Pub Date : 2026-02-01Epub Date: 2025-12-01DOI: 10.1016/j.prp.2025.156312
Zhiheng He , Linjie Zhao , Jiarui Liu , Wanjie Zheng , Chengjun Gong , Chengxuan Gong , Li Guo , Tingming Liang
Adipokines are bioactive signaling molecules secreted by adipose tissue that play crucial roles in the regulation of energy metabolism and inflammatory responses. With the global rise in obesity and related metabolic disorders, understanding adipokine-mediated regulation has become increasingly important for addressing chronic inflammation and its systemic consequences. However, the adipokine-mediated crosstalk between metabolic dysregulation and inflammatory pathways remains incompletely understood. Beyond classical adipokines, adipose tissue-derived microRNAs (miRNAs) have been identified as novel paracrine and endocrine signaling molecules, capable of modulating distant cellular functions through exosome-mediated transport. These extracellular vesicle-encapsulated miRNAs are increasingly recognized as key regulators in inter-organ communication and disease development. This review summarizes the current understanding of adipokine secretion mechanisms, roles in metabolic and inflammatory regulation, and the dual functions in both metabolic diseases and cancer. Emerging therapeutic strategies focusing on targeting adipokines and the signaling pathways downstream are also discussed, highlighting the translational potential of adipokines as promising biomarkers and therapeutic targets for the prevention and treatment of metabolic diseases and cancer.
{"title":"Adipokine-mediated crosstalk between metabolic dysregulation and inflammatory pathways","authors":"Zhiheng He , Linjie Zhao , Jiarui Liu , Wanjie Zheng , Chengjun Gong , Chengxuan Gong , Li Guo , Tingming Liang","doi":"10.1016/j.prp.2025.156312","DOIUrl":"10.1016/j.prp.2025.156312","url":null,"abstract":"<div><div>Adipokines are bioactive signaling molecules secreted by adipose tissue that play crucial roles in the regulation of energy metabolism and inflammatory responses. With the global rise in obesity and related metabolic disorders, understanding adipokine-mediated regulation has become increasingly important for addressing chronic inflammation and its systemic consequences. However, the adipokine-mediated crosstalk between metabolic dysregulation and inflammatory pathways remains incompletely understood. Beyond classical adipokines, adipose tissue-derived microRNAs (miRNAs) have been identified as novel paracrine and endocrine signaling molecules, capable of modulating distant cellular functions through exosome-mediated transport. These extracellular vesicle-encapsulated miRNAs are increasingly recognized as key regulators in inter-organ communication and disease development. This review summarizes the current understanding of adipokine secretion mechanisms, roles in metabolic and inflammatory regulation, and the dual functions in both metabolic diseases and cancer. Emerging therapeutic strategies focusing on targeting adipokines and the signaling pathways downstream are also discussed, highlighting the translational potential of adipokines as promising biomarkers and therapeutic targets for the prevention and treatment of metabolic diseases and cancer.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156312"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652025","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 : 2026-02-01Epub Date: 2025-12-04DOI: 10.1016/j.prp.2025.156313
Wanlun Wang , Si Wu , Jie Luo , Jiale Ji , Jianhua Dai , Senlin Xu
Gastric cardiac carcinoma associated with dysplastic gastritis cystica profunda (GCP) with represents a rare clinicopathological entity. Its distinct histological features pose diagnostic challenges, as GCP with mild dysplasia can mimic invasive carcinoma, potentially leading to overdiagnosis, overtreatment, and increased patient morbidity. We report a case of early gastric cardiac carcinoma with dysplastic GCP, treated by endoscopic submucosal dissection (ESD). Histopathological examination revealed a moderately differentiated tubular adenocarcinoma confined to the mucosa, adjacent to submucosal cystic glands exhibiting mild dysplasia, cystic dilation, abundant mucin secretion, and focal mucin pools. Immunohistochemically, the carcinoma was positive for CK7 but negative for MUC2 and MUC5AC, while the cystic glands showed the opposite profile. The Ki67 proliferative index was significantly lower in the cystic glands than in the carcinoma. The final diagnosis was intramucosal moderately differentiated adenocarcinoma of the gastric cardia with mildly dysplastic GCP. No recurrence was observed during the 12-month follow-up. This case highlights the diagnostic pitfalls of this entity, and underscores the importance of accurate pathological recognition to guide clinical management.
