{"title":"Temporal dynamics of thermal warming in brown trout hepatocyte spheroids: ultrastructural and immunocytochemical evidence of cellular remodelling.","authors":"Rodrigo Alves, Fernanda Malhão, Célia Lopes, Eduardo Rocha, Tânia Vieira Madureira","doi":"10.1007/s00441-026-04089-y","DOIUrl":"10.1007/s00441-026-04089-y","url":null,"abstract":"<p><p>Temperature is a key environmental driver of hepatic physiology in ectotherms, and three-dimensional (3D) fish liver models may serve as an ethically advantageous platform to investigate warming effects under controlled conditions while reducing the need for experimental animals. Despite their increasing use in toxicology, their application to assess climate-relevant temperature effects on liver function remains limited. This study investigated the temporal effects of a warming scenario on primary hepatocyte spheroids from juvenile brown trout (Salmo trutta), a bioindicator species. The study explores how a + 3 °C increase can affect spheroid development and maintenance, as well as its impact on metabolic activity, cell proliferation and death, and morphology over time. Spheroids were maintained at 18 °C and 21 °C for 25 days and analysed at five time points using metabolic, morphometric, immunocytochemical, and ultrastructural approaches. Mitochondrial metabolic activity, assessed by resazurin reduction, showed no significant temperature-related differences. In contrast, warming accelerated spheroid formation and produced larger spheroids. Proliferative activity, assessed by proliferating cell nuclear antigen (PCNA) immunostaining, was significantly reduced at 21 °C, while caspase-3 levels remained unchanged, indicating no increase in apoptosis. The autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3A/B) showed lower immunoreactivity at 21 °C, with no temporal variation. Ultrastructural analysis revealed preserved hepatocyte integrity at both temperatures and abundant cytoplasmic dense bodies consistent with autolysosomal structures, which increased over time. Overall, a realistic warming scenario altered growth dynamics and cellular morphology. Further, this data reinforces that 3D fish liver models are viable alternative systems for assessing climate-driven effects.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"405 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Integrated morphological analyses of Cladomorphus phyllinus and transcriptomic analysis of Cladomorphus trimariensis provide insights into the cardiac morphophysiology of stick insects (Phasmida: Phasmatidae).","authors":"Vinícius Cordeiro Rocha, Henrique Barbosa da Silva, Renata Cristina Barbosa, Gustavo Ferreira Martins","doi":"10.1007/s00441-026-04088-z","DOIUrl":"10.1007/s00441-026-04088-z","url":null,"abstract":"","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"405 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13328124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura Hannig, Barbara M Braunger, Nikolai Kleefeldt, Lea Cagol, Jonathan Zimmermann, Bianka Brunne, Hamza Ahmad, Mario Vallon, Süleyman Ergün, Jost Hillenkamp, Andreas Neueder, Anja Schlecht
{"title":"Deletion of CEACAM1 does not affect retinal and choroidal morphology or transcriptome.","authors":"Laura Hannig, Barbara M Braunger, Nikolai Kleefeldt, Lea Cagol, Jonathan Zimmermann, Bianka Brunne, Hamza Ahmad, Mario Vallon, Süleyman Ergün, Jost Hillenkamp, Andreas Neueder, Anja Schlecht","doi":"10.1007/s00441-026-04087-0","DOIUrl":"10.1007/s00441-026-04087-0","url":null,"abstract":"<p><p>CEACAM1 (CC1) is an important mediator of cell proliferation and adhesion and serves as an angiogenic factor through interaction with VEGF. Although the role of CC1 has been extensively studied in organs such as the heart, liver and lung in which CC1 is considered an important regulator of various pathological conditions, little is known about the function of CEACAM1 in the eye. In this study, we investigated the expression and function of CC1 in the retina and choroid of healthy adult mice using immunohistochemistry, fluorescence activated cell sorting (FACS) and RNA sequencing. We found CC1 to be expressed in endothelial and myeloid