The FASEB Journal最新文献

{"title":"A Novel Mechanism of the p53 Isoform Δ40p53α in Regulating Collagen III Expression in TGFβ1-Induced LX-2 Human Hepatic Stellate Cells","authors":"Sun-Young Lee,&nbsp;Yunseong Jang,&nbsp;Hye-Yeon Seok,&nbsp;Yong-Hwan Moon","doi":"10.1096/fj.202403146RR","DOIUrl":"https://doi.org/10.1096/fj.202403146RR","url":null,"abstract":"<p>Injured liver cells undergoing chronic wound healing produce excessive amounts of extracellular matrix (ECM) components, such as collagen and fibronectin, leading to fibrosis. This process is largely mediated by transforming growth factor-β (TGFβ) signaling, which intersects with the tumor suppressor p53 pathway. However, the roles of specific p53 isoforms in this interaction remain unclear. In this study, we report the involvement of the Δ40p53α isoform, an N-terminal truncated variant of p53, in regulating ECM gene expression in TGFβ1-activated LX-2 human hepatic stellate cells. RT-PCR analysis of cirrhotic liver tissues revealed clinically relevant increases in Δ40p53 expression. Knockdown of Δ40p53 using antisense oligonucleotides in LX-2 cells attenuated TGFβ1-induced activation and significantly reduced collagen production and deposition, particularly fibrillar collagen III. Conversely, overexpression of Δ40p53α upregulated collagen III expression in concert with full-length p53 (FLp53). Co-immunoprecipitation analysis demonstrated that Δ40p53α forms a complex with FLp53, which associates with phosphorylated Smad3 following TGFβ1 stimulation. These findings suggest that Δ40p53 enhances collagen III expression by interacting with FLp53 and Smads, highlighting its role in profibrogenic ECM expression.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403146RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting MLL1/WDR5-Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a","authors":"Daisuke Hara,&nbsp;Kensuke Sasaki,&nbsp;Shigehiro Doi,&nbsp;Takeshi Ike,&nbsp;Kazuya Maeda,&nbsp;Maria Yoshida,&nbsp;Akira Takahashi,&nbsp;Yosuke Osaki,&nbsp;Naoki Ishiuchi,&nbsp;Yujiro Maeoka,&nbsp;Toshiki Doi,&nbsp;Takuto Chiba,&nbsp;Ayumu Nakashima,&nbsp;Takao Masaki","doi":"10.1096/fj.202402382R","DOIUrl":"https://doi.org/10.1096/fj.202402382R","url":null,"abstract":"<p>Peritoneal fibrosis poses a significant challenge to the long-term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting the role of cellular senescence in its pathogenesis. p16^INK4a is a cell cycle regulator that has been implicated in cellular senescence. Mixed-lineage leukemia 1 (MLL1) forms a complex with WD-40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown that inhibition of the MLL1/WDR5 complex reduces p16^INK4a expression and attenuates renal senescence after injury in mice. This study aimed to investigate whether inhibiting MLL1/WDR5 attenuates peritoneal senescence, inflammation, and fibrosis in both human samples and in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO-injected mice), while also exploring the associated underlying mechanisms. MLL1/WDR5, histone 3 lysine 4 trimethylation (H3K4me3), and p16^INK4a expression were elevated in TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs), non-adherent cells obtained from patients undergoing PD, and the submesothelial compact zones of MGO-injected mice. Notably, p16^INK4a expression in these cells was positively correlated with the dialysate/plasma creatinine ratio. Treatment with the MLL1/WDR5 protein–protein interaction inhibitors MM-102 and OICR-9429 reduced H3K4me3 levels and p16^INK4a expression, suppressing fibrosis in HPMCs as well as peritoneal fibrosis and inflammation in MGO-injected mice. These inhibitors also improved peritoneal function in MGO-injected mice. Additionally, we demonstrated that MLL1/WDR5-induced H3K4me3 directly regulates <i>p16</i>^<i>INK4a</i> gene transcription, and that inhibiting MLL1/WDR5 reduces H3K4me3, thereby suppressing <i>p16</i>^<i>INK4a</i> gene transcription. These findings suggest that targeting MLL1/WDR5 activation alleviates peritoneal senescence, inflammation, and fibrosis, highlighting its potential as a promising therapeutic strategy for peritoneal fibrosis.