zhou , Haiyan Cao , Guolian Xue , Yueyang Mou , Zhicheng Fan , Yunpeng Kou , Peigang Ji , Min Chao , Liang Wang","doi":"10.1016/j.prp.2026.156368","DOIUrl":"10.1016/j.prp.2026.156368","url":null,"abstract":"<div><div>Glioblastoma (GBM), the most prevalent primary brain tumor, is characterized by rapid proliferation, invasive growth patterns, and poor clinical outcomes. This study investigates the expression and clinical significance of DNA damage-binding protein 2(DDB2) in GBM, aiming to identify potential prognostic biomarkers and therapeutic targets. In this study, we demonstrated that DDB2 expression was negatively associated with patient prognosis in GBM patients. DDB2 knockdown inhibited the proliferation, invasion, and migration capacity of U87 and LN229 cells. In vivo, DDB2 knockdown inhibited the growth of xenograft tumors derived from inoculated GBM cells. DDB2 knockdown inhibited epithelial-mesenchymal transition (EMT) in U87 and LN229 cells. Mechanistically, DDB2 down-regulation led to the inhibition of nuclear translocation of P65 subunit, which inhibited the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and resulted in the reduced expression of EMT-related transcription factors. Taken together, the present study demonstrates that DDB2 promotes EMT by activating the NF-κB pathway in GBM. These findings provide new insights into the role of DDB2 in GBM, suggesting that DDB2 could serve as a potential therapeutic target and prognostic marker for this malignancy.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156368"},"PeriodicalIF":3.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023919","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 : 2026-01-15DOI: 10.1016/j.prp.2026.156365
Siyi Ou , Xiaobo Wang , Yulan Sun , Yongfeng Liang , Jing Bai , Chuanchun Han , Jing Song
Brusatol (BRU), an extract from Brucea javanica, has been found to inhibit cancer progression. However, the downstream targets of Brusatol and its underlying mechanisms in lung cancer still not fully elucidate and warrant further investigation. Here, we identified that Brusatol significantly downregulated the mRNA and protein levels of phosphoserine aminotransferase 1 (PSAT1). Notably, overexpression of PAST1 could impair the antitumour effects of Brusatol on lung cancer cells in vitro and in vivo. Further mechanism studies revealed that FOXM1, an important transcription factor, was directly bound to the promoter of PSAT1, facilitating its transcription. Besides, FOXM1 upregulation antagonizes Brusatol’s suppression of PSAT1 and sustains tumor cell viability. Collectively, our data suggested that the FOXM1/PSAT1 axis might play an important role in the antitumour effects of Brusatol and that Brusatol may hold promise as a novel therapeutic strategy for lung cancer.
{"title":"Targeting FOXM1/PSAT1 axis by Brusatol inhibits lung cancer malignant progression","authors":"Siyi Ou , Xiaobo Wang , Yulan Sun , Yongfeng Liang , Jing Bai , Chuanchun Han , Jing Song","doi":"10.1016/j.prp.2026.156365","DOIUrl":"10.1016/j.prp.2026.156365","url":null,"abstract":"<div><div>Brusatol (BRU), an extract from Brucea javanica, has been found to inhibit cancer progression. However, the downstream targets of Brusatol and its underlying mechanisms in lung cancer still not fully elucidate and warrant further investigation. Here, we identified that Brusatol significantly downregulated the mRNA and protein levels of phosphoserine aminotransferase 1 (PSAT1). Notably, overexpression of PAST1 could impair the antitumour effects of Brusatol on lung cancer cells in vitro and in vivo. Further mechanism studies revealed that FOXM1, an important transcription factor, was directly bound to the promoter of PSAT1, facilitating its transcription. Besides, FOXM1 upregulation antagonizes Brusatol’s suppression of PSAT1 and sustains tumor cell viability. Collectively, our data suggested that the FOXM1/PSAT1 axis might play an important role in the antitumour effects of Brusatol and that Brusatol may hold promise as a novel therapeutic strategy for lung cancer.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156365"},"PeriodicalIF":3.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980042","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 : 2026-01-15DOI: 10.1016/j.prp.2026.156364
Qing Zhu , Ao Zhang , Yang Gao , Zhenzhong Feng , Nan Li , Qiang Wu
Serine/arginine-rich splicing factor 1 (SRSF1) is a pre-mRNA-splicing factor functioning as an oncogene in multiple cancers. However, the biological roles of SRSF1 in endometrial cancer (EC) have not been explored. Here we demonstrated its pivotal function and the regulatory mechanism in regulating ferroptosis and glycolysis in EC. Results showed that SRSF1 inhibited ferroptosis in EC cells, indicated by decreased cell death rate, lipid peroxidation and Fe2 + concentration. SRSF1 accelerated glycolysis in EC cells, evidenced by enhanced glucose uptake, lactate production and adenosine triphosphate production. Mechanistically, SRSF1 elevated the levels of phosphorylated mTOR and β-catenin in EC cells. Besides, the regulation of glycolytic enzyme proteins by SRSF1 in EC cells was dependent on mTOR and β-catenin. Furthermore, rescue assays unveiled that mTOR, β-catenin, and glycolysis involved in the regulatory function of SRSF1 on ferroptosis in EC cells. Finally, animal study proved that SRSF1 knockdown restrained in vivo tumor growth and potentiated the antitumor efficacy of ferroptosis inducer through glycolysis inhibition. In conclusion, the present study uncovered that SRSF1 acts as a tumor promoter in EC through activating mTOR and β-catenin to inhibit ferroptosis and facilitate glycolysis, proposing a therapeutic target for EC.