cells of the retina and the choroid. However, deletion of CC1 did not result in vascular abnormalities of the retina and choroid or changes in retinal myeloid cell morphology and number. Furthermore, the retinal architecture was not affected and morphometric measurements of the thickness of the inner and outer retinal layers were not altered by deletion of CC1. Accordingly, we did not observe structural or transcriptomic changes in the choroid. Our data suggest that the role of CC1 in the adult eye during steady state is attenuated or can be compensated by other molecular mediators. However, one could speculate that CC1 may become functionally relevant during pathological conditions, such as in neovascular eye diseases like proliferative diabetic retinopathy or neovascular age-related macular degeneration.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"405 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shaoxian Wang, Zhenjun Li, Ning Yang, Jie Xu, Bo Yang, Zengxiang Dong, Xiaohui Zhou, Wei Han
{"title":"Cardiac α2δ1 C-terminal contributes to left atrial hypertrophy in chronic ischemic heart failure, in association with changes in membrane GluN1 and p-CAMKII/p-HDAC4 signaling.","authors":"Shaoxian Wang, Zhenjun Li, Ning Yang, Jie Xu, Bo Yang, Zengxiang Dong, Xiaohui Zhou, Wei Han","doi":"10.1007/s00441-026-04086-1","DOIUrl":"10.1007/s00441-026-04086-1","url":null,"abstract":"<p><p>Left atrial remodeling (LAR) critically contributes to the progression of heart failure (HF) and the development of atrial fibrillation (AF) following myocardial infarction (MI). The protein α2δ1, primarily known for its role in neuropathic pain, is abundantly expressed in atrial tissue, but its involvement in post-MI LAR remains unclear. Here, LAR models were established in rats post-MI, and atrial hypertrophy was induced in HL-1 cells using angiotensin II (AngII). The role of α2δ1 in atrial hypertrophy was examined through treatment with either the α2δ1 inhibitor gabapentin or a C-terminal interfering peptide (α2δ1 CT-pep). A significant upregulation of α2δ1 expression was observed in the left atrium (LA) of MI rats and in AngII-treated HL-1 cells. Western blot analysis revealed increased α2δ1 levels in membrane fractions and decreased levels in the cytoplasmic fractions compared to controls. Both gabapentin and α2δ1 CT-pep treatment significantly reduced HL-1 cell hypertrophy and inhibited CAMKII and HDAC4 phosphorylation. Co-immunoprecipitation assays demonstrated an interaction between α2δ1 and GluN1, which was enhanced by AngII stimulation. Inhibition of α2δ1 attenuated the α2δ1-GluN1 interaction and reduced GluN1 translocation to the plasma membrane. In MI-induced HF rats, gabapentin treatment diminished atrial hypertrophy, suppressed AF inducibility and duration, and decreased membrane-associated α2δ1 and GluN1 levels. These findings suggest that the C-terminal domain of α2δ1 may contribute to left atrial hypertrophy in chronic ischemic heart failure and is associated with altered membrane GluN1 abundance and p-CAMKII/p-HDAC4 signaling. α2δ1 may therefore represent a potential therapeutic target for left atrial remodeling in ischemic heart failure.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"405 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonathan M Wilson, Chris M Wood, Pierre Laurent, Claudine Chevalier, Patrícia G Ferreira, Kevin V Brix, Gudrun DeBoeck, Harold L Bergman, Adalto Bianchini, Lucas Feijó Bianchini, John N Maina, Ora E Johannsson, Geraldine D Kavembe, Michael B Papah, Rodi O Ojoo
