FEBS Open Bio最新文献

{"title":"FGFR Like1 drives esophageal cancer progression via EMT, PI3K/Akt, and notch signalling: insights from clinical data and next-generation sequencing analysis.","authors":"Aprajita Srivastava, Anoop Saraya, Deepak Gunjan, Rinu Sharma","doi":"10.1002/2211-5463.70167","DOIUrl":"10.1002/2211-5463.70167","url":null,"abstract":"<p><p>FGFRL1, one of the least explored FGFRs, has recently been shown to have implications in cancer, but its functional significance in esophageal cancer (EC) remains largely unexplored. We evaluated FGFRL1 expression in EC patients (n = 106) using immunohistochemistry, observing a significant increase in preneoplastic and neoplastic tissues (P < 0.001, OR = 73.2; AUC = 0.817). RNAi-coupled next-generation sequencing revealed enrichment of EMT, PI3K/Akt, and Notch pathways. Quantitative RT-PCR validated the downregulation of top cluster and Notch pathway genes (P < 0.05). Western blot showed decreased phospho-GSK3β, phospho-Akt, and mesenchymal markers. TCGA data supported a positive correlation with EMT. Functional assays demonstrated FGFRL1's oncogenic role, showing G1 phase arrest, and reduced proliferation, migration, and invasion (P < 0.001). Our study highlights FGFRL1 as a key driver of EC progression.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"979-999"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin promotes mitochondrial integrity through AMPK-signaling in Leber's hereditary optic neuropathy.","authors":"Chatnapa Panusatid, Rapasviranda Soiyangsuk, Maneeluck Tanadjindarat, Chayanon Peerapittayamongkol","doi":"10.1002/2211-5463.70165","DOIUrl":"10.1002/2211-5463.70165","url":null,"abstract":"<p><p>Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder caused by mitochondrial DNA mutations in complex I of the respiratory chain, leading to impaired ATP production, mitochondrial fragmentation, and oxidative stress that contribute to vision loss. This study investigated the potential repurposing of metformin, a widely used antidiabetic drug, in fibroblasts from LHON patients carrying the m.11778G>A mutation. Fibroblasts from LHON patients and healthy individuals were treated with metformin, and mitochondrial function was assessed using high-content imaging, biochemical assays, immunoblotting, immunofluorescence, and Seahorse analysis. Metformin reduced mitochondrial fragmentation, increased network length, stabilized mitochondrial membrane potential, enhanced ATP production, and lowered ROS accumulation under oxidative stress. Metformin significantly increased mitophagy and autophagic flux, as shown by LC3B puncta quantification with and without chloroquine, and activated AMPK signaling through increased AMPKα1/2 phosphorylation and AMPKβ1 Ser182 phosphorylation. In addition, metformin promoted PGC-1α nuclear translocation, indicating stimulation of mitochondrial biogenesis, while maintaining mtDNA copy number and supporting oxidative phosphorylation. These findings suggest that metformin, at clinically relevant concentrations, enhances mitochondrial health and function in LHON fibroblasts, supporting its potential as an affordable and safe therapeutic option to mitigate vision loss in LHON.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"885-905"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intercompartmental communication in senescence.","authors":"Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng, Myriam Gorospe","doi":"10.1002/2211-5463.70236","DOIUrl":"10.1002/2211-5463.70236","url":null,"abstract":"<p><p>Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"837-856"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing photoactivation of PA-mCherry for optical pooled CRISPR screens.","authors":"Sravasti Mukherjee, Giulia Zanetti, Bram van den Broek, Kees Jalink","doi":"10.1002/2211-5463.70249","DOIUrl":"https://doi.org/10.1002/2211-5463.70249","url":null,"abstract":"<p><p>Optical pooled CRISPR screens have become an attractive tool for the rapid identification of genes involved in biological processes. In such screens, mixed populations of cells, each with a single gene knocked out, are screened by microscopy for phenotypes of interest. Identified hit cells can then be tagged by photoactivation of a co-expressed marker, such as PA-mCherry, and subsequently isolated by FACS to identify the responsible guide RNA by next-generation sequencing. Photoactivation is typically performed by selective irradiation of cells with UV light, using either a digital mirror device (DMD), an external fixed UV laser, or, conveniently, by using the 405 nm laser line present in most confocal scanning microscopes. In this study, the latter approach is optimized for PA-mCherry, a bright red phototag used by us and others in optical pooled screens. We find that although normal scanning with intense 405 nm light can rapidly activate PA-mCherry, it also leads to rapid photobleaching. Instead, much higher cellular brightness is achieved by limiting intensity and pixel dwell time during scanning, as well as by slightly defocusing the laser. These results should help optimize cell tagging for genotype-phenotype mapping in optical pooled screens, as well as for other applications.