American Journal of Pathology最新文献_第2页

The Gut-Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease and Associated Hepatocellular Carcinoma: Pathogenesis and Therapeutic Interventions. 代谢功能障碍相关脂肪性肝病和相关肝细胞癌的肠-肝轴：发病机制和治疗干预

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-25 DOI: 10.1016/j.ajpath.2026.09.004

Qian Huai, Xiaolei Li, Hua Wang, Shi Yin

{"title":"The Gut-Liver Axis in Metabolic Dysfunction-Associated Steatotic Liver Disease and Associated Hepatocellular Carcinoma: Pathogenesis and Therapeutic Interventions.","authors":"Qian Huai, Xiaolei Li, Hua Wang, Shi Yin","doi":"10.1016/j.ajpath.2026.09.004","DOIUrl":"10.1016/j.ajpath.2026.09.004","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases from simple steatosis to metabolic dysfunction-associated steatohepatitis and its associated fibrosis, cirrhosis, and MASLD-associated hepatocellular carcinoma (MASLD-HCC). MASLD affects over one-third of the global adult population and is closely associated with insulin resistance, obesity, genetic factors, and, increasingly recognized, gut microbiome dysbiosis. The gut-liver axis, referring to the communication network between the intestinal microbiota and liver, is critical to the progression of MASLD. The gut microbiota composition and/or functions are disrupted, leading to intestinal barrier destruction, systemic inflammation, and modulation of hepatic metabolism and immune responses. This review aims to summarize the effects of gut microbiota on MASLD and its malignant transition to associated HCC based on the roles of microbial metabolites, immune regulation, and associated genetic factors, and to discuss the potential application of microbiome-targeted therapeutic strategies, including probiotics and prebiotics, synbiotics and postbiotics, fecal microbiota transplantation, engineered bacteria and bacteriophage therapy, small-molecule inhibitors, and microbiota-derived metabolites, with the aim of providing a new vision in the treatment of MASLD and MASLD-HCC. Finally, current challenges in basic and clinical research of the role of microbiome in MASLD are discussed, and future directions are proposed to drive progress in this field.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Context-Dependent Roles of Mouse Corneal Epithelial Cell-Derived Exosomes in Diabetic Corneal Wound Healing. 小鼠角膜上皮细胞来源的外泌体在糖尿病角膜伤口愈合中的作用

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-25 DOI: 10.1016/j.ajpath.2026.08.009

Nan Gao, Qi Chen, Paul M Stemmer, Fu-Shin X Yu

{"title":"Context-Dependent Roles of Mouse Corneal Epithelial Cell-Derived Exosomes in Diabetic Corneal Wound Healing.","authors":"Nan Gao, Qi Chen, Paul M Stemmer, Fu-Shin X Yu","doi":"10.1016/j.ajpath.2026.08.009","DOIUrl":"10.1016/j.ajpath.2026.08.009","url":null,"abstract":"Delayed corneal wound healing and sensory neuropathy are hallmarks of diabetic keratopathy, yet the role of corneal epithelial cell (CEC)-derived exosomes in these processes remains unclear. This study characterized exosomes secreted by the mouse corneal epithelial progenitor cell line TKE2 at either quiescent state or scratch wounded. The isolated extrasellar vesicles were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blot analysis. Exosomal cargo was analyzed by liquid chromatography-tandem mass spectrometry proteomics. The roles of exosome and selected proteins were assessed for effects on wounded healing of normoglycemic and streptozotocin-induced diabetic C57BL/6J mice. The isolated vesicles exhibited canonical exosomal features and were readily taken up by CEC at 1 dpw and trigeminal sensory neurons at 3 dpw. Exosomes derived from healing, but not quiescent, cultures accelerated delayed epithelial wound closure in diabetic corneas, while having little effect on normoglycemic corneas. High-temperature requirement A serine peptidase 1, enriched in healing exosomes, contributed to epithelial wound healing in normal corneas, as its inhibition attenuated wound closure in normoglycemic but not diabetic mice. In contrast, treating healing exosomes with a STAT3 inhibitor, which permanently blocks its activity without altering protein content, partially reduced exosome-mediated wound healing in diabetic corneas. Collectively, these findings support context-dependent effects of CEC-derived exosomes in corneal wound repair and suggest that exosomal components may contribute to the regulation of diabetic corneal wound healing.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149057094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transforming Growth Factor-β3-Mediated Suppression of SOX2 and OCT4 Drives a Predominantly Noncanonical Profile of Epithelial-Mesenchymal Transition during Palatal Fusion. 在腭融合过程中，TGF-β3介导的SOX2和OCT4的抑制主要驱动非典型的上皮-间质转化。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-23 DOI: 10.1016/j.ajpath.2026.09.002