{"title":"Serine/arginine-rich splicing factor 1 inhibits ferroptosis and promotes glycolysis in endometrial cancer via activating mTOR and β-catenin","authors":"Qing Zhu , Ao Zhang , Yang Gao , Zhenzhong Feng , Nan Li , Qiang Wu","doi":"10.1016/j.prp.2026.156364","DOIUrl":"10.1016/j.prp.2026.156364","url":null,"abstract":"<div><div>Serine/arginine-rich splicing factor 1 (SRSF1) is a pre-mRNA-splicing factor functioning as an oncogene in multiple cancers. However, the biological roles of SRSF1 in endometrial cancer (EC) have not been explored. Here we demonstrated its pivotal function and the regulatory mechanism in regulating ferroptosis and glycolysis in EC. Results showed that SRSF1 inhibited ferroptosis in EC cells, indicated by decreased cell death rate, lipid peroxidation and Fe<sup>2 +</sup> concentration. SRSF1 accelerated glycolysis in EC cells, evidenced by enhanced glucose uptake, lactate production and adenosine triphosphate production. Mechanistically, SRSF1 elevated the levels of phosphorylated mTOR and β-catenin in EC cells. Besides, the regulation of glycolytic enzyme proteins by SRSF1 in EC cells was dependent on mTOR and β-catenin. Furthermore, rescue assays unveiled that mTOR, β-catenin, and glycolysis involved in the regulatory function of SRSF1 on ferroptosis in EC cells. Finally, animal study proved that SRSF1 knockdown restrained <em>in vivo</em> tumor growth and potentiated the antitumor efficacy of ferroptosis inducer through glycolysis inhibition. In conclusion, the present study uncovered that SRSF1 acts as a tumor promoter in EC through activating mTOR and β-catenin to inhibit ferroptosis and facilitate glycolysis, proposing a therapeutic target for EC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156364"},"PeriodicalIF":3.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019122","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 : 2026-01-15DOI: 10.1016/j.prp.2026.156367
Janavie Patel, Siddhi Bagwe Parab, Gaurav M. Doshi
One of the main causes of chronic kidney disease (CKD), ischemic nephropathy, is brought on by maladaptive cellular stress responses, specifically endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signalling, in addition to vascular insufficiency. The primary goals of UPR activation via the Protein kinase R-like ER kinase (PERK), Inositol-requiring enzyme 1 (IRE1), and Activating Transcription Factor 6 (ATF6) pathways are to support renal tubular cell survival and restore proteostasis. Prolonged or severe ER stress, on the other hand, causes the UPR to shift toward pathogenic outcomes by triggering apoptotic (C/EBP homologous protein [CHOP], caspase-12), inflammatory (c-Jun N-terminal Kinase [JNK], nuclear factor kappa B [NF-κB]), and fibrotic (transforming growth factor-beta [TGF-β]/SMAD) cascades that lead to progressive renal dysfunction, tubular atrophy, and interstitial fibrosis. Furthermore, ER-mitochondria crosstalk connects acute ischemia injury to chronic fibrosis by exacerbating mitochondrial failure, oxidative stress, and cell death. Targeting therapy requires an understanding of the UPR's dual nature, which is beneficial during brief stress but harmful during prolonged ischemia. Promising approaches to maintain kidney function include interventions that alter particular UPR branches, improve autophagy, lower oxidative damage, and restore ER equilibrium. In addition to outlining the molecular bases of ER stress and UPR in ischemic nephropathy, this review suggests innovative therapeutic strategies meant to shift the equilibrium from maladaptive to adaptive stress responses, providing novel possibilities to slow or alter the course of CKD. This review aims to critically evaluate the molecular mechanisms of ER stress and the UPR in ischemic nephropathy, with a focus on identifying potential therapeutic strategies to preserve renal function and slow CKD progression.
