Cell Stress最新文献

{"title":"Stress management by benzodiazepines in septic shock and critical illness: mechanistic and clinical evidence supporting alternative sedative strategies.","authors":"Flavia Lambertucci, David Skurnik, Damien Roux, Laurence Arbibe, Lucillia Bezu, Isabelle Martins, Guido Kroemer","doi":"10.15698/cst2026.08.320","DOIUrl":"10.15698/cst2026.08.320","url":null,"abstract":"<p><p>Critical care involves the management of organismal stress by sedation. Benzodiazepines remain widely used for anxiolysis and sedation in critical care, including in septic shock. Yet converging mechanistic, preclinical and clinical evidence suggests that benzodiazepines and the endogenous ligand of benzodiazepine-binding sites, the \"endozepine\" acyl-CoA binding protein/diazepam binding inhibitor (ACBP/DBI), may impair host immune defenses, exacerbate organ dysfunction and contribute to long-term morbidity after intensive care. A unifying framework is that benzodiazepines may accelerate \"iatrogenic aging\" by antagonizing adaptive stress responses (notably autophagy) and favoring cellular senescence, chronic inflammation, immunosuppression and neurocognitive perturbations. Here, we synthesize evidence supporting benzodiazepine avoidance in sepsis-heavy intensive care populations. We propose that replacing benzodiazepines with alternative sedative strategies may improve both short-term outcomes and long-term trajectories of post-sepsis disability. We hypothesize that post-intensive-care syndrome (PICS), including -as a specific case- post-sepsis syndrome (PSS), is caused by premature aging of the organism and that PICS/PSS might be attenuated by the avoidance of benzodiazepine administration during and after critical care.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"10 ","pages":"64-73"},"PeriodicalIF":3.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13454948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148707866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triptolide inhibits ovarian cancer growth and metastasis via reprogramming of tumor-associated macrophages.","authors":"Ziqi Chen, Jie Zhang, Jianting Lao, Chaoqin Yu, Hong Yang","doi":"10.15698/cst2026.07.319","DOIUrl":"10.15698/cst2026.07.319","url":null,"abstract":"<p><p>Triptolide, an extract from the Chinese herb Thunder God Vine, a compound renowned for its anti-cancer properties, exhibits an elusive mechanism of action. While extensive research has elucidated its direct effects on cancer cells, the indirect impact on non-tumor cells within the cancer microenvironment remains poorly understood. In this study, we investigated the influence of Triptolide on tumor-associated macrophages (TAMs), pivotal contributors to ovarian cancer progression. Using cell culture and promoter assay, cellular viability assessment, cell clock assay, transwell assays, flow cytometry, ELISA, TUNEL staining, and mouse models, we found that Triptolide does not significantly affect macrophage proliferation or survival; instead, it induces differentiation of naive macrophages towards the M1 phenotype and reprograms M2-polarized macrophages into a similar inflammatory state. These observations suggest that modulation of TAMs may partially underlie Triptolide's hindrance of ovarian cancer progression. Mechanistically, we reveal that Triptolide inhibits Nrf2 transcription - a master regulator governing anti-inflammatory responses in macrophages. Functional gain- and loss-of-function studies further confirmed that Nrf2 inhibition is essential for Triptolide-mediated TAM reprogramming and subsequent suppression of cancer cell progression. Co-culturing with macrophages substantially enhances ovarian cancer cell growth, invasion, and migration; however, all these effects are abrogated by treatment with Triptolide. Collectively, our findings indicate that the suppression of ovarian cancer by Triptolide is mediated in part through its capacity to reprogram TAMs via the Nrf2 pathway.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"10 ","pages":"53-63"},"PeriodicalIF":3.