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402382R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenesis of Focal Segmental Glomerulosclerosis Caused by a Leu754Val Mutation in ARHGAP32","authors":"Sipei Chen,&nbsp;Li Wang,&nbsp;Yang Zou,&nbsp;Yi Li,&nbsp;Xiang Zhong,&nbsp;Guisen Li","doi":"10.1096/fj.202403242R","DOIUrl":"https://doi.org/10.1096/fj.202403242R","url":null,"abstract":"<div>\u0000 \u0000 <p>Focal segmental glomerulosclerosis (FSGS) shows a poor response to hormones and other treatment schemes and rapidly progresses to end-stage renal disease. Genetic factors are important causes of FSGS. We recently identified a new candidate pathogenic <i>ARHGAP32</i> mutation in a family affected by FSGS and further investigated its functional impact through in vivo and in vitro studies. We established in vitro models of <i>ARHGAP32</i> overexpression in podocytes and COS-7 kidney cells by plasmid transfection. Mice with the point mutation were established using CRISPR/Cas9 technology, followed by the establishment of a kidney injury model by adriamycin administration via the tail vein. The ARHGAP32 protein was found to be expressed in human kidney tissues. Podocytes transfected with mutant <i>ARHGAP32</i> showed a significant decrease in the expression of the podocyte markers nephrin. Similarly, COS-7 cells transfected with mutant <i>ARHGAP32</i> showed decreased expression of the cytoskeletal protein F-actin. The ARHGAP32 mutant protein had 20-fold higher affinity for Cdc42 than the wild-type protein. Adriamycin-induced L405V mutant mice showed slow growth, proteinuria, increased serum creatinine and blood urea nitrogen levels, and pathological kidney damage. RhoA, Rac1, and Cdc42 all showed decreased expression in podocytes overexpressing mutant <i>ARHGAP32</i> and in the kidneys of mutant mice. These findings suggest that the <i>ARHGAP32</i> L754V mutation induces podocyte damage, leading to kidney damage and the potential development of FSGS. This study provides a new basis for elucidating the pathogenesis of FSGS and the exploration of new therapeutic measures.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amuc_1434 From Akkermansia muciniphila Enhances CD8+ T Cell-Mediated Anti-Tumor Immunity by Suppressing PD-L1 in Colorectal Cancer","authors":"Jiahao Zhu,&nbsp;Shaolei Qin,&nbsp;Ruike Gu,&nbsp;Shengjun Ji,&nbsp;Gang Wu,&nbsp;Ke Gu","doi":"10.1096/fj.202403295RR","DOIUrl":"https://doi.org/10.1096/fj.202403295RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Colorectal cancer (CRC) shows a limited response to programmed death-ligand 1 (PD-L1) immunotherapies. <i>Akkermansia muciniphila</i> (AKK) may enhance tumor immunity. This study examines how its Outer Membrane Vesicles (OMVs) and Amuc_1434 influence PD-L1 expression and CD8+ T cell activity in CRC. OMVs were isolated and their characteristics were examined through transmission electron microscopy and Western blotting. PD-L1 expression was quantified via Western blot, while CD8+ T cell proliferation was measured using flow cytometry. Cytokine production (interferon-gamma (IFN-γ) and interleukin-2 (IL-2)) was evaluated using ELISA. A CRC mouse model was employed to examine its impact on tumor growth and immune cell infiltration. In CRC cells, treatment with AKK-derived OMVs (AKK-OMVs) significantly downregulated PD-L1 expression (<i>p</i> &lt; 0.05) and markedly increased CD8+ T cell proliferation and the levels of IFN-γ and IL-2 (<i>p</i> &lt; 0.01). Amuc_1434 was identified as the key protein mediating these effects. In vivo, AKK-OMVs treatment substantially reduced tumor volume (<i>p</i> &lt; 0.01) and significantly enhanced CD8+ T cell infiltration into the tumor microenvironment (<i>p</i> &lt; 0.01). Additionally, AKK-OMVs-treated mice showed increased expression of immune activation markers within the tumor tissue, further indicating enhanced antitumor immunity. This study reveals that AKK-OMVs, particularly those containing Amuc_1434, can modulate PD-L1 expression and potentiate CD8+ T cell-mediated antitumor immunity in CRC. These findings suggest a novel approach to overcoming resistance to immune checkpoint inhibitors in CRC.