{"title":"Clinicopathological features and diagnostic challenges of early gastric cardiac carcinoma with dysplastic gastritis cystica profunda: A case report","authors":"Wanlun Wang , Si Wu , Jie Luo , Jiale Ji , Jianhua Dai , Senlin Xu","doi":"10.1016/j.prp.2025.156313","DOIUrl":"10.1016/j.prp.2025.156313","url":null,"abstract":"<div><div>Gastric cardiac carcinoma associated with dysplastic gastritis cystica profunda (GCP) with represents a rare clinicopathological entity. Its distinct histological features pose diagnostic challenges, as GCP with mild dysplasia can mimic invasive carcinoma, potentially leading to overdiagnosis, overtreatment, and increased patient morbidity. We report a case of early gastric cardiac carcinoma with dysplastic GCP, treated by endoscopic submucosal dissection (ESD). Histopathological examination revealed a moderately differentiated tubular adenocarcinoma confined to the mucosa, adjacent to submucosal cystic glands exhibiting mild dysplasia, cystic dilation, abundant mucin secretion, and focal mucin pools. Immunohistochemically, the carcinoma was positive for CK7 but negative for MUC2 and MUC5AC, while the cystic glands showed the opposite profile. The Ki67 proliferative index was significantly lower in the cystic glands than in the carcinoma. The final diagnosis was intramucosal moderately differentiated adenocarcinoma of the gastric cardia with mildly dysplastic GCP. No recurrence was observed during the 12-month follow-up. This case highlights the diagnostic pitfalls of this entity, and underscores the importance of accurate pathological recognition to guide clinical management.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156313"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743712","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 : 2026-02-01Epub Date: 2025-12-25DOI: 10.1016/j.prp.2025.156343
Hao Cheng , Suzeng Wang , Chunyu Yang , Feiyu Qin , Mengyuan Qian , Heyuan Jia , Kaiqing Wang , Surui Yao , Zhaohui Huang , Bojian Fei
RAB18 (Ras-related protein Rab-18) plays a crucial role in diverse cellular processes including autophagy, secretion and lipid droplet biogenesis. Recent studies suggest that RAB18 participates in tumorigenesis and progression. However, its role in colorectal cancer (CRC) is unclear. In this study, we observed significantly increased RAB18 expression in CRC tissues compared with paired normal tissues, which was associated with poor prognosis. RAB18 knockdown significantly inhibited cell proliferation, cell cycle progression, migration and invasion in CRC cells. Moreover, silencing RAB18 expression suppressed tumorigenesis in a mouse xenografted CRC model. Mechanistically, RNA-seq and pathway enrichment analyses suggested that RAB18 knockdown induced p53 pathway activation and decreased levels of E2F Targets and G2M checkpoint genes. Further validation identified stratifin (SFN) and mouse double minute 2 (MDM2) as potential downstream mediators of RAB18’s pro-tumorigenic effects in CRC. Collectively, our findings demonstrate the oncogenic role of RAB18 in CRC and highlight its potential as both a prognostic biomarker and a therapeutic target.
