Functional & Integrative Genomics最新文献

{"title":"FOXP3 inhibits inflammatory activation of conjunctival epithelial cells in allergic conjunctivitis via the KAT5/PDCD4 axis","authors":"Zifeng Deng","doi":"10.1007/s10142-025-01700-3","DOIUrl":"10.1007/s10142-025-01700-3","url":null,"abstract":"<div><p>Allergic conjunctivitis (AC) is an IgE-mediated type I hypersensitivity disorder characterized by conjunctival hyperemia, itching, and increased tear secretions. This study aims to investigate the mechanism of FOXP3 in the inflammatory activation of human conjunctival epithelial cells (HConEpiCs) in AC. Serum samples were collected from AC patients and healthy volunteers for correlation analysis of FOXP3 with inflammatory cytokines (IL-6/IL-8/TNF-α/CRP) and immunoglobulins (IgG/IgA/IgE). FOXP3, KAT5, and PDCD4 expression were measured by RT-qPCR, followed by Pearson correlation analysis. HConEpiCs were used to establish an AC cell model, followed by assessment of cell viability and inflammatory cytokines (IL-6/IL-8/TNF-α/IL-10/IL-4). The binding of FOXP3 to the KAT5 promoter and KAT5 and H3K27ac enrichment on the PDCD4 promoter were detected. FOXP3 expression was downregulated in AC patient, while KAT5 and PDCD4 were upregulated. FOXP3 negatively correlated with IL-6, IL-8, TNF-α, C-reactive protein, serum IgG, IgA, IgE, and eosinophil ratio. In histamine-stimulated HConEpiCs, FOXP3 overexpression inhibited inflammation. Mechanistically, FOXP3 bound to the KAT5 promoter to inhibit KAT5 expression, reduced KAT5 and H3K27ac enrichment on the PDCD4 promoter, and downregulated PDCD4 expression. KAT5 or PDCD4 overexpression reversed FOXP3-mediated inhibition of HConEpiC inflammatory activation. In conclusion, FOXP3 overexpression attenuates inflammatory activation of HConEpiCs by inhibiting KAT5 expression and reducing KAT5/H3K27ac-mediated PDCD4 transcription.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145073717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction of a prognostic model for hepatocellular carcinoma based on necrosis by sodium overload-related genes and identification of ANKRD13B as a new prognostic marker","authors":"Xiangyu Qu,&nbsp;Yigang Zhang,&nbsp;Yilun Shi,&nbsp;Suchen Wang,&nbsp;Yi Tan,&nbsp;Lianbao Kong,&nbsp;Deming Zhu","doi":"10.1007/s10142-025-01674-2","DOIUrl":"10.1007/s10142-025-01674-2","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Hepatocellular carcinoma (HCC), a prevalent malignant tumor of the digestive tract worldwide, is characterized by poor prognosis and high mortality rates. Necrosis by sodium overload (NECSO) represents a novel form of cell death that has been implicated in various cancer types. However, its functional role in HCC pathogenesis remains poorly understood. We conducted a co-expression analysis of the NECSO-associated gene TRPM4, followed by clustering analysis and weighted gene co-expression network analysis (WGCNA) to identify NECSO-related genes. Through evaluation of 101 distinct machine learning algorithm combinations, we developed prognostic models for HCC, with the optimal model selected based on the highest mean concordance index (C-index) across training and validation cohorts. Patients were stratified into high-risk and low-risk groups according to computed risk scores. Subsequent analyses compared intergroup differences in biological functions, immune microenvironment characteristics, and therapeutic responses to immunotherapy and chemotherapy. To identify pivotal biomarkers, we employed three feature selection methodologies: LASSO, SVM-RFE, and random forest algorithms. The biological significance of the identified core gene ANKRD13B was experimentally validated through in vitro cellular experiments. Using a correlation coefficient (cor) &gt; 0.6, we identified 78 co-expressed genes. Subsequent clustering analysis of HCC samples based on these genes revealed 1,402 NECSO-associated genes. Further WGCNA, differential expression, and prognostic analyses of these genes yielded 31 prognostically genes. Among 101 machine learning combinations, the StepCox[both] combined with GBM algorithm emerged as the optimal prognostic model, achieving the highest mean C-index across training and validation cohorts. Survival analysis confirmed significantly poorer prognosis in the high-risk group. Receiver operating characteristic (ROC) curve analysis demonstrated good predictive performance. Functional enrichment revealed distinct intergroup biological profiles, with the high-risk group and the low-risk group showing enrichment in immune-related pathways, metabolic regulation, and cell