Natcha Mahatumarat, Sarina Sahmeddini, Carla Alvarez-Rivas, Tomaz Alves, Leticia Rojas Cortez, Saba Mohammadi, Dorathy Vargas, Melih Motro, Leslie A Will, Philip C Trackman, Alpdogan Kantarci

{"title":"Transforming Growth Factor-β3-Mediated Suppression of SOX2 and OCT4 Drives a Predominantly Noncanonical Profile of Epithelial-Mesenchymal Transition during Palatal Fusion.","authors":"Natcha Mahatumarat, Sarina Sahmeddini, Carla Alvarez-Rivas, Tomaz Alves, Leticia Rojas Cortez, Saba Mohammadi, Dorathy Vargas, Melih Motro, Leslie A Will, Philip C Trackman, Alpdogan Kantarci","doi":"10.1016/j.ajpath.2026.09.002","DOIUrl":"10.1016/j.ajpath.2026.09.002","url":null,"abstract":"Epithelial-mesenchymal transition (EMT) of medial edge epithelial cells is a critical mechanism underlying embryonic palatal fusion, driven by transforming growth factor-β3 (TGF-β3). However, its regulatory interplay with pluripotency factors (SOX2/OCT4) and reliance on downstream cascades remain poorly understood. This study investigates these networks to elucidate the mechanisms of cellular reprogramming during palatogenesis. Embryonic day 15 C57BL6/J mouse palatal epithelial cells were isolated to eliminate mesenchymal interference. Cells were subjected to recombinant TGF-β3 (1, 3, and 10 ng/mL) or targeted siRNA knockdowns of Tgfb3, Sox2, Oct4, and Smad2/3, and evaluated via RNA sequencing, quantitative RT-PCR, immunofluorescence, transepithelial electrical resistance, and flow cytometry. Treatment with 1 to 3 ng/mL TGF-β3 successfully induced EMT in vitro, characterized by decreased E-cadherin, increased fibronectin, diminished membrane resistance, and a fibroblast-like morphologic shift. This transition was predominantly associated with noncanonical pathways; phosphorylated Smad2/3 levels remained unchanged, whereas Smad-independent mediators (p38 mitogen-activated protein kinase and Mmp13) were up-regulated (P < 0.05). Furthermore, TGF-β3 down-regulated the pluripotency markers Sox2 and Oct4 (P < 0.05). Combined Sox2/Oct4 knockdown with TGF-β3 yielded the most pronounced EMT characteristic. Although Tgfb3 knockdown heavily attenuated EMT, partial mesenchymal transition persisted, indicating redundant compensatory networks. In conclusion, optimal TGF-β3 concentrations (1 to 3 ng/mL) shift EMT toward Smad-independent pathways during palatogenesis. This reprogramming requires TGF-β3 to suppress SOX2 and OCT4, underlining their roles as negative regulators of EMT during palatal fusion.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transforming Growth Factor-β-Activated Kinase 1 Impedes Peripheral Nerve Regeneration after Injury by Evoking Sustained Inflammation. TAK1通过引发持续炎症阻碍损伤后周围神经再生。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-22 DOI: 10.1016/j.ajpath.2026.09.001

Xiaoyu Liu, Shouping Zhang, Zhiguan Wu, Meichen Zhang, Qianqian Ju, Xin Tang, Yu Chen, Cheng Sun

