Cell Biology and Toxicology最新文献

{"title":"MAP4K4 inhibition enhances the anti-ferroptosis effect of the FTO/YAP/ATF4 axis in doxorubicin-induced cardiotoxicity.","authors":"Youyou Yan, Dandan Song, Longbo Li, Junnan Wang","doi":"10.1007/s10565-026-10221-z","DOIUrl":"10.1007/s10565-026-10221-z","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but its clinical application was constrained by irreversible cardiotoxicity. Increasing evidence indicates that ferroptosis is a central mechanism of DOX-induced cardiotoxicity (DIC). Both the m⁶A demethylase FTO and yes-associated protein (YAP) are found to suppress ferroptosis in DIC. Importantly, both YAP and its upstream negative regulator, MAP4K4, are potential targets of FTO. However, whether FTO regulates DOX-induced cardiac ferroptosis via the MAP4K4/YAP signaling axis remains unexplored.</p><p><strong>Methods: </strong>FTO and YAP expressions were analyzed in DOX-treated cardiac tissues and cardiomyocytes. The effect of FTO on ferroptosis, as well as on the expression of YAP, ATF4, and MAP4K4, was evaluated in DOX-treated mouse heart and cardiomyocytes using cardiac-specific FTO AAV delivery or lentiviral transfection. Pharmacological inhibition of YAP, ATF4, or MAP4K4 was further performed to investigate the underlying mechanisms. In addition, the m⁶A modifications of FTO on MAP4K4 and YAP transcripts were examined.</p><p><strong>Results: </strong>FTO and YAP were significantly reduced in DOX-treated cardiac tissues and cardiomyocytes. FTO overexpression markedly attenuated DIC by inhibiting ferroptosis by enhancing YAP and ATF4 expressions. Inhibition of YAP or ATF4 significantly abolished the protective and anti-ferroptotic effects of FTO. FTO also increased MAP4K4 expression, whereas MAP4K4 inhibition further enhanced the anti-ferroptotic effects mediated by the FTO/YAP/ATF4 axis. Mechanistically, FTO promoted m⁶A demethylation of MAP4K4 and YAP transcripts and enhanced their mRNA stability.</p><p><strong>Conclusions: </strong>FTO protects against DIC by inhibiting ferroptosis via up-regulation of the YAP/ATF4 axis, and inhibition of MAP4K4 further enhances the FTO/YAP/ATF4-mediated cardioprotective and anti-ferroptotic effects.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose-derived CLEC3B promotes osteogenesis through a CLEC3B-IGFBP4-related paracrine axis associated with mitochondrial adaptation in postmenopausal osteoporosis.","authors":"Zhihao Xia, Liangliang Wei, Jiajia Ji, Shaobo Wu, Yue Sun, Gaoyang Zong, Xiangyang Li, Yuxing Ye, Yan Zhang, Dageng Huang","doi":"10.1007/s10565-026-10223-x","DOIUrl":"10.1007/s10565-026-10223-x","url":null,"abstract":"<p><p>Postmenopausal osteoporosis (PMOP) develops within a complex metabolic milieu, but the adipose-derived cues that regulate osteoblast function are not fully defined. Here, plasma ELISA analysis showed preferential elevation of circulating C-type lectin domain family 3 member B (CLEC3B) in the high-BMI PMOP subgroup. CLEC3B was enriched in adipose tissue and negatively regulated by estradiol. In vivo, adipose-targeted overexpression of Clec3b increased trabecular bone mass and promoted osteoblast-associated bone formation without markedly altering osteoclast-related parameters. To investigate the underlying mode of action, we used an adipocyte-osteoblast conditioned-medium model. Conditioned medium from Clec3b-overexpressing adipocytes promoted osteogenic differentiation of primary calvarial osteoblasts, whereas conditioned medium from Clec3b-silenced adipocytes produced the opposite effect. Adipocyte transcriptomic analysis nominated Igfbp4 as a secretome-associated candidate reduced after Clec3b overexpression. Recombinant insulin-like growth factor-binding protein 4 (IGFBP4) reduced the increases in osteogenic gene expression, RUNX2 abundance, and matrix deposition induced by Clec3b-enriched conditioned medium. In parallel, recombinant IGFBP4 (rIGFBP4) partially attenuated the associated changes in mitochondrial superoxide-related fluorescence, intracellular oxidative fluorescence, mitochondrial membrane potential, and PINK1/PRKN-related signaling. Collectively, the data are consistent with a model whereby adipose-derived CLEC3B promotes osteogenesis through a CLEC3B-IGFBP4-related paracrine axis associated with mitochondrial adaptation in osteoblasts. These findings define a testable adipose-to-bone signaling mechanism relevant to osteoblast dysfunction in PMOP.