American Journal of Pathology最新文献

{"title":"Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice","authors":"Siddhi Jain ,&nbsp;Ranjan Mukherjee ,&nbsp;Gillian Williams ,&nbsp;Jia-Jun Liu ,&nbsp;Lanuza A.P. Faccioli ,&nbsp;Zhiping Hu ,&nbsp;Rodrigo M. Florentino ,&nbsp;George K. Michalopoulos ,&nbsp;Alejandro Soto-Gutierrez ,&nbsp;Silvia Liu ,&nbsp;Joseph Locker ,&nbsp;Bharat Bhushan","doi":"10.1016/j.ajpath.2025.09.010","DOIUrl":"10.1016/j.ajpath.2025.09.010","url":null,"abstract":"<div><div>Despite the well-known role of MET in liver regeneration after partial hepatectomy, its role in the clinically relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from partial hepatectomy because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET knockout (MET KO) mice were administered a toxic dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated the initial hepatotoxicity and consequentially impaired the compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative damage, releasing apoptosis-inducing factor into cytosol. Excess JNK activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET signaling. Pharmacologic activation of AKT reduced JNK activation and hepatotoxicity in MET KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling but also activation of cell death/senescence pathways along with an impaired unfolded protein response in MET KO mice. Analysis of published single-nucleus RNA-sequencing data showed that proliferation in livers from patients with APAP-induced acute liver failure was associated with strong activation of hepatocyte growth factor/MET signaling in hepatocytes, with spatial transcriptomics showing striking induction of hepatocyte growth factor surrounding the necrotic zones. Interestingly, 35% of the genes altered in human acute liver failure were regulated by MET in the mouse AILI model. The current study shows that MET is crucial for restraining hepatotoxicity after APAP overdose via inhibition of the mitochondrial cell death signaling pathway.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 388-406"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211340","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}

{"title":"Macrophages Are Critical Inducers of Bleomycin-Induced Fibrosis in a Systemic Scleroderma Model","authors":"Blandine Baffert ,&nbsp;Kevin Schneider ,&nbsp;Audrey Wetzel ,&nbsp;Ludivine Dal Zuffo ,&nbsp;Cécile Chagué ,&nbsp;Eléa Mitifiot ,&nbsp;Francis Bonnefoy ,&nbsp;Alicja Kuzniewska ,&nbsp;Philippe Saas ,&nbsp;Jamal Bamoulid ,&nbsp;Gwenael Rolin ,&nbsp;Sylvain Perruche ,&nbsp;Sanja Arandjelovic","doi":"10.1016/j.ajpath.2025.09.009","DOIUrl":"10.1016/j.ajpath.2025.09.009","url":null,"abstract":"<div><div>Macrophages are critical regulators of inflammation with an essential role in maintaining and re-establishing homeostasis after inflammatory insults. However, excessive macrophage activation could promote fibrosis, highlighting their potential as a therapeutic target in chronic inflammatory diseases. Two preclinical models of systemic sclerosis, bleomycin-induced systemic scleroderma and sclerodermatous graft-<em>versus</em>-host disease, were used to analyze the role of macrophages in the establishment of fibrosis. In both models, macrophage numbers increase in the skin and lungs, in association with elevated collagen content and correlating with fibrosis development. These macrophages had a Ly6c^lowCD206⁺MerTk⁺ phenotype, suggesting a profibrotic role during disease progression. Using macrophage depletion and differentiation blocking approaches, this work shows that reduced macrophage accumulation effectively prevented bleomycin-induced fibrosis development. Direct profibrotic activity of bleomycin-exposed macrophages was revealed by s.c. macrophage injections in naïve mice, which was sufficient to induce systemic fibrosis. Finally, bleomycin-treated primary mouse and human macrophages display reduced clearance of apoptotic cells and secrete factors that promote fibroblast activation and collagen production. Metabolic and mitochondrial dysfunction, changes in receptor shedding, and cytoskeletal reorganization in bleomycin-treated macrophages further contribute to their impaired efferocytosis and enhanced profibrotic activity. Collectively, this work identifies macrophages as critical promoters of tissue fibrosis and suggests that inhibition of macrophage activation represents a new potent therapeutic avenue in efforts to reverse fibrosis associated with chronic inflammation.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 460-478"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996366","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}