{"title":"Transforming Growth Factor-β-Activated Kinase 1 Impedes Peripheral Nerve Regeneration after Injury by Evoking Sustained Inflammation.","authors":"Xiaoyu Liu, Shouping Zhang, Zhiguan Wu, Meichen Zhang, Qianqian Ju, Xin Tang, Yu Chen, Cheng Sun","doi":"10.1016/j.ajpath.2026.09.001","DOIUrl":"10.1016/j.ajpath.2026.09.001","url":null,"abstract":"Peripheral nerve injury often leads to severe functional deficits, yet the molecular mechanisms underlying nerve regeneration remain incompletely understood. Here, the function of transforming growth factor-β-activated kinase 1 (TAK1) in peripheral nerve regeneration was examined using murine and rat models of sciatic nerve injury. The results show that TAK1 overexpression impairs nerve regeneration and functional recovery, whereas pharmacologic inhibition of TAK1 with takinib promotes these processes. Mechanistically, the detrimental effects of TAK1 are associated with sustained inflammatory responses within the sciatic nerve. TAK1 is predominantly expressed in Schwann cells and fibroblasts in the sciatic nerve, where it activates NF-κB signaling. Specifically, TAK1 phosphorylates protein phosphatase 1 regulatory subunit 18 at serine 213, thereby relieving its suppression on the NF-κB pathway and facilitating the nuclear accumulation of NF-κB p65. This activation drives chemokine expression, leading to enhanced recruitment of M1 macrophages and the establishment of a proinflammatory microenvironment that impedes remyelination and nerve regeneration. Collectively, these findings identify TAK1 as a critical negative regulator of peripheral nerve repair and highlight TAK1 inhibition as a potential therapeutic approach for improving recovery following peripheral nerve injury.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Complement Factor B Blockade by Iptacopan Drives Antitumor Complement-Based Immunomodulation in Pancreatic Cancer Microenvironment. iptacopan阻断补体因子B驱动胰腺癌微环境中抗肿瘤补体免疫调节。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-22 DOI: 10.1016/j.ajpath.2026.08.005

Daren Zhou, Shigetsugu Takano, Kazuyuki Sogawa, Ryo Moriyasu, Tsukasa Takayashiki, Daisuke Suzuki, Nozomu Sakai, Masayuki Ohtsuka

{"title":"Complement Factor B Blockade by Iptacopan Drives Antitumor Complement-Based Immunomodulation in Pancreatic Cancer Microenvironment.","authors":"Daren Zhou, Shigetsugu Takano, Kazuyuki Sogawa, Ryo Moriyasu, Tsukasa Takayashiki, Daisuke Suzuki, Nozomu Sakai, Masayuki Ohtsuka","doi":"10.1016/j.ajpath.2026.08.005","DOIUrl":"10.1016/j.ajpath.2026.08.005","url":null,"abstract":"Recent advanced comprehensive analyses reveal complement factors as critical regulators of cancer-immune system interactions. It was previously identified that complement factor B (CFB), a key secreted component of the alternative complement pathway, is aberrantly up-regulated in pancreatic ductal adenocarcinoma (PDAC) and contributes to tumor progression. Iptacopan (LNP023), a selective CFB inhibitor, has established efficacy in complement-mediated disorders; however, its anticancer potential remains unexplored. The effects of iptacopan on PDAC cell biology and the tumor immune microenvironment were investigated using in vitro assays and orthotopic mouse models. Iptacopan significantly suppressed human and murine PDAC cell proliferation and enhanced gemcitabine cytotoxicity. Mechanistically, CFB inhibition induced senescence, as evidenced by increased senescence-associated β-galactosidase activity and p21 up-regulation. In in vivo preclinical studies, iptacopan reduced tumor growth, diminished intratumoral CFB and C5b-9 deposition, and increased p21 expression, indicating tumor-localized complement inhibition. Furthermore, iptacopan decreased conventional Foxp3+ regulatory T cells and the immunosuppressive CD8+/Foxp3+ regulatory T-cell subset while enhancing CD8+ tumor-infiltrating lymphocytes, reshaping the tumor immune microenvironment. Combination therapy with immune checkpoint blockades (anti-programmed death-1 and anti-cytotoxic T-lymphocyte-associated protein 4) further augmented antitumor effects, and triple therapy with gemcitabine/nab-paclitaxel yielded the greatest tumor suppression. These results show that iptacopan exerts dual antitumor effects by inducing tumor-intrinsic senescence and promoting an immunostimulatory tumor immune microenvironment. CFB inhibition therefore represents a promising complement-based immunomodulatory treatment for PDAC.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Immunologically Active Cardiac Fibroblasts Expressing Major Histocompatibility Complex-II Promote Doxorubicin Cardiotoxicity. 免疫活性心脏成纤维细胞表达MHC-II促进阿霉素心脏毒性。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-21 DOI: 10.1016/j.ajpath.2026.08.007