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148449629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyamine-mediated inhibition of ferroptosis contributes to geroprotection.","authors":"Frank Madeo, Didac Carmona-Gutierrez, Guido Kroemer","doi":"10.15698/cst2026.07.318","DOIUrl":"10.15698/cst2026.07.318","url":null,"abstract":"<p><p>Geroprotection aims at extending healthspan by delaying age-associated pathologies. Polyamines including spermine and spermidine are interconvertible metabolites whose longevity-promoting effects have traditionally been attributed to autophagy induction. In addition, recent evidence identifies spermine as an endogenous Fe²⁺ chelator that suppresses ferroptosis, thereby complementing the autophagy-inducing activity of spermidine. Indeed, spermidine inhibits EP300 acetyltransferase activity and supports hypusination-dependent activation of TFEB, both leading to autophagy. However, enhanced autophagic flux may increase susceptibility to ferroptosis through ferritinophagy and lipid remodeling. In parallel, polyamine catabolism generates H₂O₂ and acrolein, both of which facilitate lipid peroxidation and ferroptotic demise. The discovery that spermine directly chelates redox-active Fe²⁺ closes a conceptual gap by explaining how polyamine supplementation can promote longevity while avoiding excessive ferroptotic cell loss. Multiple lines of evidence including metabolomics, isotope tracing, cell-free lipid peroxidation systems, Fe²⁺-binding biophysics, mass spectrometry, Raman spectroscopy, nuclear magnetic resonance and disease models demonstrate that spermine limits labile iron and ferroptosis. Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"10 ","pages":"49-52"},"PeriodicalIF":3.4,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13358466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148438349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<ArticleTitle xmlns:ns0=\"http://www.w3.org/1998/Math/MathML\">The IRE1 <ns0:math><ns0:mi>α</ns0:mi></ns0:math> -XBP1s-NF <ns0:math><ns0:mi>κ</ns0:mi></ns0:math> B axis controls cell survival and epithelial differentiation under osmotic stress through arachidonic acid metabolism activation.","authors":"Leandro Gastón Parra, Cecilia Irene Casali, Dylan Ezequiel Sendyk, Ailén Florencia Salafia, Sabrina Andrea Flor, Silvia Edith Lucangioli, María Del Carmen Fernández Tome","doi":"10.15698/cst2026.04.317","DOIUrl":"10.15698/cst2026.04.317","url":null,"abstract":"<p><p>Arachidonic acid (AA) metabolism plays a critical role in renal cell osmoadaptation. We recently demonstrated that hypertonicity induces the expression and activation of cytosolic phospholipase A <math><msub><mrow></mrow> <mrow><mn>2</mn></mrow> </msub> </math> (cPLA <math><msub><mrow></mrow> <mrow><mn>2</mn></mrow> </msub> </math> ). On one hand, AA released by cPLA <math><msub><mrow></mrow> <mrow><mn>2</mn></mrow> </msub> </math> enhances triacylglyceride (TG) synthesis and accumulation. On the other hand, AA is converted into prostaglandins (PG) through cyclooxygenase 2 (COX2) activity. Both processes are required for renal cell survival under osmotic stress. However, the mechanisms by which hypertonicity induces cPLA <math><msub><mrow></mrow> <mrow><mn>2</mn></mrow> </msub> </math> expression remain poorly understood. Given that we previously shown that hypertonicity regulates TG synthesis through the IRE1 <math><mi>α</mi></math> -XBP1s branch of the unfolded protein response (UPR), here we examined whether XBP1s regulates the cPLA <math><msub><mrow></mrow> <mrow><mn>2</mn></mrow> </msub> </math> -AA-COX2 axis in renal cells subjected to osmotic stress. We found that XBP1s modulates hypertonicity-induced expression of cPLA <math><msub><mrow></mrow> <mrow><mn>2</mn></mrow> </msub> </math> and COX2 by increasing NF <math><mi>κ</mi></math> B transcriptional activity. Inhibition of IRE1 <math><mi>α</mi></math> impaired normal COX2 degradation and disrupted AA metabolism, leading to a decrease in cell viability and preventing hypertonicity-induced epithelial differentiation. Prostaglandin E2 (PGE2) contributed to cell polarization facilitating adherens junction (AJ) assembly. Together, these findings highlight a central role for the IRE <math><mi>α</mi></math> -XBP1s-NF <math><mi>κ</mi></math> B signaling axis in coordinating cell stress responses and epithelial differentiation through AA metabolism activation.