death mechanisms. Notably, the high-risk group exhibited enhanced immune activation status and superior response rates to immune checkpoint inhibitors therapy. Correlation analyses established significant associations between model genes/risk scores and cell death genes, including ferroptosis, pyroptosis, cuproptosis, and disulfidptosis. Drug sensitivity analysis identified eight chemotherapeutic agents with heightened sensitivity in high-risk patients: BI.2536, Bleomycin, Cisplatin, Doxorubicin, Epothilone B, Gemcitabine, Mitomycin C, and Paclitaxel. In vitro validation confirmed ANKRD13B promoted the proliferation, invasion and migration of HCC. We established a novel NECSO prognostic model demonstrating good predictive capacity for HCC prognosis and therapeutic resp","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting FOXK2 in triple-negative breast cancer: Role of the P53/MCAS1/miR-211–5p regulatory axis","authors":"Zankai Wu,&nbsp;Yanting Zhang,&nbsp;Dandan Xiang,&nbsp;Tian Li,&nbsp;Yiping Gong,&nbsp;Qibin Song,&nbsp;Jin Hu","doi":"10.1007/s10142-025-01697-9","DOIUrl":"10.1007/s10142-025-01697-9","url":null,"abstract":"<div><p>Forkhead box K2 (FOXK2) is over-expressed in several human malignancies, yet how it is regulated triple-negative breast cancer (TNBC) remained unclear. We aimed to clarify whether FOXK2 drives TNBC progression, and elucidate the upstream molecular circuitry that controls FOXK2 abundance. FOXK2 mRNA and protein were quantified by qPCR and Western blot in 30 paired TNBC and adjacent tissues. Some assays assessed proliferation, migration and invasion after FOXK2 knockdown or overexpression. Bioinformatics predicted miR-211-5p targeting FOXK2 and lncRNA MCM3AP-AS1 (MCAS1) targeting miR-211-5p. RNA immunoprecipitation (RIP) and dual-luciferase assays validated these interactions. RNA pulldown, mass spectrometry and ChIP identified p53 binding to the MCAS1 promoter. FOXK2 was upregulated in TNBC tissues as opposed to the para-carcinoma tissues. FOXK2 silencing significantly reduced proliferation, migration and invasion, whereas overexpression accelerated these phenotypes. Mechanistically, MCAS1 acts as a sponge for miR-211-5p, ultimately protecting its target gene FOXK2 from degradation. Furthermore, employing RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays, our studies revealed a direct interaction between P53 and the promoter of MCAS1. This interaction resulted in the suppression of MCAS1 transcription. Clinical samples from TNBC patients further confirmed a correlation between FOXK2 expression and tumor size, lymphatic involvement, as well as the expression level of Ki-67. Our findings unveil a novel P53/MCAS1/miR-211-5p/FOXK2 regulatory axis that dictates TNBC aggressiveness. FOXK2 may sever as both a prognostic biomarker and a therapeutic target in TNBC.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-025-01697-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145037157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolutionary and functional differentiation of the glutamate receptor-like family in tea (Camellia sinensis) plants and other plants","authors":"Tian Deng,&nbsp;Changli Yang,&nbsp;Xiaowei Yang,&nbsp;Yan Li,&nbsp;Sihui Liang,&nbsp;Xinlong Dai,&nbsp;Qiang Shen","doi":"10.1007/s10142-025-01696-w","DOIUrl":"10.1007/s10142-025-01696-w","url":null,"abstract":"<div><p>Glutamate receptor-like (<i>GLR</i>) is a ligand-gated ion channel essential for plant growth, development, and response to environmental stressors. This study identified <i>GLR</i> family members from 15 representative plants. Phylogenetic analysis revealed that the <i>GLRs</i> may have originated from early algae. Subcellular localization and structure predictions suggest functional diversity of GLR family proteins. Furthermore, we revealed the evolutionary trajectory of <i>GLRs</i> via conserved motif analysis. Moreover, transcriptome expression profiling revealed functional differentiation of the <i>CsGLR</i> family during long-term evolution. Notably, the results of stress treatment and gene suppression indicate that <i>CsGLRs</i> not only respond to drought and salt stress but also affect the abscission of tea flowers. The results of the correlation analysis suggested that <i>CsGLRs</i> may participate in the metabolism of theobromine and jasmonic acid. Overall, our results provide valuable insights into the origin, evolution and biological functions of the <i>GLR</i> family.