{"title":"Gill ionocytes of the Lake Magadi tilapia (Oreochromis Alcolapia grahami), an extremophilic teleost native to a highly alkaline environment.","authors":"Jonathan M Wilson, Chris M Wood, Pierre Laurent, Claudine Chevalier, Patrícia G Ferreira, Kevin V Brix, Gudrun DeBoeck, Harold L Bergman, Adalto Bianchini, Lucas Feijó Bianchini, John N Maina, Ora E Johannsson, Geraldine D Kavembe, Michael B Papah, Rodi O Ojoo","doi":"10.1007/s00441-026-04081-6","DOIUrl":"10.1007/s00441-026-04081-6","url":null,"abstract":"<p><p>The Magadi tilapia thrives in arguably the most extreme aquatic environment on earth for fish, the hot springs of Lake Magadi in Kenya with its severe water chemistry: pH 10, alkalinity 300 mEq·L<sup>-1</sup>. This fish is 100% ureotelic yet has an osmoregulation pattern typical of marine teleosts, although the dominant water anion is HCO<sub>3</sub><sup>-</sup> rather than Cl<sup>-</sup>. The gills must actively export base equivalents (HCO<sub>3</sub><sup>-</sup> + CO<sub>3</sub><sup>2-</sup>) and Na<sup>+</sup> against strong electrochemical gradients, yet simultaneously take up Cl<sup>-</sup>, for which a hypothetical \"Laurent model\" based on ionocyte structure alone was proposed. This model has been tested using immunohistochemistry to characterize ionocyte types based on ion transport protein expression patterns [CFTR anion channel, Na<sup>+</sup>:K<sup>+</sup>:2Cl- cotransporter (NKCC)/Na<sup>+</sup>:Cl<sup>-</sup> cotransporter (NCC), Na<sup>+</sup>:HCO<sub>3</sub><sup>-</sup> co-transporter (NBC), Na<sup>+</sup>/K<sup>+</sup>-ATPase (NKA), and urea transporter (UT)]. A typical \"seawater ionocyte\" (Type IV) with apical CFTR and basolateral NKCC1 and NKA, is present validating key elements of the model. A \"freshwater ionocyte\" (Type II) is also present (apical NCC, weaker NKA and strong NBCe1 basolateral staining). A third Type I ionocyte with only NKA staining was also identified. An acid excreting Type III ionocyte (apical NHE3 and basolateral NKA) was not present. The Magadi tilapia is unusual in having co-expression of both Type IV and Type II ionocytes, which are typically associated with Cl<sup>-</sup> excretion and uptake, respectively. Instead, we propose Type IV ionocytes are involved in base equivalent and Na<sup>+</sup> excretion and Type II ionocytes in Cl<sup>-</sup> uptake. In these ureotelic fishes, the UT occurs only in lamellar pavement cells.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"405 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Integrated morphological analyses of Cladomorphus phyllinus and transcriptomic analysis of Cladomorphus trimariensis provide insights into the cardiac morphophysiology of stick insects (Phasmida: Phasmatidae).","authors":"Vinícius Cordeiro Rocha, Henrique Barbosa da Silva, Renata Cristina Barbosa, Gustavo Ferreira Martins","doi":"10.1007/s00441-026-04084-3","DOIUrl":"10.1007/s00441-026-04084-3","url":null,"abstract":"<p><p>The heart of Phasmida (stick insects) remains poorly understood, particularly regarding its overall physiology and associated cells. Here, we integrate the morphology of the heart and associated cells in Cladomorphus phyllinus with transcriptomic profiling of corresponding structures in Cladomorphus trimariensis. The heart is a tubular structure composed of cardiomyocytes physically associated with alary muscles, with a location and structure similar to that described in other insects. Numerous pericardial cells are organized in cord-like aggregations around the heart, displaying abundant membrane invaginations and an extensive endocytic and lysosomal machinery, consistent with their role in hemolymph filtration. Given their abundance, these cells likely represent the main source of the numerous transcripts related to endocytosis, vesicular trafficking and lysosome-mediated digestion. Hemocytes are also present around the heart, often forming aggregations indicative of immune responses. The transcriptomic analysis indicates immune activity, including melanization and antibacterial defense, predominantly driven by the hemocytes, with the pericardial cells providing a supportive role. Our results confirm that heart and associated cells act not only in hemolymph propulsion, but also as a site involved in maintaining hemolymph homeostasis and immune defense. This work provides an integrated morphological and functional framework for the circulatory system of Phasmida, expanding comparative perspectives across insects.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"405 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13287227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Silvana Piersanti, Manuela Rebora, Gianandrea Salerno, Sylvia Anton