{"title":"Stimulator of Interferon Genes Is a Fine-Tuner, but Not a Prime Mover, of Kidney Inflammation","authors":"Madiha Zahra Syeda ,&nbsp;Emily S.H. Yeung ,&nbsp;Lisa Y.Q. Hong ,&nbsp;Suzanne L. Advani ,&nbsp;Youan Liu ,&nbsp;Laurette Geldenhuys ,&nbsp;Ferhan S. Siddiqi ,&nbsp;Veera Ganesh Yerra ,&nbsp;Sri Nagarjun Batchu ,&nbsp;Andrew Advani","doi":"10.1016/j.ajpath.2025.10.013","DOIUrl":"10.1016/j.ajpath.2025.10.013","url":null,"abstract":"<div><div>Recent years have seen substantial scientific excitement in the role that the double-stranded DNA sensor and mediator of inflammation, stimulator of interferon genes (STING), plays in kidney disease. However, the STING pathway is not the sole regulator of inflammation, and STING has roles other than in inflammation. Here, elevated STING levels were observed in both human and mouse kidney disease, and the effects of STING deletion from kidney tubule cells, myeloid cells, and globally in experimental kidney disease were examined. Inflammatory gene up-regulation in tubule cells, induced by double-stranded DNA, was attenuated (but not negated) by STING knockout. Either myeloid or global knockout of STING marginally diminished fibroinflammatory gene up-regulation in mice with kidney injury caused by unilateral ureteral obstruction, whereas tubule cell knockout of STING unexpectedly augmented inflammatory gene up-regulation. Global knockout of STING similarly worsened diabetic kidney disease, likely due to heightened hyperglycemia. Antagonism of STING attenuated autophagy induction in human tubule cells, but not in human glomerular endothelial cells or podocytes. These findings serve as a counterweight to the enthusiasm that has recently emerged as to the roles of STING-mediated signaling in kidney disease. The actions of STING extend beyond its role in inflammation, and they are cell type dependent. STING may be a fine-tuner, but it is unlikely to be a prime mover, of inflammation in kidney disease.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 515-531"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996367","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}

{"title":"Silencing Ubiquitin-Specific Peptidase 10 Alleviates Persistent Corneal Epithelial Defect in Mice","authors":"Arpan Banerjee ,&nbsp;Mohammad Anjum Shaik ,&nbsp;Christine Tilstra-Smith ,&nbsp;Nileyma Castro ,&nbsp;Jelissa Reynoso-Garcia ,&nbsp;Michael E. Zuber ,&nbsp;Audrey M. Bernstein","doi":"10.1016/j.ajpath.2025.10.006","DOIUrl":"10.1016/j.ajpath.2025.10.006","url":null,"abstract":"<div><div>Persistent corneal epithelial defect is a condition in which the corneal epithelium fails to heal properly after injury, resulting in vision loss. Previous studies demonstrate that the deubiquitinase, ubiquitin-specific peptidase 10 (USP10), is a key regulator of wound healing and scarring in the cornea. Here, a highly modified <em>in vivo</em> self-delivering siRNA (sdRNA) targeting USP10 in a mouse model of persistent corneal epithelial defect was used. In this model, the corneal epithelium is scraped from the basement membrane and, although the wound initially closes, the epithelium re-opens at day 28, thereby modeling a persistent corneal defect. These studies revealed that one dose of USP10-targeting sdRNA after wounding prevented re-opening of the wound at day 28. Optical coherence tomography images, hematoxylin and eosin staining, and immunohistochemistry demonstrated improved corneal morphology and normal epithelial stratification of the regrown epithelium, with re-establishment of hemidesmosomes and reduced scarring and inflammation (CD45⁺ cells). Correspondingly, RNA sequencing of the regenerated corneal epithelium revealed that USP10 knockdown altered gene expression and pathways controlling tissue repair. Specifically, cell proliferation pathways were enhanced, whereas extracellular matrix, integrin, and immune cell signatures that lead to scar formation were reduced. The results demonstrate that a one-time application of <em>in vivo</em> sdRNA targeting USP10 is a novel method to prevent epithelial wound re-opening and subsequent scarring and inflammation and may be useful to promote regenerative healing in other tissues.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 575-597"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476709","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}