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Key copper homeostasis genes and inflammatory mechanisms in ischemic stroke: A bioinformatics and experimental study","authors":"Ting Shi,&nbsp;Zhifeng Wang,&nbsp;Jiao Yang,&nbsp;Pengfen He,&nbsp;Daman Tian,&nbsp;Junfeng Lan,&nbsp;Shuangfeng Xu,&nbsp;Aiming Yang,&nbsp;Liwei Xing,&nbsp;Yujiang Xi,&nbsp;Jian Wang","doi":"10.1007/s10142-025-01692-0","DOIUrl":"10.1007/s10142-025-01692-0","url":null,"abstract":"<div><p>Ischemic stroke (IS) has high morbidity/mortality with limited treatments. This study screened core copper homeostasis-related genes in IS and validated their function as precise intervention targets. Human IS gene chip data were retrieved from GEO, and copper homeostasis genes from multiple databases. After data correction/normalization, IS differentially expressed genes (DEGs) were identified and intersected with copper genes. DAVID for GO/KEGG enrichment, STRING for PPI network, CytoHubba for key genes, and ROC curves for diagnostic value. MCAO rat models were established; after 14-day rearing, protein expression was validated via relevant assays. 1,425 IS DEGs and 2,610 copper genes intersected to 235 genes, enriched in inflammatory response, innate immunity, and TNF/NOD-like/Toll-like receptor pathways. Key genes HIF-1α, TNF, TLR4, IL-1β had IS diagnostic AUC 0.70–0.80. MCAO rats showed worse neurological deficits, larger infarcts, neuronal damage, brain copper accumulation, and upregulated key genes linked to neuroinflammation, BBB disruption, and neuronal injury. Bioinformatics and animal studies revealed copper homeostasis imbalance-related genes mediate inflammation, oxidative stress, and mitochondrial regulation, supporting the \"copper accumulation–inflammation–oxidative stress\" cascade. These genes may be novel IS targets. Further study on dynamic expression across ischemic time windows/brain regions and interactions with other cell death modes is needed.</p><h3>Graphical abstract</h3><p>This study used a system approach: bioinformatics screening → experimental validation → mechanism elucidation. Three cerebral ischemia datasets from GEO (GSE16561, GSE22255, GSE58294) underwent DEG analysis; Venn diagram identified core shared DEGs. GO/KEGG enrichment, STRING for PPI network, Cytoscape for hub genes, ROC curves for diagnostic potential. Rat MCAO model was established; validity verified via relevant staining; Cu2+ accumulation detected; molecular expression validated by assays.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative analysis identifies FERMT3 as a key regulator of metabolic reprogramming in keloid scarring and metabolic syndrome","authors":"Qian Lin,&nbsp;Beichen Cai,&nbsp;Feng Dong,&nbsp;Ruonan Ke,&nbsp;Xiuying Shan,&nbsp;Xuejun Ni,&nbsp;Lu Chen,&nbsp;Chuanshu Cai,&nbsp;Biao Wang","doi":"10.1007/s10142-025-01705-y","DOIUrl":"10.1007/s10142-025-01705-y","url":null,"abstract":"<div><p><i>Background</i>. Keloid scarring and Metabolic Syndrome (MS) are distinct conditions marked by chronic inflammation and tissue dysregulation, suggesting shared pathogenic mechanisms. Identifying common regulatory genes could unveil novel therapeutic targets. <i>Methods</i>. We performed an integrative analysis of public microarray datasets from keloid, MS, and respective healthy control tissues. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify shared gene modules. A diagnostic gene signature was developed using LASSO regression and machine learning, and validated on independent datasets. Single-cell RNA sequencing (scRNA-seq) data were analyzed to localize gene expression to specific cell types. The function of a top candidate gene, <i>FERMT3</i>, was investigated via in vitro experiments in macrophages and fibroblasts. <i>Results</i>. We identified 2,788 differentially expressed genes (DEGs) in keloids and 2,639 in MS compared to healthy controls, with 146 genes overlapping. WGCNA identified a key co-expression module (termed the “salmon” module) significantly associated with both conditions and enriched in metabolic and immune pathways. A 23-gene signature demonstrated fair to good predictive performance for both keloids (validation AUC = 0.783) and MS (AUC = 0.905). scRNA-seq analysis revealed that FERMT3 was highly expressed in macrophages and fibroblasts in keloid tissue. In vitro, modulation of FERMT3 in these cell types significantly altered their metabolic profiles (glycolysis, oxidative phosphorylation), inflammatory cytokine production, proliferation, and migration. <i>Conclusions</i>. Our integrative analysis identifies a shared transcriptomic signature between keloids and MS and highlights <i>FERMT3</i> as a key potential regulator of the metabolic and inflammatory phenotypes in these conditions. These findings suggest that <i>FERMT3</i> could be a promising therapeutic target for diseases driven by fibro-metabolic dysregulation.