{"title":"RAB18 is upregulated in colorectal cancer and promotes tumor progression.","authors":"Hao Cheng , Suzeng Wang , Chunyu Yang , Feiyu Qin , Mengyuan Qian , Heyuan Jia , Kaiqing Wang , Surui Yao , Zhaohui Huang , Bojian Fei","doi":"10.1016/j.prp.2025.156343","DOIUrl":"10.1016/j.prp.2025.156343","url":null,"abstract":"<div><div>RAB18 (Ras-related protein Rab-18) plays a crucial role in diverse cellular processes including autophagy, secretion and lipid droplet biogenesis. Recent studies suggest that RAB18 participates in tumorigenesis and progression. However, its role in colorectal cancer (CRC) is unclear. In this study, we observed significantly increased RAB18 expression in CRC tissues compared with paired normal tissues, which was associated with poor prognosis. RAB18 knockdown significantly inhibited cell proliferation, cell cycle progression, migration and invasion in CRC cells. Moreover, silencing RAB18 expression suppressed tumorigenesis in a mouse xenografted CRC model. Mechanistically, RNA-seq and pathway enrichment analyses suggested that RAB18 knockdown induced p53 pathway activation and decreased levels of E2F Targets and G2M checkpoint genes. Further validation identified stratifin (SFN) and mouse double minute 2 (MDM2) as potential downstream mediators of RAB18’s pro-tumorigenic effects in CRC. Collectively, our findings demonstrate the oncogenic role of RAB18 in CRC and highlight its potential as both a prognostic biomarker and a therapeutic target.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156343"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145863240","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 : 2026-02-01Epub Date: 2025-12-23DOI: 10.1016/j.prp.2025.156344
Shangtong Hu , Chunxiu Hu , Minfeng Tong
Mitochondrial-derived microproteins (MDPs) translate mitochondrial stress into cellular decisions that shape aging, metabolism, cancer biology, and neurodegeneration. Humanin, MOTS-c, SHLPs, and the recently identified SHMOOSE act through distinct intracellular and receptor-mediated pathways to regulate apoptosis, nutrient sensing, redox balance, and mito-nuclear communication. These programs confer neuroprotection in post-mitotic tissues but can be co-opted by tumors for survival, invasion, and therapy resistance, helping explain the inverse comorbidity between cancer and Alzheimer’s disease. This review synthesizes the divergent signaling architectures of major MDPs, including Humanin-FPR2/gp130, MOTS-c-AMPK/NRF2-LARS1/mTORC1, SHLP2-CXCR7, and SHMOOSE’s genotype-dependent activity, and outlines how these mechanisms produce disease-specific outcomes. Recent advances in mitoribosome profiling, DIA-based proteogenomics, and mitochondrial base editing have accelerated the discovery and functional characterization of MDPs. Emerging translational opportunities include MDP-targeted agonists, antagonists, and engineered delivery systems designed for application in neurodegenerative disorders and cancer. Overall, MDPs represent a druggable signaling layer whose context-dependent effects can be selectively directed across diseases.
{"title":"Mitochondrial-derived microproteins in cancer and neurodegeneration: A new era of cross-disease mechanistic insights","authors":"Shangtong Hu , Chunxiu Hu , Minfeng Tong","doi":"10.1016/j.prp.2025.156344","DOIUrl":"10.1016/j.prp.2025.156344","url":null,"abstract":"<div><div>Mitochondrial-derived microproteins (MDPs) translate mitochondrial stress into cellular decisions that shape aging, metabolism, cancer biology, and neurodegeneration. Humanin, MOTS-c, SHLPs, and the recently identified SHMOOSE act through distinct intracellular and receptor-mediated pathways to regulate apoptosis, nutrient sensing, redox balance, and mito-nuclear communication. These programs confer neuroprotection in post-mitotic tissues but can be co-opted by tumors for survival, invasion, and therapy resistance, helping explain the inverse comorbidity between cancer and Alzheimer’s disease. This review synthesizes the divergent signaling architectures of major MDPs, including Humanin-FPR2/gp130, MOTS-c-AMPK/NRF2-LARS1/mTORC1, SHLP2-CXCR7, and SHMOOSE’s genotype-dependent activity, and outlines how these mechanisms produce disease-specific outcomes. Recent advances in mitoribosome profiling, DIA-based proteogenomics, and mitochondrial base editing have accelerated the discovery and functional characterization of MDPs. Emerging translational opportunities include MDP-targeted agonists, antagonists, and engineered delivery systems designed for application in neurodegenerative disorders and cancer. Overall, MDPs represent a druggable signaling layer whose context-dependent effects can be selectively directed across diseases.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156344"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864794","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 : 2026-02-01Epub Date: 2025-12-20DOI: 10.1016/j.prp.2025.156340
Xiongjie He , Tilong Huang , Ai Yang , Yafang Li , Liping Bai , Yanmei Chen , Jie Bai , Xianwen Zhang
Parkinson’s disease (PD) is a neurodegenerative disorder marked by the accumulation of alpha-synuclein protein within dopamine-producing neurons and their consequent death. Although the specific etiology of PD remains unclear, emerging evidences suggest that disrupted neurogenesis plays a crucial role in pathophysiology of PD. Neurogenesis has a regenerative effect and is a promising therapeutic target for PD. Recent studies demonstrated that impaired neurogenesis in the subventricular zone (SVZ), hippocampus (HIP) and substantia nigra (SN) contributed to motor/nonmotor deficits in PD. However, the precise correlation between the pathogenesis of PD and neurogenesis remains to be explored. This study aimed to investigate the role of the dopaminergic signaling pathway, neurotrophic factors, gut microbiota, neuroinflammation, and mutations in PD-related genes in adult neurogenesis in PD. First, a comprehensive review of recent studies was carried out to explore how neurogenesis impacts PD pathophysiology. Then, the challenges and future perspectives associated with promoting endogenous neurogenesis to compensate for the loss of dopaminergic neurons in PD were investigated. The study offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. Furthermore, it offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. This article also emphasizes the importance of the precise manipulation of neurogenesis in PD with the aim of promoting the translation of these findings into clinical treatment.