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13574853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The application progress of organoid technology in the toxicity assessment of environmental pollutants.","authors":"Guojie Zhao, Yishuang Cui, Hongjiao Wu, Ye Jin, Junqing Gan, Weinan Yao, Yanna Bi, Yanlei Ge, Guogui Sun","doi":"10.1007/s10565-026-10224-w","DOIUrl":"10.1007/s10565-026-10224-w","url":null,"abstract":"<p><p>Human production activities and daily life are the main sources of environmental pollutants, and their potential health impacts have attracted growing attention. Currently, the assessment of environmental pollutant toxicity depends heavily on animal models and some cell culture models. However, these approaches have inherent limitations, such as their inability to recapitulate the in vivo microenvironment and the presence of interspecies differences. Organoids not only recapitulate cell types and tissue structures of human organs, but also exhibit key physiological functions, rendering them ideal alternative models for assessing the health risks of environmental pollutants. In this review, we briefly introduce the development history of organoids as models for environmental pollutant toxicity assessment. Additionally, organoids are categorized by cell sources, and current mainstream organoid culture techniques are systematically summarized. Next, we highlight the application value of typical organoids including lung, brain, cardiac, intestine, liver and kidney organoids in environmental pollutant toxicity assessment. Finally, we thoroughly analyze the strengths and limitations of organoid models for such toxicity testing. Therefore, this review aims to advance organoid technology, and provide new insights into the toxicity assessment of environmental pollutants and the exploration of relevant toxic mechanisms.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPK orchestrates mitochondrial homeostasis via dynamics and mitophagy to combat hypoxia-induced energetic crisis in keratocytes.","authors":"Xinlin Yan, Yi Guan, Guozhen Chen, Shumei Yang, Zhengyu Cao, Xuan Li","doi":"10.1007/s10565-026-10222-y","DOIUrl":"10.1007/s10565-026-10222-y","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia disrupts corneal stromal physiology and alters cellular energy metabolism. This study aimed to elucidate the molecular role of the cellular energy sensor AMP-activated protein kinase (AMPK) in modulating the energy metabolism of human keratocytes (HKs) under hypoxic conditions and to explore a potential therapeutic strategy.</p><p><strong>Methods: </strong>In vitro, HKs were exposed to 1% O₂ for 2 h and 24 h to simulate hypoxia. In vivo, a mouse corneal alkali burn model was established, in which hypoxia is recognized as an important contributing factor to tissue injury. The expression of AMPK and its influence on downstream pathways related to mitochondrial metabolism were investigated. The AMPK agonist AICAR was administered in these models to assess its effects. Key molecular pathways, including AMPK/MFF/DRP1, AMPK/MTFR1L/OPA1 (mitochondrial dynamics), and AMPK/ULK1/PINK1/PARKIN (mitophagy), were analyzed to understand the mechanisms of action.</p><p><strong>Results: </strong>In vitro, hypoxia shifted HKs energy production from oxidative phosphorylation to anaerobic glycolysis over time, accompanied by AMPK upregulation. AICAR restored mitochondrial function, increased OCR, reduced ECAR and ROS, and improved mitochondrial membrane potential. AMPK knockdown abolished these protective effects. In vivo, AICAR treatment of alkali-burned mouse corneas significantly reduced corneal opacity and fluorescein staining scores, restored mitochondrial respiration and glycolysis balance. Mechanistically, AICAR activated AMPK to regulate mitochondrial dynamics via the AMPK/MFF/DRP1 and AMPK/MTFR1L/OPA1 pathways and enhanced mitophagy through the AMPK/ULK1/PINK1/PARKIN axis. This coordinated action increased mitochondrial oxidative phosphorylation capacity.