{"title":"Antennal sensilla and brain morphology during development in caddisflies.","authors":"Silvana Piersanti, Manuela Rebora, Gianandrea Salerno, Sylvia Anton","doi":"10.1007/s00441-026-04085-2","DOIUrl":"10.1007/s00441-026-04085-2","url":null,"abstract":"<p><p>The present study investigates the antennae and brain of the immature stages of the caddisfly Hydropsyche pellucidula (Andersen, and Klubnes 1834) using scanning and transmission electron microscopy as well as fluorescence microscopy. The larval antenna is unsegmented and bears two long, articulated trichoid sensilla and two large, non-articulated basiconic sensilla, all with an internal structure typical of mechanoreceptors. No changes were detected between the larval stages examined, but larval sensilla differ completely from the adult sensilla previously described in the same species, which include several chemoreceptors (e.g. trichoid, pseudoplacoid, pseudoplacoid, chaetoid, coronary, and styloconic sensilla). A preliminary account of larval brain anatomy reveals a small central body without columnar elements, mushroom bodies without calyces, and no antennal lobes in any larval stage. This condition differs markedly from the pupal brain, which-similar to the adult brain-shows a central body with a vague fan-shaped structure, mushroom bodies with small calyces, and well-structured antennal lobes containing few but relatively large glomeruli. Such dramatic change is similar to what occurs in other closely related holometabolous insects, such as Lepidoptera, but it is more pronounced, probably because of the ecological differences between larvae and adults, as also observed in other aquatic insects such as mosquitoes. The results of this research shed light on overlooked aspects of caddisfly biology. Moreover, they may enhance our understanding of the evolution of insect olfaction, since caddisflies are among the most important orders of aquatic insects and the closest relatives of Lepidoptera, a key model system in insect chemical ecology.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"404 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bruno Calsa, José Antônio Rocha Gontijo, Milton Santamaria-Jr, Patrícia Aline Boer
{"title":"Effects of gestational protein restriction on autophagy dynamics during odontogenesis.","authors":"Bruno Calsa, José Antônio Rocha Gontijo, Milton Santamaria-Jr, Patrícia Aline Boer","doi":"10.1007/s00441-026-04079-0","DOIUrl":"10.1007/s00441-026-04079-0","url":null,"abstract":"<p><p>Autophagy is a cellular process essential for maintaining homeostasis and supporting development. Herein, we aimed to evaluate the effects of gestational protein restriction (GPR) on tooth germ autophagy. CAG-RFP-EGFP-LC3 female mice were mated and randomly assigned to normal protein or low-protein groups. Embryos were collected, and autophagy flux in the molar tooth germ was quantified. At the bud stage, GPR induced a decrease in autolysosomes in the condensed mesenchyme, alongside an increase in autophagosomes in the dental epithelium. At the cap stage, an increase in lysosome markers was observed in the dental papilla, while a decrease in autolysosomes was observed in enamel organ. By the bell stage, dental papilla exhibited a decrease in autolysosomes and an increase in lysosome markers. Similarly, inner enamel epithelium showed reduced autolysosomes and elevated lysosome markers. Bud stage was the most significantly affected; we further quantified apoptosis and mitosis, revealing impaired cell proliferation and enhanced apoptosis. Our data suggest that GPR block or delay acidification of autophagic vesicles, potentially impairing the recycling of cellular components critical for tooth germ proliferation and differentiation.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"404 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nick J Spencer, Melinda A Kyloh, Lee Travis, Vladimir P Zagorodnyuk, Luke Grundy, Tim Hibberd