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of CDKN1A as a potential key risk factor in MASLD progression","authors":"Lijuan Deng,&nbsp;Jianxin Deng,&nbsp;Liping Luo,&nbsp;Hongjia Yang,&nbsp;Mengxue Sun,&nbsp;Yucheng Gao,&nbsp;Qing Liu,&nbsp;Ebenezeri Erasto Ngowi,&nbsp;Yinghua Zhou,&nbsp;Rongrong Zhang,&nbsp;Xiaojun Liu,&nbsp;Aijun Qiao","doi":"10.1096/fj.202402942R","DOIUrl":"https://doi.org/10.1096/fj.202402942R","url":null,"abstract":"<p>Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is recognized as a highly heterogeneous condition. The elusive mechanisms driving its progression contribute to the lack of reliable diagnostic markers and effective treatments. In this study, we first identified 52 differentially expressed genes (DEGs) in MASLD stage by analyzing two public datasets, GSE126848 and GSE135251, using the DESeq2 and edgeR packages. Subsequently, these DEGs were subjected to protein–protein interaction (PPI) network analysis, revealing the top 10 hub genes. By intersecting the top 10 hub genes with another public dataset GSE260222, we observed that CDKN1A was the sole gene consistently upregulated in the livers of MASLD patients across all analyses. The elevated protein expression of CDKN1A was further validated in the livers of MASLD patients compared to control subjects. Consistently, compared to their respective control groups, both CDKN1A mRNA and protein levels were dramatically increased in the livers of MASLD animal models, including high-fat diet (HFD) induced obese mice, leptin-deficient obese (<i>ob/ob</i>) mice and leptin receptor-deficient (<i>db/db</i>) mice, and in mouse primary hepatocytes treated with free fatty acids (FFA), respectively. Interestingly, we found that CDKN1A transcript levels were progressively and significantly increased with the severity of MASLD in four out of five datasets and positively correlated with both the NAFLD activity score (NAS) and fibrosis stage, two important clinicopathological features of MASLD. Collectively, our results illustrated that CDKN1A may serve as a promising biomarker and therapeutic target for MASLD; however, its role in the disease's pathology warrants further investigation.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin Modulate Endoplasmic Reticulum Stress by Targeting SIRT1 to Ameliorate DSS-Induced Ulcerative Colitis in Mice","authors":"Hai-Xiang Guo,&nbsp;Zhong-Hao Ji,&nbsp;Bing-Bing Wang,&nbsp;Yu Xiao,&nbsp;Jin-Ping Hu,&nbsp;Yi Zheng,&nbsp;Wei Gao,&nbsp;Bao Yuan","doi":"10.1096/fj.202403418R","DOIUrl":"https://doi.org/10.1096/fj.202403418R","url":null,"abstract":"<div>\u0000 \u0000 <p>Ulcerative colitis (UC) is a recurrent, chronic disease whose main symptoms include weight loss, diarrhea, and blood in the stool. In recent years, the incidence of UC has been increasing year by year, which seriously affects the daily life of patients. Luteolin (Lut), as a flavonoid, is widely found in a variety of vegetables and fruits and has been shown to have a variety of pharmacological activities. This work investigated the effects of Lut on dextrose sodium sulfate (DSS)-induced ulcerative colitis (UC) in mice, with a special focus on the role of endoplasmic reticulum (ER) stress in this. The outcomes demonstrated that colitis symptoms, including disease phenotype, elevated inflammatory factor levels, intestinal barrier damage, and gut microbiota disruption, were considerably alleviated in UC model mice treated with luteolin. Also, Lut alleviated ER stress