{"title":"Adult neurogenesis dysfunction in Parkinson’s disease: Molecular pathology and functional implications","authors":"Xiongjie He , Tilong Huang , Ai Yang , Yafang Li , Liping Bai , Yanmei Chen , Jie Bai , Xianwen Zhang","doi":"10.1016/j.prp.2025.156340","DOIUrl":"10.1016/j.prp.2025.156340","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is a neurodegenerative disorder marked by the accumulation of alpha-synuclein protein within dopamine-producing neurons and their consequent death. Although the specific etiology of PD remains unclear, emerging evidences suggest that disrupted neurogenesis plays a crucial role in pathophysiology of PD. Neurogenesis has a regenerative effect and is a promising therapeutic target for PD. Recent studies demonstrated that impaired neurogenesis in the subventricular zone (SVZ), hippocampus (HIP) and substantia nigra (SN) contributed to motor/nonmotor deficits in PD. However, the precise correlation between the pathogenesis of PD and neurogenesis remains to be explored. This study aimed to investigate the role of the dopaminergic signaling pathway, neurotrophic factors, gut microbiota, neuroinflammation, and mutations in PD-related genes in adult neurogenesis in PD. First, a comprehensive review of recent studies was carried out to explore how neurogenesis impacts PD pathophysiology. Then, the challenges and future perspectives associated with promoting endogenous neurogenesis to compensate for the loss of dopaminergic neurons in PD were investigated. The study offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. Furthermore, it offers promising therapeutic strategies to activate the endogenous neurogenesis in PD. This article also emphasizes the importance of the precise manipulation of neurogenesis in PD with the aim of promoting the translation of these findings into clinical treatment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156340"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820492","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 : 2026-02-01Epub Date: 2025-12-17DOI: 10.1016/j.prp.2025.156333
Jinlin Wang , Kai Zhang , Chen Zheng , Xiao Chen
Background
m6A modification is important in cancer progression. In the research, we explored the functions and mechanisms of WTAP (the key component of m6A) in HCC.
Methods
Expression of WTAP and ITGB4 was examined by qRT-PCR, western blot and IHC assays. Tumor cell proliferation, apoptosis, metastasis and stemness were investigated via colony formation, flow cytometry, transwell and sphere formation assays. The interaction between WTAP and ITGB4 was estimated by RIP, meRIP and dual-luciferase reporter experiments.
Results
ITGB4 was upregulated in HCC. Knockdown of ITGB4 repressed HCC cell growth, motility and stemness, accelerated HCC cell apoptosis in vitro, and blocked tumorigenesis in vivo. Through SRAMP website and a series experiments, WTAP catalysed m6A modification on ITGB4 mRNA, recognized by the reader YTHDF1, leading to increased mRNA stability. WTAP overexpression aggravated the malignant behaviors and stemness of HCC cells, with ITGB4 deficiency abrogated the effects. In addition, we demonstrated that WTAP could activate FAK/PI3K/AKT signaling pathway via regulating ITGB4 expression.
Conclusion
WTAP mediated the m6A methylation modification of ITGB4 to promote HCC progression and tumor stemness, providing a new idea for HCC therapy.