{"title":"Inactivation of Atp7b Copper Transporter in Intestinal Epithelial Cells Is Associated with Altered Lipid Processing and Cell Growth Machinery Independent from Hepatic Copper Accumulation and Severity of Liver Histology","authors":"Amanda Caceres ,&nbsp;Noreene M. Shibata ,&nbsp;Christian D. Davalos-Gutierrez ,&nbsp;Gaurav V. Sarode ,&nbsp;Hisham Hussan ,&nbsp;Margarida Bettencourt ,&nbsp;Adriana Fontes ,&nbsp;Hans Zischka ,&nbsp;Svetlana Lutsenko ,&nbsp;Marie C. Heffern ,&nbsp;Valentina Medici","doi":"10.1016/j.ajpath.2025.09.015","DOIUrl":"10.1016/j.ajpath.2025.09.015","url":null,"abstract":"<div><div>The clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and brain, but little is known about the role of other organs expressing the ATP7B copper transporter on metabolic and ultrastructural changes characterizing WD. To examine the consequences of intestinal <em>Atp7b</em> inactivation in the absence of hepatic copper accumulation, a new mouse model (<em>Atp7b</em>^ΔIEC) characterized by enterocyte-specific <em>Atp7b</em> inactivation was generated. <em>Atp7b</em>^ΔIEC mice were compared with wild-type mice with the same genetic background (iWT). The <em>Atp7b</em> global knockout (<em>Atp7b</em>^–/–) model of WD on a C57Bl/6 background was previously generated and compared with its respective wild type (WT). Hepatic copper, lipid metabolism, liver and intestine histology, and electron microscopy were assessed over time up to 30 weeks of age. Although there was no evidence of intestine copper accumulation in <em>Atp7b</em>^ΔIEC mice, transcriptome analysis in <em>Atp7b</em>^ΔIEC mice revealed changes in genes involved in AMP-activated protein kinase signaling, fatty acid metabolism, and cell cycle both with partial overlap between the intestinal epithelial cells and the liver. Mitochondrial and other ultrastructural changes were observed in the intestinal epithelial cells of both <em>Atp7b</em>^–/– and <em>Atp7b</em>^ΔIEC mice. Intestine-specific <em>Atp7b</em> deficit affects systemic metabolic pathways and intestine morphology, and hepatic metabolic perturbations are associated with intestinal dysfunction, independently from hepatic copper accumulation, providing evidence that the WD phenotype is at least partially influenced by organ-specific ATP7B variants.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 407-427"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318061","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}

{"title":"Intrahost Genomic Variation of Haemophilus influenzae Isolates from Asymptomatic Nasopharyngeal Carriers Involves Genes Encoding Proteins with Diverse Inferred Functions","authors":"Randall J. Olsen ,&nbsp;S. Wesley Long ,&nbsp;Yuvanesh Vedaraju ,&nbsp;Sandra Tomasdottir ,&nbsp;Helga Erlendsdottir ,&nbsp;Ásgeir Haraldsson ,&nbsp;Karl G. Kristinsson ,&nbsp;James M. Musser ,&nbsp;Gunnsteinn Haraldsson","doi":"10.1016/j.ajpath.2025.09.014","DOIUrl":"10.1016/j.ajpath.2025.09.014","url":null,"abstract":"<div><div><em>Haemophilus influenzae</em> is a human-specific pathogen that causes infections, ranging in severity from otitis media to potentially fatal meningitis. It also asymptomatically colonizes the upper respiratory tract. Although intrahost genomic variation of <em>H. influenzae</em> has been investigated in some anatomic sites, the genes most frequently acquiring nonsynonymous (amino acid–changing) or nonsense (protein-truncating) single-nucleotide polymorphisms (SNPs) during human carriage remain largely unidentified. To study intrahost genomic variation of <em>H. influenzae</em> during human asymptomatic carriage in the nasopharynx, the genomes of 805 isolates recovered from 24 healthy Icelandic children were sequenced. Most children were colonized with isolates with a single multilocus sequence type, although some were concurrently colonized with isolates with multiple multilocus sequence types. Intrahost genomic variation was discovered, with 120 genes acquiring SNPs in at least one isolate. Among them, 69 genes were recurrently polymorphic in isolates recovered from multiple children, and 72 SNPs occurred in multiple isolates recovered from the same child. The polymorphic genes encode proteins with diverse inferred functions, including transcription regulators and putative virulence factors. Many of the proteins likely play roles in bacterial fitness, virulence, and host-pathogen molecular interactions. This intrahost variation study provides a model for understanding the genomic diversity acquired by <em>H. influenzae</em> during human asymptomatic carriage in the nasopharynx.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 479-492"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312189","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}