and apoptosis in UC mice. We then explored the effects of Lut on ER stress and apoptosis induced by thapsigargin (TG) and tunicamycin (TM) in HT29 cells in vitro. It was found that Lut treatment inhibited TM/TG-induced ER stress and apoptosis. However, these inhibitory effects of Lut were attenuated by SIRT1 silencing in TM-treated HT29 cells. In conclusion, our results suggest that Lut supplementation in a mouse model of colitis improves the symptoms of colitis in mice, which provides a theoretical basis for further application of Lut in the prevention of inflammation-related diseases in humans.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle-Derived miR-200a-3p Through Light-Intensity Exercise May Contribute to Improve Memory Dysfunction in Type 2 Diabetic Mice","authors":"Takeru Shima,&nbsp;Hayate Onishi,&nbsp;Chiho Terashima","doi":"10.1096/fj.202500336R","DOIUrl":"https://doi.org/10.1096/fj.202500336R","url":null,"abstract":"<p>Memory dysfunction associated with type 2 diabetes mellitus (T2DM) poses a threat to well-being. Engaging in light-intensity exercise has favorable effects on hippocampal function and molecular profiles, including <i>Mct2</i> mRNA and miR-200a-3p. Here, we investigated the involvement of exosomal miR-200a-3p secretion from gastrocnemius muscles in T2DM mice undergoing light-intensity exercise intervention, focusing on its potential to ameliorate memory dysfunction. We initially assessed the effects of light-intensity exercise over a 4-week period on memory function, the secretion of gastrocnemius muscle-derived exosomal miR-200a-3p, and hippocampal mRNA. Subsequently, the impact of a daily intraperitoneal injection of the mmu-miR-200a-3p mimic over a 4-week duration on hippocampal dysregulation in ob/ob mice was investigated. The light-intensity exercise intervention improved gastrocnemius muscle-derived and plasma exosomal miR-200a-3p levels in ob/ob mice, concomitant with improved memory dysfunction. Intriguingly, the daily intraperitoneal injection of the mmu-miR-200a-3p mimic also improved memory function in ob/ob mice. Notably, both the exercise intervention and miR-200a-3p mimic treatment induced downregulation in hippocampal <i>Keap1</i> and upregulation in <i>Hsp90aa1</i> and <i>Mct2</i> mRNA in ob/ob mice. These results imply that the augmentation of peripherally derived miR-200a-3p contributes to ameliorating memory dysfunction in T2DM mice undergoing light-intensity exercise, with a possible contribution from gastrocnemius muscle-derived exosomal miR-200a-3p to these exercise effects.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500336R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in Subacute Thyroiditis: Pathogenesis, Diagnosis, and Therapies","authors":"Yuchuan Li,&nbsp;Yue Hu,&nbsp;Yi Zhang,&nbsp;Kewen Cheng,&nbsp;Chunhai Zhang,&nbsp;Junhui Wang","doi":"10.1096/fj.202403264R","DOIUrl":"https://doi.org/10.1096/fj.202403264R","url":null,"abstract":"<div>\u0000 \u0000 <p>Subacute thyroiditis (SAT) is an inflammatory thyroid disease that is often associated with viral infections. In particular, SARS-COV-2 and its vaccine were found to cause SAT during the recent COVID-19 pandemic. However, the pathogenesis, clinical features, and processes still need further profiling. Recently, there are new findings and understanding about the pathogenic mechanisms of SAT. Some HLA genes have been shown to increase the risk of SAT development, and inflammatory cytokine storms could promote the progression of SAT. Some new diagnostic criteria for SAT have been proposed to facilitate clinicians' diagnosis of SAT when facing atypical symptoms in a manner of rapidity and accuracy. Plus, new treatments for SAT with herbal medicines have been proposed recently as an addition to the conventional steroidal drugs and NSAIDs. This review will provide a summary of these recent progresses of SAT on pathogenesis, diagnosis, and therapies with emphasis on the role of a variety of virus pathogens, including the COVID-19 virus.