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"10 ","pages":"32-48"},"PeriodicalIF":3.4,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13159483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147933743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifaceted role of CNPY2 beyond ER stress: Disease implications and therapeutic potential.","authors":"Shima Ebadollahibaruq, Lingbin Meng, Feng Hong","doi":"10.15698/cst2026.03.316","DOIUrl":"10.15698/cst2026.03.316","url":null,"abstract":"<p><p>Canopy homolog protein 2 (CNPY2), an endoplasmic reticulum (ER) luminal protein exhibits broad tissue distribution and regulates cellular homeostasis, including unfolded protein responses (UPR), mitochondrial dynamics, oxidative stress, and apoptosis. Beyond its role in cancer progression through pathways such as NF- <math><mi>κ</mi></math> B, AKT/GSK3 <math><mi>β</mi></math> , PI3K/Akt/mTOR and HIF-1 <math><mi>α</mi></math> , promoting epithelial-mesenchymal transition (EMT), tumor survival and metastasis, CNPY2 is also critical in non-cancer conditions. In neurodegenerative disorders including Parkinson's and Huntington's, it exerts neuroprotective role by reducing oxidative stress and mitochondrial dysfunction. In cardiovascular tissues, CNPY2 leads to hypoxia-driven angiogenesis, tissue repair, and ischemia-reperfusion protection. Moreover, recent meta-analyses have linked CNPY2 downregulation with Keratoconus pathogenesis, further highlighting its tissue- specific roles. Hence, this review meticulously dissects CNPY2's structural characteristics, expression patterns, and biological functions across cancer, cardiovascular disease, inflammation and neurological disorders, emphasizing its role on tumor initiation, microenvironmental stress, and chemoresistance, and evaluating its potential as a therapeutic target.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"10 ","pages":"19-31"},"PeriodicalIF":3.4,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antifungal peptides: From modes of action to synergistic and immunologic potential.","authors":"Didac Carmona-Gutierrez, Maria A Bauer, Katharina Kainz, Martin N Odabas, Frank Madeo","doi":"10.15698/cst2026.01.315","DOIUrl":"10.15698/cst2026.01.315","url":null,"abstract":"<p><p>Fungal infections pose a significant global health threat with rising morbidity and mortality rates. However, the repertoire of effective antifungal drugs remains narrow, a challenge that is further exacerbated by the increasing emergence of (multi)drug-resistant strains. This underscores the urgent need for novel therapeutic strategies. Among them, antifungal peptides (AFPs) have emerged as a promising alternative. AFPs are small, naturally occurring peptides produced by a wide range of organisms, including plants, animals, fungi, and bacteria, as part of their innate immune defense. In addition, synthetic and semisynthetic variants have also been engineered. We here underscore the potential of AFPs as viable candidates for the development of next-generation antifungal therapies. In particular, we advocate their multimodal advantage that spans beyond standalone activity, including their synergistic and immune-regulatory potential.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"10 ","pages":"9-18"},"PeriodicalIF":3.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversal of Cushing syndrome by antibody-mediated neutralization of ACBP/DBI.","authors":"Zhe Shen, Hui Pan, Xiaolian Deng, Oliver Kepp, Isabelle Martins, Guido Kroemer","doi":"10.15698/cst2026.01.314","DOIUrl":"https://doi.org/10.15698/cst2026.01.314","url":null,"abstract":"<p><p>Cushing syndrome (CS) is caused by an increase in endogenous or exogenous glucocorticoids, leading to major alterations in body composition, including visceral obesity, sarcopenia, osteoporosis, type 2 diabetes, and dyslipidemia. Cardiovascular complications resulting from CS are often lethal. We previously demonstrated that CS induced by oral corticosterone (CORT) supplementation in mice can be prevented by inhibition of the peptide hormone acyl-CoA binding protein (ACBP), encoded by the gene diazepam binding inhibitor (DBI). Here, we investigated whether ACBP/DBI inhibition could be used to treat, rather than prevent, CS. To this end, we initiated treatment with anti-ACBP/DBI monoclonal antibodies (mAbs) in mice three weeks after the start of CORT supplementation, when hyperphagia and body weight gain were already established. Two anti-ACBP/DBI mAbs, 7G4a (specific for mouse ACBP/DBI only) and 82 (which recognizes both mouse and human ACBP/DBI), were able to normalize food intake and halt weight gain in mice under continuous CORT treatment. In addition, both mAbs attenuated CORT-induced sarcopenia, adiposity in inguinal, perigonadal, and visceral fat depots, and fully restored metabolic parameters, including type-2 diabetes, insulinemia, free fatty acids, triglycerides, and liver transaminases. In conclusion, neutralization of ACBP/DBI may serve as an effective therapeutic strategy for the treatment of established CS.