慢性肾脏疾病（CKD）的主要原因之一，缺血性肾病，是由不适应的细胞应激反应，特别是内质网（ER）应激和未折叠蛋白反应（UPR）信号，以及血管功能不全引起的。UPR通过蛋白激酶r -样ER激酶（PERK）、肌醇要求酶1 （IRE1）和激活转录因子6 （ATF6）途径激活的主要目的是支持肾小管细胞存活和恢复蛋白质稳态。另一方面，长期或严重的内质网应激会通过触发凋亡（C/EBP同源蛋白[CHOP]、caspase-12）、炎症（C - jun n -末端激酶[JNK]、核因子κB [NF-κB]）和纤维化（转化生长因子-β [TGF-β]/SMAD）级联反应导致进行性肾功能障碍、肾小管萎缩和间质纤维化，从而导致UPR向致病结果转变。此外，er -线粒体串扰通过加剧线粒体衰竭、氧化应激和细胞死亡将急性缺血损伤与慢性纤维化联系起来。靶向治疗需要了解UPR的双重性质，它在短暂应激时是有益的，但在长时间缺血时是有害的。维持肾功能的有希望的方法包括干预改变特定的UPR分支，改善自噬，降低氧化损伤和恢复内质网平衡。除了概述缺血性肾病中内质网应激和UPR的分子基础外，本综述还提出了创新的治疗策略，旨在将平衡从适应不良转变为适应应激反应，为减缓或改变CKD的进程提供新的可能性。这篇综述旨在批判性地评估内质网应激和UPR在缺血性肾病中的分子机制，重点是确定潜在的治疗策略，以保持肾功能和减缓CKD的进展。
{"title":"Endoplasmic reticulum stress and the unfolded protein response in ischemic nephropathy: Pathogenic mechanisms and emerging therapeutic strategies","authors":"Janavie Patel, Siddhi Bagwe Parab, Gaurav M. Doshi","doi":"10.1016/j.prp.2026.156367","DOIUrl":"10.1016/j.prp.2026.156367","url":null,"abstract":"<div><div>One of the main causes of chronic kidney disease (CKD), ischemic nephropathy, is brought on by maladaptive cellular stress responses, specifically endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signalling, in addition to vascular insufficiency. The primary goals of UPR activation via the Protein kinase R-like ER kinase (PERK), Inositol-requiring enzyme 1 (IRE1), and Activating Transcription Factor 6 (ATF6) pathways are to support renal tubular cell survival and restore proteostasis. Prolonged or severe ER stress, on the other hand, causes the UPR to shift toward pathogenic outcomes by triggering apoptotic (C/EBP homologous protein [CHOP], caspase-12), inflammatory (c-Jun N-terminal Kinase [JNK], nuclear factor kappa B [NF-κB]), and fibrotic (transforming growth factor-beta [TGF-β]/SMAD) cascades that lead to progressive renal dysfunction, tubular atrophy, and interstitial fibrosis. Furthermore, ER-mitochondria crosstalk connects acute ischemia injury to chronic fibrosis by exacerbating mitochondrial failure, oxidative stress, and cell death. Targeting therapy requires an understanding of the UPR's dual nature, which is beneficial during brief stress but harmful during prolonged ischemia. Promising approaches to maintain kidney function include interventions that alter particular UPR branches, improve autophagy, lower oxidative damage, and restore ER equilibrium. In addition to outlining the molecular bases of ER stress and UPR in ischemic nephropathy, this review suggests innovative therapeutic strategies meant to shift the equilibrium from maladaptive to adaptive stress responses, providing novel possibilities to slow or alter the course of CKD. This review aims to critically evaluate the molecular mechanisms of ER stress and the UPR in ischemic nephropathy, with a focus on identifying potential therapeutic strategies to preserve renal function and slow CKD progression.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156367"},"PeriodicalIF":3.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980041","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