{"title":"Prostaglandin E2 Signaling Triggers CD31-Independent Transendothelial Migration in Vitro and in Vivo","authors":"Vanessa Hayashi ,&nbsp;Michael A. Seidman ,&nbsp;William A. Muller","doi":"10.1016/j.ajpath.2025.09.012","DOIUrl":"10.1016/j.ajpath.2025.09.012","url":null,"abstract":"<div><div>Genetic deletion or antibody blockade of platelet endothelial cell adhesion molecule-1 (PECAM; CD31) inhibits transendothelial migration (TEM) of leukocytes in all mouse strains studied except C57BL/6. A prior publication showed that this phenotype maps to a single 35.8-Mb locus on mouse chromosome 2, that contains the genes <em>Ptgs1</em>, <em>Ptges</em>, and <em>Ptges2</em>, which encode key enzymes involved in the prostaglandin E₂ (PGE₂) synthesis pathway. PGE₂ is a proinflammatory lipid mediator that binds four E prostanoid receptors (EPs 1 to 4). It was hypothesized that PGE₂ signaling supports TEM via a CD31-independent mechanism. <em>In vitro</em> TEM assays demonstrate that PGE₂ or 16,16-dimethyl PGE₂ can restore transmigration of polymorphonuclear leukocytes and peripheral blood mononuclear cells despite a TEM blockade with anti-CD31. This protransmigratory effect could be blocked with the EP1 antagonist, SC-51089, or with transient receptor potential canonical 6 antagonist, BI-749327. 17-Phenyl trinor PGE₂, an agonist of EP1 and EP3, also restored transmigration of polymorphonuclear leukocytes blocked with anti-CD31. <em>In vivo</em>, PGE₂ overcame an anti-CD31 blockade when administered to FVB/n mice in thioglycolate peritonitis or croton oil dermatitis models, whereas blocking EP1 with SC-51089 decreased TEM in C57BL/6 <em>pecam1</em>^−/− mice. The findings support earlier data that identified PGE₂ as a candidate inducer of CD31-independent TEM, and pinpoint EP1 as the receptor that relays that signal to activate transient receptor potential canonical 6.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 618-632"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328146","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}

{"title":"The D2.B10-Dmdmdx/J Mouse Model of Duchenne Muscular Dystrophy Exhibits a Severe Mitochondrial Deficiency Not Observed in the C57BL/10ScSn-Dmdmdx/J Mouse","authors":"Jennifer A. Tinklenberg ,&nbsp;Jessica Sutton ,&nbsp;Rebecca A. Slick ,&nbsp;Hui Meng ,&nbsp;Margaret Haberman ,&nbsp;Mariah J. Prom ,&nbsp;Margaret J. Beatka ,&nbsp;Tatyana A. Vetter ,&nbsp;Audrey L. Daugherty ,&nbsp;Christina A. Pacak ,&nbsp;J. Patrick Gonzalez ,&nbsp;Michael W. Lawlor","doi":"10.1016/j.ajpath.2025.09.005","DOIUrl":"10.1016/j.ajpath.2025.09.005","url":null,"abstract":"<div><div>Duchenne muscular dystrophy (DMD) is caused by mutations in the <em>DMD</em> gene, resulting in dystrophin deficiency in skeletal/cardiac muscle and progressive loss of function. Although the genetic causes of DMD have been thoroughly investigated, the energetic consequences have not been well examined across animal models. Previously, the laboratory examined mitochondrial function across nemaline myopathy mouse models of varying disease severity; here, mitochondrial phenotypes in DMD are assessed through the comparison of the milder C57BL/10ScSn-<em>Dmd</em>^<em>mdx</em>/J (B10-<em>mdx</em>) and the more severe D2.B10-<em>Dmd</em>^<em>mdx</em>/J mouse (D2-<em>mdx</em>) mouse models. D2-<em>mdx</em> exhibit a significant decrease in mitochondrial respiration, undetectable ATP concentrations, increased mitochondrial membrane potential, and alterations in electron transport chain enzyme activities. In contrast, B10-<em>mdx</em> show only mild mitochondrial phenotypes, including decreased ATP content. The D2-<em>mdx</em> mouse has genetic modifiers, including latent transforming growth factor-β–binding protein 4 (LTBP4) and annexin A6, that have been shown to alter DMD severity in humans. However, these modifiers did not account for mitochondrial differences seen in <em>mdx</em> mice. Both models were treated with a microdystrophin adeno-associated virus gene therapy to assess whether dystrophin restoration rescued mitochondrial phenotypes. Gene therapy attenuated the ATP deficiency in the B10-<em>mdx</em> mice, but only improved mitochondrial membrane potentials in D2-<em>mdx</em> mice. The exact cause of the D2-<em>mdx</em> mitochondrial phenotypes remains unknown, but secondary disease processes that affect mitochondrial phenotypes should be taken into consideration when choosing an animal model for DMD studies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 532-549"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211343","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}