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide identification analysis of aldo–keto reductase gene family in cotton and GhAKR40 role in salt stress tolerance","authors":"Yiman Liu,&nbsp;Qiankun Liu,&nbsp;Yuqing Hou,&nbsp;Guangxing Zhang,&nbsp;Jiangping Han,&nbsp;Zhaoguo Li,&nbsp;Aziz Khan,&nbsp;Zhongli Zhou,&nbsp;Xiaoyan Cai,&nbsp;Yanchao Xu,&nbsp;Jie Zheng,&nbsp;Fang Liu","doi":"10.1007/s10142-025-01678-y","DOIUrl":"10.1007/s10142-025-01678-y","url":null,"abstract":"<div><p>In this study, a comprehensive genome-wide identification and analysis of the aldo–keto reductase (AKR) gene family was performed to explore the role of <i>Gossypium hirsutumAKR40</i> under salt stress in cotton. A total of 249 AKR genes were identified with uneven distribution on the chromosomes in four cotton species. The diversity and evolutionary relationship of the cotton AKR gene family was identified using physio-chemical analysis, phylogenetic tree construction, conserved motif analysis, chromosomal localization, prediction of cis-acting elements, and calculation of evolutionary selection pressure under 300 mM NaCl stress. The real-time qPCR showed that genes encoding members of the aldo–keto reductase (AKR) family in <i>Gossypium hirsutum</i> displayed distinct expression patterns various stress treatments. Specifically, the expression levels of certain genes were significantly upregulated under drought and salt stress. Notably, the role of <i>GhAKR40</i> gene in salt stress tolerance was validated using virus-induced gene silencing (VIGS) technology in cotton. The <i>GhAKR40</i>-silenced plants experienced leaf wilting under salt stress compared with wild-type and null-control plants. In addition, a series of physio-biochemical such as DAB staining and measurement of RWCL (relative water content in leaves) indexes also indicated that silencing of the <i>AKR40</i> gene reduced the salt tolerance in cotton. Transcriptome sequencing and analysis of the VIGS-silenced lines suggest that <i>GhAKR40</i> may enhance salt tolerance in cotton plants by potentially participating in plant-pathogen interactions and the MAPK signaling pathway, thereby modulating both pathways. These data demonstrate that <i>GhAKRs</i> play a significant role in salt stress tolerance. <i>GhAKR40</i> functions as a positive regulator with a significant impact on stress tolerance. This study not only establishes a theoretical foundation for the comprehensive utilization of resistant germplasm resources in cotton but also paves the way for further exploration of resistance genes in the species.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircSHPRH inhibits malignancy progression of head and neck squamous cell carcinoma by regulating PI3K/AKT/mTOR signaling pathway","authors":"Fei Zhang,&nbsp;Liu Chen,&nbsp;Chuanxin Duan,&nbsp;Yingnan Zhu","doi":"10.1007/s10142-025-01677-z","DOIUrl":"10.1007/s10142-025-01677-z","url":null,"abstract":"<div><h3>Background</h3><p>Head and neck squamous cell carcinoma (HNSCC) stands as a significant global health concern, marked by its substantial impact on both morbidity and mortality rates. Although previous studies have suggested that circular RNAs (circRNAs) may influence HNSCC progression, the underlying mechanisms remain largely unclear.</p><h3>Methods</h3><p>In this study, we first used quantitative real-time polymerase chain reaction (qRT-PCR) to measure the expression levels of circSHPRH in HNSCC tissues and cell lines. Subsequently, we assessed its impact on cell proliferation, migration, invasion, and apoptosis using CCK-8 assays, colony formation assays, wound healing assays, Transwell assays, and flow cytometry. Additionally, we investigated the molecular mechanisms by which circSHPRH exerts its effects, focusing on the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In vivo experiments were conducted using a xenograft tumor model in nude mice to validate the tumor-suppressive effects of circSHPRH.</p><h3>Results</h3><p>Our results demonstrated a significant downregulation of circSHPRH in HNSCC tissues and cell lines compared to their normal counterparts. Overexpression of circSHPRH in HNSCC cells led to a marked reduction in cell proliferation, migration, and invasion, while promoting apoptosis. Mechanistically, we found circSHPRH exerts its tumor-suppressive effects by suppressing the PI3K/AKT/mTOR signaling pathway. This finding was corroborated by in vivo experiments in nude mice, where an upregulation of circSHPRH led to a reduction in tumor growth in HNSCC.