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403264R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Impact of Inflammatory Versus Psychophysiological Stress on Brain-Wide Activation of Melanocortin Receptor 4–Expressing Neurons","authors":"Myunghyun Cheon,&nbsp;Woonhee Kim,&nbsp;ChiHye Chung","doi":"10.1096/fj.202403158R","DOIUrl":"https://doi.org/10.1096/fj.202403158R","url":null,"abstract":"<p>Central melanocortin signaling plays a critical role in maintaining energy homeostasis by regulating energy intake and expenditure, with impairment of this system closely related to metabolic diseases such as obesity. Among melanocortin receptor subtypes, melanocortin receptor 4 (MC4R) is the primary mediator of these effects within the central nervous system. Accumulating evidence suggests that MC4R contributes to stress-induced disruptions in feeding behavior and energy homeostasis. However, the precise neural mechanisms by which stress alters MC4R activity remain incompletely understood. In this study, we compared brain-wide c-Fos expression patterns induced by two distinct stress paradigms: lipopolysaccharide (LPS)-induced inflammatory stress and restraint stress in male mice, and further examined the involvement of MC4R-expressing (MC4R⁺) neurons in these stress conditions. We found that both stressors elicited c-Fos activation in brain areas associated with stress responses as well as feeding regulation. Notably, LPS-induced stress, but not restraint stress, selectively activated MC4R⁺ neurons in the central amygdala (CeA) and oval nucleus of the bed nucleus of stria terminalis (ovBNST). These results highlight the distinct recruitment of MC4R⁺ neurons during acute inflammatory stress in male mice, offering novel insights into the role of MC4R in the stress-induced imbalance of energy homeostasis depending on stressor types.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403158R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR•101 and miR•122 Targeting δ-Catenin to Regulate Keratinocyte Responsiveness to IL-17A in Psoriasis","authors":"Yingjie Shen,&nbsp;Yitong Zhou,&nbsp;Kuziwakwashe Alice Chiwa,&nbsp;Junxin Wang,&nbsp;Shihong Ren,&nbsp;Mingxuan Wang,&nbsp;Hongru Ren,&nbsp;Yeyi Zheng,&nbsp;Ying Yu,&nbsp;Lutao Jiang,&nbsp;Jingmou Yu,&nbsp;Yuchun Qiao,&nbsp;Litai Jin,&nbsp;Jianlin Lou,&nbsp;Xiangkuo Zheng","doi":"10.1096/fj.202500003R","DOIUrl":"https://doi.org/10.1096/fj.202500003R","url":null,"abstract":"<div>\u0000 \u0000 <p>Psoriasis is an immune-mediated inflammatory dermatological disorder characterized by the interaction between immune cells and keratinocytes, which perpetuates cutaneous inflammation and cellular hyperproliferation. In this study, we identified a strong δ-catenin signature in psoriatic skin; however, the precise role of δ-catenin remains to be elucidated. Additionally, we observed that Interleukin (IL)-17A, a pivotal cytokine involved in the development of psoriatic lesions, induces δ-catenin expression in HEKn and HACAT cells. From a mechanistic perspective, δ-catenin initiated NF-κB signaling, subsequently leading to the activation of IL-6 and IL-8 production. Furthermore, silencing δ-catenin expression mitigated IL-17A-induced hyperproliferation of keratinocytes through the NF-κB pathway. Our study further identified miR-101 and miR-122 as upstream regulators of δ-catenin, exerting their effects by downregulating δ-catenin protein levels. We demonstrated that miR-101 and miR-122 can inhibit the hyperproliferation of keratinocytes induced by δ-catenin. These findings validate the role of δ-catenin in the pathogenesis of psoriasis, particularly in keratinocyte-mediated inflammatory responses and cellular hyperproliferation. Consequently, miR-101 and miR-122 hold potential as therapeutic agents in the treatment of psoriasis.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}