Maria Antonia Zambrano, Abraham L Bayer, Ramon Bossardi Ramos, Constanza Stortini, Kuljeet Kaur, Kenneth Bedi, Kenneth B Margulies, Pilar Alcaide

{"title":"Immunologically Active Cardiac Fibroblasts Expressing Major Histocompatibility Complex-II Promote Doxorubicin Cardiotoxicity.","authors":"Maria Antonia Zambrano, Abraham L Bayer, Ramon Bossardi Ramos, Constanza Stortini, Kuljeet Kaur, Kenneth Bedi, Kenneth B Margulies, Pilar Alcaide","doi":"10.1016/j.ajpath.2026.08.007","DOIUrl":"10.1016/j.ajpath.2026.08.007","url":null,"abstract":"A common adverse effect of the chemotherapeutic anthracycline, doxorubicin, is cardiotoxicity and progression to heart failure. Patients treated with anthracyclines show increased circulating cytotoxic CD8+ interferon (IFN)-γ+ T cells. In mice, cumulative doses of doxorubicin also result in increased circulating and cardiac infiltrating CD8+IFN-γ+ T cells, and these cells are required for pathologic fibrosis and contractile dysfunction. The present study demonstrates that cardiac fibroblasts become immunologically active and express major histocompatibility complex (MHC) class II on the onset of doxorubicin cardiotoxicity in humans and in mice. Using adoptive transfer and in vitro mechanistic studies, the results show that CD8+IFN-γ+ T cells are required for cardiac fibroblast expression of MHC-II in mice treated with doxorubicin, and that doxorubicin induces cardiac fibroblast expression of CXCL9, resulting in CD8+IFN-γ+ T-cell cardiotropism. Selective deletion of MHC-II in cardiac fibroblasts ameliorates systolic dysfunction and dampens cardiac fibrosis induced by doxorubicin in mice. Mechanistically, this study shows that cardiac fibroblast MHC-II is required for cardiac CD4+IFN-γ+ T-cell infiltration and proliferation, necessary for cardiac CD8+ T-cell immune responses and cytotoxicity. These results position cardiac fibroblast MHC-II as a key mediator of contractile dysfunction in doxorubicin cardiotoxicity.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retinal Inflammation in Diabetes. 糖尿病视网膜炎症。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-19 DOI: 10.1016/j.ajpath.2026.08.004

Irina De la Huerta, M D Imam Uddin, Milind N Muthiah, John S Penn

引用次数: 0

Establishment of a Colorectal Cancer Liver Metastasis Solitary Tumor Mouse Model. 结直肠癌肝转移孤立性肿瘤小鼠模型的建立。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-19 DOI: 10.1016/j.ajpath.2026.08.008

Audrey Kapelanski-Lamoureux, Shuo Ren, Anastasia Tsatoumas, Anthoula Lazaris, Peter Metrakos

引用次数: 0

IL-17 and IL-6 Trans-Signaling Coordinate Mesothelial Vascular Endothelial Growth Factor Production and Angiogenesis in the Peritoneum. IL-17和IL-6反式信号调节腹膜间皮血管内皮生长因子的生成和血管生成。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-09-19 DOI: 10.1016/j.ajpath.2026.08.006

Rusan Catar, Edyta Kawka, Michael Adu-Gyamfi, Nada Al-Arawe, Pinchao Wang, Zexian Gong, Maria Bartosova Medvid, Joanna Żuraszek-Szymańska, Muhammad I Ashraf, Bruno Ranchin, Julian Kamhieh-Milz, Honorata Stadnik, Marek Karczewski, Guido Moll, Claus P Schmitt, Achim Jörres, Janusz Witowski