</p><p><strong>Conclusions: </strong>Activation of AMPK via AICAR ameliorates hypoxia‑induced energy imbalance in HKs in vitro and in mouse corneal alkali burn in vivo by restoring mitochondrial homeostasis. This mechanism represents a novel therapeutic target for hypoxia-related keratopathy and suggests a promising approach for energy replacement therapy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HP1γ promotes the progression of colorectal cancer through interaction with RBPJ of the Notch signaling pathway.","authors":"Rui-Bao Zhu, Yi-Jia Xie, Yu-Ting Han, Bo Peng, Wen-Ting Wang, Xin-Yi Lu, Yu-Tong Li, De-Cai Mao, Jin Sun, De-Xin Chen, Qin-Yun Che, Li Zheng, Dong-Lin Li, Feng-Rui Hou, Meng-Lin Mo, Shi-Yao Gong, Yi-Zhi Dong, Rong-Zhi Fu, Qing-Fei Liu, Fang-Lin Sun, Zhi-Jie Chang, Jian-Quan Ni, Ming-Yang Li","doi":"10.1007/s10565-026-10205-z","DOIUrl":"10.1007/s10565-026-10205-z","url":null,"abstract":"<p><p>Epigenetic dysregulation plays a pivotal role in cancer progression. Unlike HP1α and HP1β, which localize primarily to heterochromatin, HP1γ predominantly occupies euchromatin, suggesting a direct role in transcriptional regulation. Here, we identify HP1γ as a high-risk oncogene in colorectal cancer (CRC). Genome-wide analysis and disease-free survival (DFS) correlation studies revealed that high expression of HP1γ is associated with poor DFS in CRC patients, and we confirmed HP1γ upregulation in colon adenocarcinoma (COAD), the predominant CRC subtype. Functional assays demonstrated that HP1γ overexpression enhances tumor cell proliferation, migration, and colony formation in vitro, while siRNA-mediated knockdown suppressed these phenotypes. In vivo studies showed that HP1γ drives tumor growth, increasing both volume and weight in xenograft models. Mechanistically, HP1γ, via its chromo shadow domain (CSD), physically interacts with the beta-transducin repeat domain (BTD) of recombination signal binding protein for immunoglobulin kappa J region (RBPJ), the transcriptional factor of the Notch pathway. Intriguingly, RBPJ upregulation counteracts HP1γ-induced hyperproliferation, implicating HP1γ as a critical modulator of Notch signaling. Our findings establish HP1γ as a promoter of CRC progression through suppression of Notch pathway components, highlighting its potential as a diagnostic marker or therapeutic target in CRC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPNMB regulates EGFR mitochondrial translocation via HK2, influencing microglial respiratory chain and metabolic defects to promote polarization and stroke progression.","authors":"Chang Gao, Qiong Nie, Yongnan Hao, Hongqiang Song, Cui-Cui Zhang","doi":"10.1007/s10565-026-10215-x","DOIUrl":"10.1007/s10565-026-10215-x","url":null,"abstract":"<p><strong>Background: </strong>One of the main reasons of disability and death is stroke in China and other countries, with growing evidence pointing to the role of microglial polarization in its pathogenesis. Epidermal growth factor receptor as well as Glycoprotein non-metastatic melanoma protein have been implicated in cellular signaling pathways relevant to microglial function. However, the mechanism by which GPNMB regulates EGFR signaling and its impact on mitochondrial translocation and polarization remains unclear.</p><p><strong>Methods: </strong>We established middle cerebral artery occlusion model in mice to investigate GPNMB expression and its role in microglial activation. Various experimental techniques, including TTC staining, western blotting, Nissl staining, H&E staining, immunofluorescence, and flow cytometry, were employed to assess cellular changes and molecular interactions. Furthermore, the effects of GPNMB on energy metabolism were evaluated through ATP assays and mitochondrial membrane potential assessments.</p><p><strong>Results: </strong>Upregulated GPNMB was observed in microglia following MCAO. GPNMB Inhibition resulted in reduced infarct volume, diminished neuronal damage, and altered microglial polarization towards the anti-inflammation phenotype. Additionally, GPNMB was found to regulate EGFR translocation, which in turn influenced HK2 expression, thereby affecting mitochondrial function and energy metabolism in microglia. Expression of respiratory-chain proteins (CYTB, MTCO2, ATP6) was increased following GPNMB inhibition. The use of EGFR activators and inhibitors further confirmed the critical role of this signaling pathway in mediating GPNMB's effects.</p><p><strong>Conclusion: </strong>In conclusion, GPNMB regulates mitochondrial translocation of ERGR via HK2, influencing microglial respiratory chain and metabolic defects to promote stroke progression.