{"title":"WTAP contributes to the malignancy and stemness of hepatocellular carcinoma through upregulating N6-methyladenosine modification of ITGB4","authors":"Jinlin Wang , Kai Zhang , Chen Zheng , Xiao Chen","doi":"10.1016/j.prp.2025.156333","DOIUrl":"10.1016/j.prp.2025.156333","url":null,"abstract":"<div><h3>Background</h3><div>m6A modification is important in cancer progression. In the research, we explored the functions and mechanisms of WTAP (the key component of m6A) in HCC.</div></div><div><h3>Methods</h3><div>Expression of WTAP and ITGB4 was examined by qRT-PCR, western blot and IHC assays. Tumor cell proliferation, apoptosis, metastasis and stemness were investigated via colony formation, flow cytometry, transwell and sphere formation assays. The interaction between WTAP and ITGB4 was estimated by RIP, meRIP and dual-luciferase reporter experiments.</div></div><div><h3>Results</h3><div>ITGB4 was upregulated in HCC. Knockdown of ITGB4 repressed HCC cell growth, motility and stemness, accelerated HCC cell apoptosis <em>in vitro</em>, and blocked tumorigenesis <em>in vivo</em>. Through SRAMP website and a series experiments, WTAP catalysed m6A modification on ITGB4 mRNA, recognized by the reader YTHDF1, leading to increased mRNA stability. WTAP overexpression aggravated the malignant behaviors and stemness of HCC cells, with ITGB4 deficiency abrogated the effects. In addition, we demonstrated that WTAP could activate FAK/PI3K/AKT signaling pathway via regulating ITGB4 expression.</div></div><div><h3>Conclusion</h3><div>WTAP mediated the m6A methylation modification of ITGB4 to promote HCC progression and tumor stemness, providing a new idea for HCC therapy.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156333"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840857","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 : 2026-02-01Epub Date: 2025-12-11DOI: 10.1016/j.prp.2025.156330
Peng Yu , Chen‑xi Li , Zhi‑qiang Song , Zhong‑cheng Gong
Synovitis of the temporomandibular joint (TMJ), a prevalent degenerative joint disease, plays an important role in the pathogenesis of TMJ osteoarthritis. This pathological condition arises from abnormal mechanical loading that induces a chronic low-grade inflammation within the synovial microenvironment through ferroptotic processes. Our research explores the impact of flow fluid-induced shear stress (FFSS) on ferroptosis in fibroblast-like synoviocytes (FLSs) and elucidates the relationship between mechanical overload and the development of TMJ synovitis. Experimental findings revealed progressive alterations in cellular morphology accompanied by significant elevations in intracellular ferrous ion (Fe2 +) concentrations and reactive oxygen species (ROS) levels with increasing FFSS intensity (all p < 0.05). Quantitative analysis showed upregulated expression of pro-inflammatory cytokines (IL-1β, IL-18), matrix-degrading enzymes (MMP-3, MMP-13), and ferroptosis-related markers (ACSL4, Nrf2), while antioxidant defense components (GPX4, system Xc-) were downregulated (all p < 0.05). Pharmacological inhibition using Ferrostatin-1 (Fer-1) significantly attenuated intracellular Fe2+ and ROS accumulation. The treatment group demonstrated reduced expression of IL-1β (p < 0.05) and ACSL4 (p < 0.001), with concomitant upregulation of GPX4 (p < 0.05) and Nrf2 (p < 0.001), though IL-18 modulation did not reach statistical significance (p > 0.05). These results establish that mechanical overload initiates ferroptosis in FLSs, driving inflammatory responses and extracellular matrix degradation through elevated Fe2+ and ROS production, ultimately contributing to TMJ synovitis pathogenesis. Our investigation provides novel mechanistic insights into FFSS-mediated ferroptosis in synovial cells, presenting foundational evidence for developing targeted therapeutic strategies that modulate this cell death pathway to enhance clinical management of TMJ synovitis.