{"title":"IL-17 and IL-6 Trans-Signaling Coordinate Mesothelial Vascular Endothelial Growth Factor Production and Angiogenesis in the Peritoneum.","authors":"Rusan Catar, Edyta Kawka, Michael Adu-Gyamfi, Nada Al-Arawe, Pinchao Wang, Zexian Gong, Maria Bartosova Medvid, Joanna Żuraszek-Szymańska, Muhammad I Ashraf, Bruno Ranchin, Julian Kamhieh-Milz, Honorata Stadnik, Marek Karczewski, Guido Moll, Claus P Schmitt, Achim Jörres, Janusz Witowski","doi":"10.1016/j.ajpath.2026.08.006","DOIUrl":"10.1016/j.ajpath.2026.08.006","url":null,"abstract":"Peritoneal angiogenesis is a key determinant of long-term peritoneal dialysis outcomes, yet the contribution of IL-17 remains unclear. This study examined the association between IL-17 and peritoneal vascularity in patients undergoing peritoneal dialysis and defined mechanisms linking IL-17 to vascular endothelial growth factor (VEGF) expression in human peritoneal mesothelial cells. Peritoneal biopsies showed sparse IL-17 expression, but IL-17 positivity correlated with increased IL-6 and VEGF expression and higher CD31+ microvessel density, indicating a coordinated pro-angiogenic network. In vitro, IL-17 induced IL-6 mRNA and protein in human peritoneal mesothelial cells in a time- and dose-dependent manner but did not directly stimulate VEGF. However, combined IL-17 and soluble IL-6 receptor markedly increased VEGF mRNA, promoter activity, and protein secretion, consistent with IL-6 trans-signaling. Genetic or antibody-mediated inhibition of IL-6 abolished VEGF induction, confirming IL-6 dependency. Mechanistically, VEGF induction by IL-17 + soluble IL-6 receptor was mediated by STAT3 and was independent of specificity protein 4 (SP4), despite IL-6-dependent SP4 up-regulation. Promoter analysis identified a VEGF region (-1290/-791) required for responsiveness, containing activator protein 1 (AP-1) and NF-κB binding sites. STAT3 acted upstream of AP-1 activation through induction of cellular Fos proto-oncogene protein (c-FOS), whereas NF-κB contributed directly to promoter activation and indirectly by enhancing IL-6 expression. These findings identify IL-17 as an indirect driver of peritoneal angiogenesis via IL-6 trans-signaling and coordinated STAT3, AP-1, and NF-κB activation.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteasome Dysfunction in Basal Keratinocytes Drives Epidermal Disruption and Dermal Inflammation. 基底角质形成细胞的蛋白酶体功能障碍驱动表皮破坏和皮肤炎症。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-08-31 DOI: 10.1016/j.ajpath.2026.08.003

Junko Morimoto, Hisanori Uehara, Koji Yasutomo

{"title":"Proteasome Dysfunction in Basal Keratinocytes Drives Epidermal Disruption and Dermal Inflammation.","authors":"Junko Morimoto, Hisanori Uehara, Koji Yasutomo","doi":"10.1016/j.ajpath.2026.08.003","DOIUrl":"10.1016/j.ajpath.2026.08.003","url":null,"abstract":"Epidermal keratinocyte differentiation and cell death are tightly regulated to maintain skin homeostasis, and their disruption leads to severe skin disorders. Proteasome dysfunction has been implicated in proteasome-associated autoinflammatory syndromes, which are characterized by dermal inflammation, as well as in keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome caused by mutations in proteasome maturation protein. However, skin manifestations in proteasome-related disorders have been attributed to distinct cellular origins, rendering it unclear whether keratinocyte-intrinsic proteasome dysfunction is a common driver of both epidermal pathology and dermal inflammation. Here, it is demonstrated that keratinocyte-specific deletion of the standard proteasome subunit β5 results in neonatal lethality associated with complete loss of the epidermis. Inducible deletion of β5 in basal keratinocytes led to impaired epidermal differentiation, reduced proliferation, and apoptosis, accompanied by accumulation of ubiquitinated proteins without evidence of endoplasmic reticulum stress. Notably, proteasome dysfunction induced epidermal hyperplasia with spongiosis, followed by epidermolysis. Although this genetic alteration was restricted to keratinocytes, pronounced infiltration of neutrophils and macrophages was observed in the dermis, together with elevated expression of inflammatory mediators. These findings demonstrate that proteasome dysfunction in basal keratinocytes disrupts epidermal integrity and triggers secondary dermal inflammation, providing insight into the skin pathology associated with proteasome-related disorders.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0