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13553693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP3 promotes glycolysis of osteosarcoma stem cells by reading RNA m⁶A to stabilize ENO1 and promote malignant biological behavior of osteosarcoma.","authors":"Binglun Zhang, Xue Ren, Bo Wang, Yuting Wang, Delong Zhang, Fanhe Meng","doi":"10.1007/s10565-026-10218-8","DOIUrl":"10.1007/s10565-026-10218-8","url":null,"abstract":"<p><p>Osteosarcoma stem cells (OSSCs) play a central role in driving osteosarcoma (OS) progression by promoting migration, proliferation, self-renewal, chemotherapy resistance, and immune evasion. However, the molecular mechanisms that sustain stemness in OS are still not well defined. In this study, we demonstrate that elevated expression of IGF2BP3 in OS correlates with the maintenance of OSSC stemness. Overexpression of IGF2BP3 enhanced OS self-renewal, cisplatin resistance, proliferation, migration, and invasion by increasing glycolysis in OSSCs. Mechanistically, as an m⁶A reader, IGF2BP3 recognized and bound m⁶A-modified ENO1 mRNA, thereby stabilizing its expression. METTL3, the methyltransferase responsible for the m⁶A modification of ENO1, synergized with IGF2BP3 to further elevate ENO1 expression. Upregulation of ENO1 promoted glycolysis and stemness in OSSCs and enhanced OS self-renewal, cisplatin resistance, invasion, migration, and proliferation. Notably, in vivo knockdown of IGF2BP3 and ENO1, together with glycolytic inhibition, attenuated OS stemness and tumorigenicity. Moreover, combined suppression of IGF2BP3 and ENO1 (IGF2BP3⁻/ENO1⁻) or ENO1 knockdown plus oxamate treatment (ENO1⁻/Oxamate) further reduced the tumorigenic potential of these cells. The results clearly demonstrate that the IGF2BP3/ENO1/glycolytic axis reduces tumorigenic potential, therefore the authors logically and convincingly conclude that this axis is a major regulator of OS stemness, chemotherapy resistance, and tumorigenesis, making it a very attractive therapeutic target for OS.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of palytoxin-induced ferroptosis in HaCaT cells via targeting TrxR1.","authors":"Cheng Zhong, Zihan Zhao, Dong Chen, Longze Lü, Wanxin Ren, Xinhao Li, Bowen Deng, Chengming Yang, Yao Yang, Lianghua Wang, Mingjuan Sun","doi":"10.1007/s10565-026-10220-0","DOIUrl":"10.1007/s10565-026-10220-0","url":null,"abstract":"<p><p>PLTX (Palytoxin) is a fatty-chain polyether marine biotoxin originally produced by benthic dinoflagellates, particularly Ostreopsis ovata and Ostreopsis siamensis. Via the marine food web, PLTX bioaccumulates in numerous organisms such as corals and shellfish, and ranks among the most lethal non-proteinaceous natural compounds described to date. Thus far, its toxicological mechanism remains unclear, and no specific clinical antidote is available. In this study, we employed a limited proteolysis‑based chemical proteomics approach (Lip‑SMap) to analyze the protection of protease cleavage sites conferred by PLTX binding. Combined with DIA (data‑independent acquisition) mass spectrometry in HaCaT (human immortalized keratinocyte) cells, we identified TrxR1 (thioredoxin reductase 1) as an intracellular direct target of PLTX. Molecular docking simulations revealed that PLTX forms stable hydrogen bonds with the active‑site residues Q230 and N234 of TrxR1. BLI (Biolayer interferometry) further confirmed a moderate‑to‑high affinity interaction between them (KD = 5.415 × 10^-1 μM). Confocal fluorescence imaging demonstrated significant spatial colocalization of PLTX with TrxR1 in the cytoplasm, providing visual evidence for their direct intracellular interaction. Functional assays showed that PLTX specifically inhibits TrxR1 activity in a concentration‑dependent manner, thereby compromising the cystine/GSH/GPx4 antioxidant axis. The ensuing cascade-glutathione (GSH) depletion, loss of GPx4 (glutathione peroxidase 4) activity, and build-up of reactive oxygen species (ROS) and malondialdehyde (MDA)-ultimately drives the cell toward ferroptosis. Importantly, overexpression of TrxR1 significantly reversed PLTX‑induced GSH depletion, the decrease in GPx4 activity, and MDA accumulation, confirming the central role of TrxR1 in PLTX toxicity. Collectively, our findings uncover a previously unrecognized mechanism by which PLTX induces ferroptosis through direct inhibition of TrxR1 in HaCaT cells. These findings not only offer a molecular basis for understanding the toxicity of PLTX, but also identify TrxR1 as a potential therapeutic target. As such, they provide a theoretical foundation for the prevention and treatment of marine toxin poisoning, as well as for the development of related antidotes.