</p><h3>Conclusion</h3><p>CircSHPRH may play a pivotal role in attenuating the growth and metastasis of HNSCC, both at the cellular level and in animal models, by disrupting the PI3K/AKT/mTOR signaling axis.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLDN4 promotes ferroptosis and inflammation involving JAK2/STAT3 pathway in acute pancreatitis","authors":"Chuanming Zheng,&nbsp;Rui Tao,&nbsp;Zhenjie Wang,&nbsp;Xi Zhang,&nbsp;Hai Jiang,&nbsp;Zhong Ji,&nbsp;Hehe Dou,&nbsp;Zhaohui Du","doi":"10.1007/s10142-025-01683-1","DOIUrl":"10.1007/s10142-025-01683-1","url":null,"abstract":"<div><p>Acute pancreatitis (AP) is a severe inflammatory disease characterized by pancreatic acinar cell injury and oxidative stress. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been implicated in AP pathogenesis. However, the molecular mechanisms linking ferroptosis to AP remain unclear. Using a cerulein-induced AP mouse model and cerulein-stimulated 266-6 pancreatic acinar cells, we performed RNA sequencing to identify differentially expressed genes (DEGs). Claudin-4 (CLDN4) was selected for further investigation. We evaluated the effects of CLDN4 knockdown on cell viability, apoptosis, inflammatory cytokine production, ferroptosis markers, and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway utilizing quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, enzyme-linked immunosorbent assays (ELISA), immunofluorescence, flow cytometry, and histopathological analyses, respectively. We found that CLDN4 expression was significantly upregulated in AP pancreatic tissues and cells. CLDN4 knockdown enhanced cell viability, reduced apoptosis, and decreased reactive oxygen species (ROS), iron accumulation, and inflammatory cytokines (TNF-α, IL-6, IL-17). It also restored glutathione peroxidase 4 (GPX4) levels and reduced acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, indicating suppression of ferroptosis. In vivo, CLDN4 knockdown ameliorated pancreatic injury and oxidative stress. Mechanistically, CLDN4 knockdown correlated with decreased activation of the JAK2/STAT3 pathway, and combined inhibition with AG490 provided additive protective effects. Our study identifies CLDN4 as a novel regulator of ferroptosis and inflammation in AP that may be linked to the JAK2/STAT3 pathway. Targeting CLDN4 may offer a promising therapeutic strategy for mitigating pancreatic injury in acute pancreatitis.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variants of LncRNA associated with splicing regulation and their impact on ovarian cancer development","authors":"Lingxiao Zou,&nbsp;Meng Zhang,&nbsp;Shan He,&nbsp;Minhui Zhuang,&nbsp;Wenjing Jia,&nbsp;Yulan Wang,&nbsp;Jingjing Liu,&nbsp;Yixuan Wang,&nbsp;Xiaofeng Song,&nbsp;Jian Zhao","doi":"10.1007/s10142-025-01687-x","DOIUrl":"10.1007/s10142-025-01687-x","url":null,"abstract":"<div><p>Ovarian cancer (OC) is a highly lethal gynecologic malignancy that lacks reliable early biomarkers. Numerous long non-coding RNAs (lncRNAs) have been found to play critical regulatory roles in OC, yet the mechanisms underlying most of them remain unclear. Recently, lncRNAs have emerged as key regulators of RNA splicing, while splicing dysregulation is widespread and plays critical roles in cancer. In addition, genetic variants of splicing regulators have been shown to contribute to disease etiology. In this study, we comprehensively analyzed 202 °C samples and characterized 21,129 lncRNA splicing quantitative trait loci (sQTLs) involving both event-level and transcript-level. We found that lncRNA sQTLs differ significantly from lncRNA expression quantitative trait loci (eQTLs), and genes regulated by lncRNA sQTLs are involved in cancer hallmark pathways and associated with immune cell infiltration and drug sensitivity. Additionally, these lncRNA sQTLs are significantly enriched in histone markers, transcription factor (TF) binding sites, and RNA-binding protein (RBP) binding sites, including several critical splicing factors (SF) in OC. Based on SF binding and partial correlation analysis, a potential lncRNA-SF-mRNA regulatory network was constructed. Finally, by integrating GWAS data, we elucidated that a specific lncRNA sQTL rs1549334 generates different isoforms by regulating the splicing of the HOXD3 gene and thus impacting OC risk. Our study provides new insights into the mechanisms of splicing regulation in OC involving lncRNA sQTL and reveals potential biomarkers for early detection and clinical treatment of OC.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}