{"title":"Inhibiting the Secreted RGDKGE Collagen Peptide Selectively Controls CD8+ T-Cell Migration on Denatured Collagen-IV and Enhances Their Accumulation in Tumors","authors":"XiangHua Han,&nbsp;Jennifer M. Caron,&nbsp;Peter C. Brooks","doi":"10.1016/j.ajpath.2025.09.008","DOIUrl":"10.1016/j.ajpath.2025.09.008","url":null,"abstract":"<div><div>The ability of the immune system to control malignant tumors depends in part on the migratory ability of CD8⁺ T cells. Developing in-depth cellular and molecular understanding into how changes in the structural organization of collagen-IV differentially governs site-specific CD8⁺ T-cell migration through restrictive tissue barriers is challenging given the dynamic biomechanical alterations occurring in the basement membranes of tumor blood vessels. Thus, uncovering new mechanisms regulating CD8⁺ T-cell migration through structurally altered or denatured collagen-IV may allow the development of clinically useful strategies to selectively enhance immune cell infiltration of tumors in a context-dependent manner. This work provides evidence that a secreted RGDKGE-containing collagen peptide limits CD8⁺ T-cell migration on denatured forms of collagen-IV, but not on normal triple helical collagen-IV by a unique mechanism. This novel pathway involves the context-dependent regulation of myosin IXB (MYO9B) and Yes-associated protein-1 (YAP) in CD8⁺ T cells, ultimately leading to altered F-actin polarization and selectively reduced migration on denatured collagen-IV that is enriched in basement membranes of tumor vessels. In addition to defining a previously unknown mechanism that contributes to the site-specific control of CD8⁺ T-cell migration, these studies provide a strategy to selectively reverse the inhibitory effects of this endogenously secreted collagen peptide using a function-blocking antibody, resulting in enhanced accumulation of CD8⁺ T cells in tumors growing <em>in vivo</em>.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 2","pages":"Pages 598-617"},"PeriodicalIF":3.6,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996368","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}

{"title":"The Sugar-Coated Truth of Alcohol-Associated Liver Disease","authors":"Doug Terry,&nbsp;Brian S. Robinson","doi":"10.1016/j.ajpath.2025.07.013","DOIUrl":"10.1016/j.ajpath.2025.07.013","url":null,"abstract":"<div><div>Alcohol-associated diver disease is a major driver of end-stage liver diseases globally. Alcohol functions as a hepatotoxin by overwhelming cell stress response pathways and deregulating hepatocellular protein, amino acid, and lipid metabolism. In addition, alcohol alters innate and adaptive inflammatory immune responses and acts on extrahepatic organs to flood the liver with pro-inflammatory stimuli. Here we examine how galectins, a class of highly conserved carbohydrate-binding proteins, regulate liver homeostasis and pathology. Next, we define how galectins affect key pathways that drive alcohol-induced liver disease, including hepatocyte cell biology (eg, altered lipid metabolism, endoplasmic reticulum and lysosomal stress, mitochondrial dysfunction), innate and immune response, intestinal dysfunction, and liver fibrosis. We then document the roles of galectins in the setting of alcohol-associated liver disease. Finally, we discuss galectins as theragnostic markers and therapeutic targets for alcohol-associated liver disease and address key open questions in the field.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 1","pages":"Pages 161-171"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939071","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}