{"title":"Effect of Ferrostatin-1 on temporomandibular joint synovitis induced by abnormal flow fluid shear stress: An in vitro study","authors":"Peng Yu , Chen‑xi Li , Zhi‑qiang Song , Zhong‑cheng Gong","doi":"10.1016/j.prp.2025.156330","DOIUrl":"10.1016/j.prp.2025.156330","url":null,"abstract":"<div><div>Synovitis of the temporomandibular joint (TMJ), a prevalent degenerative joint disease, plays an important role in the pathogenesis of TMJ osteoarthritis. This pathological condition arises from abnormal mechanical loading that induces a chronic low-grade inflammation within the synovial microenvironment through ferroptotic processes. Our research explores the impact of flow fluid-induced shear stress (FFSS) on ferroptosis in fibroblast-like synoviocytes (FLSs) and elucidates the relationship between mechanical overload and the development of TMJ synovitis. Experimental findings revealed progressive alterations in cellular morphology accompanied by significant elevations in intracellular ferrous ion (Fe<sup>2 +</sup>) concentrations and reactive oxygen species (ROS) levels with increasing FFSS intensity (all <em>p</em> < 0.05). Quantitative analysis showed upregulated expression of pro-inflammatory cytokines (IL-1β, IL-18), matrix-degrading enzymes (MMP-3, MMP-13), and ferroptosis-related markers (ACSL4, Nrf2), while antioxidant defense components (GPX4, system Xc-) were downregulated (all <em>p</em> < 0.05). Pharmacological inhibition using Ferrostatin-1 (Fer-1) significantly attenuated intracellular Fe<sup>2+</sup> and ROS accumulation. The treatment group demonstrated reduced expression of IL-1β (<em>p</em> < 0.05) and ACSL4 (<em>p</em> < 0.001), with concomitant upregulation of GPX4 (<em>p</em> < 0.05) and Nrf2 (<em>p</em> < 0.001), though IL-18 modulation did not reach statistical significance (<em>p</em> > 0.05). These results establish that mechanical overload initiates ferroptosis in FLSs, driving inflammatory responses and extracellular matrix degradation through elevated Fe<sup>2+</sup> and ROS production, ultimately contributing to TMJ synovitis pathogenesis. Our investigation provides novel mechanistic insights into FFSS-mediated ferroptosis in synovial cells, presenting foundational evidence for developing targeted therapeutic strategies that modulate this cell death pathway to enhance clinical management of TMJ synovitis.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156330"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749026","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 : 2026-02-01Epub Date: 2025-11-21DOI: 10.1016/j.prp.2025.156301
Haiyang Cui , Xuejiao Fan
Background
Bladder cancer (BCa) is a prevalent malignancy with high recurrence and metastasis rates. Nuclear receptor subfamily 4 group A member 3 (NR4A3), a member of the orphan nuclear receptor superfamily, is implicated in various cancers, but its functional role and mechanisms in BCa have not been well understood. This study aimed to explore the functional significance and diagnostic value of NR4A3 in BCa, with a focus on its regulation of endoplasmic reticulum (ER) stress and anoikis sensitivity via ATF6 and RNF139.
Methods
NR4A3 expression in BCa cell lines was assessed by qRT-PCR and Western blot. Gain-of-function assays were performed to evaluate cell proliferation, apoptosis, and anoikis sensitivity in vitro. ER stress markers and ATF6 degradation were examined by immunoblotting, cycloheximide chase, and ubiquitination assays. The role of RNF139 and its regulation by NR4A3 via KLF2 and KLF4 were determined via various biological assays. In vivo tumorigenesis was assessed using a xenograft mouse model. Additionally, the diagnostic performance of NR4A3 was evaluated in 100 clinical patients using serum ELISA and color Doppler ultrasound.
Results
NR4A3 was downregulated in BCa cells, and its overexpression suppressed cell proliferation, colony formation and promoted apoptosis and anoikis sensitivity. Mechanistically, NR4A3 inhibited ER stress by promoting ATF6 ubiquitination and degradation via transcriptional activation of RNF139 through KLF2 and KLF4. RNF139 directly interacted with ATF6 and mediated its ubiquitination at lysine 152. In vivo, NR4A3 overexpression inhibited tumor growth. Clinically, combining color Doppler ultrasound with serum NR4A3 levels significantly improved diagnostic accuracy for BCa (AUC = 0.986).
Conclusion
NR4A3 suppresses BCa progression via the KLF2/4-RNF139-ATF6 axis and enhances diagnostic efficacy when combined with ultrasound imaging.