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of ethanol and acetaldehyde on multi-organ genomic mutation landscapes.","authors":"Bérénice Chavanel, Eva Tibaldi, François Virard, Christine Carreira, Sergey Senkin, Behnoush Abedi-Ardekani, Vincent Cahais, Michael Korenjak, Zdenko Herceg, Silvia Balbo, Daniele Mandrioli, Jiri Zavadil","doi":"10.1007/s10565-026-10217-9","DOIUrl":"10.1007/s10565-026-10217-9","url":null,"abstract":"<p><p>Alcohol consumption is a major risk factor for cancer, particularly of the head and neck. Acetaldehyde, the main ethanol metabolite, is linked to oral carcinogenesis, but the mechanisms are not well understood. While some mutational signatures such as single-base substitution signature SBS16, doublet-base substitution signature DBS4, and indel signature ID11 have been linked to alcohol use, they are not limited to alcohol-related cancers. We examined the genome-wide in vivo mutation landscapes of rats chronically exposed to ethanol or acetaldehyde, focusing on head-and-neck tumors (involving the cheek and the Zymbal gland) and tumors of the forestomach and liver. Mutational signature analysis revealed early-onset, exposure-associated formation of signature SBS17 in ~ 38% of head-and-neck tumors, suggesting inflammation and oxidative damage may mediate carcinogenesis in these sites. We observed relative enrichment of driver-like mutations in Tp53, Mtor and Hras in exposed tumors, where all Tp53-mutated tumors were SBS17-positive, recapitulating a similar scenario from human gastro-esophageal adenocarcinomas. Next, the doublet-base, indel, copy number and structural variant changes were sporadic and not following exposure-specific patterns. No signatures previously associated with alcohol consumption in humans were observed in the exposed animals. Thus, in this animal cancer model, alcohol-related carcinogenesis across multiple organs is unlikely to be driven mainly by direct mutagenicity of ethanol or acetaldehyde. Rather, the results support a role for non-mutational processes in mediating their carcinogenic effects. Further investigation is warranted to clarify the relationship between mutational signature SBS17 and TP53 loss-of-function mutations as potential biomarkers of alcohol-related carcinogenesis in animals and humans.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13526727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell immunoprofiling reveals a dysfunctional-like immune microenvironment and malignant phenotype in aging penile squamous cell carcinoma.","authors":"Jian Cao, Lin Du, Zailong Qin, Aiwei Ma, Hao Bo, Xueheng Zhao, Yanwei Luo, Chunlin Ou, Zhizhong Liu, Yu Xie, Wancong Zhang, Shijie Tang, Yu Tian, Junbin Yuan, Zhaojian Gong, Jie Guo","doi":"10.1007/s10565-026-10212-0","DOIUrl":"10.1007/s10565-026-10212-0","url":null,"abstract":"<p><strong>Background: </strong>Penile squamous cell carcinoma (PSCC) can affect men of any age, but we know little about the differences between non-old and old patients with PSCC, which severely limits the precise diagnosis and treatment of PSCC.</p><p><strong>Methods: </strong>We collected 2 non-old and 3 old PSCC samples and performed single-cell RNA sequencing and single-cell TCR-Seq analysis. All samples were subjected to UMAP clustering, and subcluster analyses were carried out on tumor cells, T cells, and myeloid cells. Furthermore, cell trajectory analyses were completed for tumor cells and T cells. We performed immunohistochemistry for DCN, KITLG, GPX4, and EPCAM and immunofluorescence for CD24 and MIF, as well as Masson staining and β-galactosidase staining on tissues. Macrophages were cultured for flow cytometry to detect the expression of HLA-DR on the cell surface after MIF treatment.</p><p><strong>Results: </strong>We found that tumor cells in older PSCC demonstrated a more pronounced senescence-associated secretory phenotype (SASP) and gave rise to a subcluster of senescence-associated tumor cells, which exhibited stronger malignant features. Interestingly, we observed similar alterations in old head and neck squamous cell carcinoma (HNSC) samples. In addition, older PSCC samples also had more dysfunctional-like CD24 + T cells and more angiogenic macrophages. Finally, we revealed enhanced MIF signaling between fibroblasts and other cells to be another significant feature of aging PSCC.</p><p><strong>Conclusions: </strong>Our study systematically addressed the effects of aging on PSCC and identified IL1B as a potential prognostic marker for PSCC, offering a framework for the classification management and treatment of PSCC patients.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13457360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}