{"title":"Different types of sensory nerve endings in the urinary bladder of mice arising from dorsal root ganglia (DRG) at the thoracolumbar region of vertebral column.","authors":"Nick J Spencer, Melinda A Kyloh, Lee Travis, Vladimir P Zagorodnyuk, Luke Grundy, Tim Hibberd","doi":"10.1007/s00441-026-04083-4","DOIUrl":"10.1007/s00441-026-04083-4","url":null,"abstract":"<p><p>The urinary bladder is innervated by two anatomically distinct populations of sensory neurons originating from dorsal root ganglia (DRG): one from the thoracolumbar (TL) and another from the lumbosacral (LS) spinal region. While we previously characterized the morphology and distribution of sensory endings arising from LS DRG, the terminals of TL afferents remain undefined. In this study, we employed anterograde neuronal tracing to map these endings in mice. Following bilateral injection of dextran biotin into T12-L3 DRG and a 7-9-day recovery, whole bladders were processed to visualize spinal afferent axons and their calcitonin gene-related peptide (CGRP) immunoreactivity. We identified four morphological types of sensory endings, similar to those described for LS DRG: simple and complex types in both the sub/urothelium and the detrusor muscle. However, their distribution was fundamentally different. Most TL afferents (79%) terminated within the sub/urothelium, with a minor proportion (21%) in the detrusor. This pattern is the inverse of LS innervation, which predominantly targets the detrusor (81%). Furthermore, nearly all TL endings (96%) were peptidergic (CGRP +). This stark anatomical and neurochemical segregation suggests that TL and LS spinal afferent populations are functionally specialized. We propose that the dense TL innervation of the sub/urothelium may constitute a protective surveillance system sensitive to chemical irritation and inflammation, whereas the predominant LS innervation of the detrusor is likely specialized for detecting mechanical stretch during bladder filling.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"404 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13246562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chronic low-dose iron exposure induces GPX4-mediated resistance to ferroptosis in a human chondrocyte cell line.","authors":"Asima Karim, Jasmin Shafarin, Savitha Suresh, Jibran Sualeh Muhammad, Rizwan Qaisar, Firdos Ahmad, Mawieh Hamad","doi":"10.1007/s00441-026-04082-5","DOIUrl":"10.1007/s00441-026-04082-5","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a degenerative joint disease closely linked to iron dysregulation. While the role of iron in OA is recognized, the precise mechanism of cell death remains unclear. This study aimed to elucidate how chronic low-dose iron exposure influences chondrocyte survival, iron metabolism, and ferroptosis susceptibility. The 32-day exposure effects of low-dose (20 µM) ferric ammonium citrate (FAC) treatment on the immortalized human chondrocyte cell line (C-20/A4) in terms of survival and susceptibility to ferroptosis were investigated. Cell viability, morphology, and expression of key iron regulatory genes (IRGs) and ferroptosis-related stress genes were assessed. At day-32 of FAC treatment, chondrocyte proliferation and glutathione peroxidase 4 (GPX4) expression increased relative to controls (p < 0.0001). Inhibition of GPX4 with RSL3 in FAC-treated cells resulted in significantly increased cell death (p < 0.001), indicating a possible protective role of GPX4. Iron chelation with deferoxamine conferred protection against ferroptosis. Dynamic changes in IRGs and cell cycle regulators, consistent with an adaptive strategy to resist iron overload and support survival, were observed. In-silico analysis of OA cartilage transcriptomic data identified 170 differentially expressed genes. Functional enrichment showed upregulation of ubiquitin-dependent catabolic processes and downregulation of mitotic pathways, supporting altered stress responses and cell cycle disruptions in iron-exposed chondrocytes. Chronic low-dose iron exposure induced an adaptive upregulation of GPX4, enhancing chondrocyte resistance to cell death by ferroptosis by maintaining lipid peroxide reduction. Therapeutic modulation of GPX4 and iron homeostasis may offer novel strategies for OA management where cartilage iron imbalance is implicated.</p>","PeriodicalId":9712,"journal":{"name":"Cell and Tissue Research","volume":"404 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}