{"title":"Targeting the NR4A3-RNF139-ATF6 pathway as a therapeutic and diagnostic strategy in bladder cancer","authors":"Haiyang Cui , Xuejiao Fan","doi":"10.1016/j.prp.2025.156301","DOIUrl":"10.1016/j.prp.2025.156301","url":null,"abstract":"<div><h3>Background</h3><div>Bladder cancer (BCa) is a prevalent malignancy with high recurrence and metastasis rates. Nuclear receptor subfamily 4 group A member 3 (NR4A3), a member of the orphan nuclear receptor superfamily, is implicated in various cancers, but its functional role and mechanisms in BCa have not been well understood. This study aimed to explore the functional significance and diagnostic value of NR4A3 in BCa, with a focus on its regulation of endoplasmic reticulum (ER) stress and anoikis sensitivity via ATF6 and RNF139.</div></div><div><h3>Methods</h3><div>NR4A3 expression in BCa cell lines was assessed by qRT-PCR and Western blot. Gain-of-function assays were performed to evaluate cell proliferation, apoptosis, and anoikis sensitivity <em>in vitro</em>. ER stress markers and ATF6 degradation were examined by immunoblotting, cycloheximide chase, and ubiquitination assays. The role of RNF139 and its regulation by NR4A3 via KLF2 and KLF4 were determined via various biological assays. <em>In vivo</em> tumorigenesis was assessed using a xenograft mouse model. Additionally, the diagnostic performance of NR4A3 was evaluated in 100 clinical patients using serum ELISA and color Doppler ultrasound.</div></div><div><h3>Results</h3><div>NR4A3 was downregulated in BCa cells, and its overexpression suppressed cell proliferation, colony formation and promoted apoptosis and anoikis sensitivity. Mechanistically, NR4A3 inhibited ER stress by promoting ATF6 ubiquitination and degradation via transcriptional activation of RNF139 through KLF2 and KLF4. RNF139 directly interacted with ATF6 and mediated its ubiquitination at lysine 152. <em>In vivo</em>, NR4A3 overexpression inhibited tumor growth. Clinically, combining color Doppler ultrasound with serum NR4A3 levels significantly improved diagnostic accuracy for BCa (AUC = 0.986).</div></div><div><h3>Conclusion</h3><div>NR4A3 suppresses BCa progression via the KLF2/4-RNF139-ATF6 axis and enhances diagnostic efficacy when combined with ultrasound imaging.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156301"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-06DOI: 10.1016/j.prp.2025.156326
Min Tang , Pengpeng Xu , Xiaogang Zhang
Glioblastoma (GBM) has been an aggressive brain tumor and it demonstrates poor prognosis and resistance to the traditional therapeutics. GBM is characterized by abnormal proliferation, high growth, and a significantly immunosuppressive tumor microenvironment (TME), making immunotherapy as an ideal treatment for GBM. The recent advances in the field of immunotherapy such as vaccines, and CAR-T cell treatments, have demonstrated significant efficacy in accelerating anticancer immune responses and improving survival outcomes. Immune checkpoint drugs targeting CTLA-4 and PD-1/PD-L1 have demonstrated synergistic effects in enhancing T cell activation and infiltration. Vaccines such as DCVax-L and oncolytic viruses including G47Δ have demonstrated promising outcomes in the clinical studies. CAR-T cell treatments have been directed against particular antigens such as EGFRvIII and IL13Rα2 and have demonstrated considerable antitumor efficacy. Nonetheless, there are a number of challenges to be considered including the immunosuppressive TME, the blood-brain barrier (BBB), and the molecular heterogeneity of GBM. Addressing these challenges requires a versatile strategy, encompassing the development of innovative combination drugs, complicated imaging methodologies to evaluate treatment efficacy, and the discovery of biomarkers to predict patient responses to immunotherapy. The future research can focus on highlighting the complicated connections between the immune system and GBM, utilizing perspectives from preclinical models and clinical studies to formulate more effective and customized treatment options. This review emphasizes on the recent research results and clinical data, providing insights into prospective developments in GBM immunotherapy and highlighting the necessity of a comprehensive strategy to enhance patient outcomes.
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Pub Date : 2026-02-01Epub Date: 2025-12-11DOI: 10.1016/j.prp.2025.156329
Jilong Qin , Longguang Li , Chi Sing Ng , Xiaodong Lin , Xina Lin , Peng Hou , Ping He
Objective
To explore the clinicopathological and immunohistochemical features of primary Rosai-Dorfman disease (RDD) in the lung and mediastinum.
Methods
Histological observation and immunohistochemical staining of 5 cases of pulmonary and mediastinal RDD, with a review of the related literature.