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"10 ","pages":"1-8"},"PeriodicalIF":3.0,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12845394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Burning fat with cysteine depletion.","authors":"Brittney Adams, Stanislaw Walkowiak, Mohammed K Hankir","doi":"10.15698/cst2025.11.313","DOIUrl":"10.15698/cst2025.11.313","url":null,"abstract":"<p><p>Removing certain essential amino acids from the diet is known to promote weight loss in rodents via effects on food intake and energy expenditure. Two complementary articles by Varghese et al [Nature 643(8072)] and Lee et al [Nature Metabolism 7(6)] now show that cysteine depletion through combined dietary and genetic means in mice evokes a unique stress response in the liver to amplify these metabolic outcomes and offer a potentially new treatment option for obesity.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"9 ","pages":"216-221"},"PeriodicalIF":3.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12635699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145589359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying replication stress in cancer without proliferation confounding.","authors":"Philipp Jungk, Maik Kschischo","doi":"10.15698/cst2025.10.312","DOIUrl":"10.15698/cst2025.10.312","url":null,"abstract":"<p><p>Replication stress (RS) is a major driver of genomic instability and cancer development through impaired DNA replication that can lead to chromosomal instability (CIN). Although RS is mechanistically linked to CIN, its relationship with cellular proliferation is complex. Depending on the context, RS can either promote or suppress cell growth. Existing RS gene expression signatures overlook this complexity, relying on the overexpression of oncogenes such as <i>MYC</i>, which introduces a proliferation bias. To disentangle genuine RS from confounding cell cycle and proliferation transcriptional profiles, we developed and validated a novel gene expression signature that accurately predicts RS independently of oncogene activity. This tumorigenic RS signature (TRSS) captures RS-related transcriptional changes across diverse cellular contexts, enabling a more robust and proliferation-independent measure of RS in both experimental and clinical samples. Applying our signature to patient data, we discovered a link between RS and the non-homologous end-joining (NHEJ) DNA repair pathway. Specifically, we observed that <i>MSH2</i> and <i>MSH6</i> - core components of mismatch repair - are associated with elevated RS and may indicate a shift toward NHEJ-mediated repair under stress conditions. Our study provides a refined approach to quantify RS and sheds light on its broader impact on DNA repair network dynamics.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"9 ","pages":"201-215"},"PeriodicalIF":3.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12632277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145589303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Datopotamab deruxtecan induces hallmarks of immunogenic cell death.","authors":"Sabrina Forveille, Marion Leduc, Allan Sauvat, Guido Kroemer, Oliver Kepp","doi":"10.15698/cst2025.08.311","DOIUrl":"10.15698/cst2025.08.311","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) offer a strategy for targeted delivery of cytotoxic agents to cancer cells. In this study, we investigated the mechanism of action of datopotamab deruxtecan, an ADC composed of a monoclonal antibody targeting tumor-associated calcium signal transducer 2 (TACSTD2, also known as trophoblast cell-surface antigen-2 (TROP2)) conjugated to the topoisomerase I inhibitor DXd. Datopotamab deruxtecan reduced the viability of human osteosarcoma U2OS cells engineered to express TROP2, but had no effect on their parental counterparts, which only expressed the CALR-GFP biosensor. In TROP2-expressing cells, it triggered the translocation of CALR-GFP from the ER to the cell periphery. Both datopotamab deruxtecan and its DXd payload elicited several features characteristic of immunogenic cell death (ICD), including detectable calreticulin exposure on the cell surface, release of high-mobility group box 1 (HMGB1), and ATP secretion into the culture medium. Importantly, the TROP2-targeted ADC also exerted a bystander antitumor effect on parental U2OS cells (lacking TROP2 expression) co-cultured with TROP2-expressing U2OS cells. These findings demonstrate that datopotamab deruxtecan delivers a cytotoxic payload capable of inducing hallmark features of ICD <i>in vitro</i>.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"9 ","pages":"194-200"},"PeriodicalIF":3.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}