Results
Two cases were located in the trachea with involvement of the lung. One case was located in the left lower lung. Two cases were located in the mediastinum. Macroscopically, 1 case had clear boundaries, while 4 cases had unclear boundaries, and grayish-white on cut surfaces. Microscopically, low power view showing alternating light and dark areas. The dark areas comprise an admixture of lymphocytes and plasma cells. The light areas comprise the characteristic pale pink histiocytic cells. Histiocytes are large with round-to-oval nuclei, dispersed chromatin, prominent nucleoli, and abundant clear-to-foamy or vacuolated cytoplasm. Emperipolesis was observed in all five cases. All five cases showed interstitial fibrosis or sclerosis and Russell bodies. Four cases (4/5, 80 %) showed lymphoid follicles with germinal centers in the interstitium. Four cases showed (4/5, 80 %) interstitial neutrophil infiltration, with three cases accompanied by microabscess formation. Immunophenotypically, the histiocytes expressed Cyclin D1(5/5, 100 %), OCT2 (5/5, 100 %), S100 protein (5/5, 100 %), CD68 (5/5, 100 %), CD163 (5/5, 100 %), BCL2 (5/5, 100 %) and CD30 (3/5, 60 %), but did not express CD1a, Langerin, IgG4 and ALK.
Conclusion
RDD of the lung and mediastinum is rare, with a wide range of ages. Histologically, there are often lymphoid follicles with germinal centers and interstitial fibrosis or sclerosis. This together with the expression of BCL2 and CD30 in the histiocytes can lead to misdiagnosis of lymphomas or other lymphoproliferative diseases or missed diagnosis, particularly in the mediastinum. Careful histological examination for the diagnostic feature of emperipolesis together with characteristic Cyclin D1, OCT2, S100 protein, and CD68 positivity are important clues for accurate diagnosis.
{"title":"Primary Rosai-Dorfman disease of lung and mediastinum: A clinicopathological and immunohistochemical study of five cases","authors":"Jilong Qin , Longguang Li , Chi Sing Ng , Xiaodong Lin , Xina Lin , Peng Hou , Ping He","doi":"10.1016/j.prp.2025.156329","DOIUrl":"10.1016/j.prp.2025.156329","url":null,"abstract":"<div><h3>Objective</h3><div>To explore the clinicopathological and immunohistochemical features of primary Rosai-Dorfman disease (RDD) in the lung and mediastinum.</div></div><div><h3>Methods</h3><div>Histological observation and immunohistochemical staining of 5 cases of pulmonary and mediastinal RDD, with a review of the related literature.</div></div><div><h3>Results</h3><div>Two cases were located in the trachea with involvement of the lung. One case was located in the left lower lung. Two cases were located in the mediastinum. Macroscopically, 1 case had clear boundaries, while 4 cases had unclear boundaries, and grayish-white on cut surfaces. Microscopically, low power view showing alternating light and dark areas. The dark areas comprise an admixture of lymphocytes and plasma cells. The light areas comprise the characteristic pale pink histiocytic cells. Histiocytes are large with round-to-oval nuclei, dispersed chromatin, prominent nucleoli, and abundant clear-to-foamy or vacuolated cytoplasm. Emperipolesis was observed in all five cases. All five cases showed interstitial fibrosis or sclerosis and Russell bodies. Four cases (4/5, 80 %) showed lymphoid follicles with germinal centers in the interstitium. Four cases showed (4/5, 80 %) interstitial neutrophil infiltration, with three cases accompanied by microabscess formation. Immunophenotypically, the histiocytes expressed Cyclin D1(5/5, 100 %), OCT2 (5/5, 100 %), S100 protein (5/5, 100 %), CD68 (5/5, 100 %), CD163 (5/5, 100 %), BCL2 (5/5, 100 %) and CD30 (3/5, 60 %), but did not express CD1a, Langerin, IgG4 and ALK.</div></div><div><h3>Conclusion</h3><div>RDD of the lung and mediastinum is rare, with a wide range of ages. Histologically, there are often lymphoid follicles with germinal centers and interstitial fibrosis or sclerosis. This together with the expression of BCL2 and CD30 in the histiocytes can lead to misdiagnosis of lymphomas or other lymphoproliferative diseases or missed diagnosis, particularly in the mediastinum. Careful histological examination for the diagnostic feature of emperipolesis together with characteristic Cyclin D1, OCT2, S100 protein, and CD68 positivity are important clues for accurate diagnosis.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"278 ","pages":"Article 156329"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145749025","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}
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