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular dynamics simulations of positively selected codons in FcγRI reveal novel biochemical binding properties.","authors":"David A Young, Omar Arias-Gaguancela, Fiona Gibson, Morgan Grainger, Jodie Score, Amit Nathubhai, Mauricio Cafiero, Lee Richard Machado","doi":"10.1002/2211-5463.70247","DOIUrl":"https://doi.org/10.1002/2211-5463.70247","url":null,"abstract":"<p><p>FcγRI is a high-affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody-based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood, and to address this we explored signatures of positive selection in the receptor's functional gene, FCGR1A, using codon-based selection tests on aligned 1-1 orthologous sequences from placental mammals (n = 32). Signatures of positive selection have occurred at several locations within the gene, with two sites (H¹⁴⁸ (M2a ω 0.997 & M8 ω = 0.993)) and (W¹⁴⁹ (M2a ω = 0.999 & M8 ω = 1.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the FcγRI-IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H¹⁴⁸P and W¹⁴⁹R codons at different nodes in the phylogeny. Employing molecular dynamics simulations, we determined how evolutionary changes at these sites may have influenced the binding of FcγRI-IgG of modern-day Homo sapiens. Measuring RMSD, free energy, radius of gyration, hydrogen bond formation, and analyzing free energy landscapes, we demonstrate that structural instability between mutant structures vs the WT counterpart; however, overall binding potential increases at position 148, yet decreases at 149 in potential. H¹⁴⁸P protonation at physiological pH remains similar, yet during acidotic calculations, protonation is likely reduced, with predicted reduction in affinity for IgG. While ancestral W¹⁴⁹R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding FcγRI-IgG interface, our data demonstrate that these two codons have evolved in humans to be relatively insensitive to shifts in pH promoting a more stable interaction with the Fc portion of IgG during diseases that promote acidosis.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of in vitro toxicity of common phytochemicals included in weight loss supplements using ¹H NMR spectroscopy.","authors":"Emily C Davies, Garth L Maker, Ian F Musgrave, Samantha Lodge","doi":"10.1002/2211-5463.70170","DOIUrl":"10.1002/2211-5463.70170","url":null,"abstract":"<p><p>Herbal and dietary supplements (HDS) are popular among consumers seeking a 'natural' approach for improving their health; however, at present, there is a lack of evidence to support the claims of efficacy and safety for most of these products. Herbal weight loss supplements (WLS) are a group of HDS that are frequently implicated in cases of toxicity; however, the causative substances often remain unknown due to the complex chemical nature of such supplements. This study aimed to analyse the in vitro safety (in human liver carcinoma (HepG2) cells and colon carcinoma (Caco-2) cells) of 12 active compounds commonly found in WLS, first with safety screening using the MTT cytotoxicity assay, followed by metabolic profiling with ¹H NMR spectroscopy. Of the phytochemicals evaluated, epigallocatechin-3,0-gallate (EGCG) was the only compound that caused a significant reduction in the viability of both cell lines (25.3% in HepG2 cells and 18.5% in Caco-2 cells), and this decrease was potentiated by CYP450 induction with rifampicin. Subsequent ¹H NMR analysis showed changes in key metabolites such as amines, amino acids, carboxylic acids, and glucose that were indicative of protein degradation and disrupted energy and lipid metabolism. While the remaining 11 active compounds analysed did not demonstrate significant toxicity in isolation, these require further assessment to determine their safety when used in combination with other phytochemicals. Given that the majority of WLS contain multiple herbal ingredients, each with a complex chemical composition, it is important to understand the role of interactions in adverse events.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"906-920"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Domain associated with zinc fingers-containing NF90-NF45 complex inhibits m⁶A modification of primary microRNA by suppressing METTL3/14 activity.","authors":"Takuma Higuchi, Shunsuke Morioka, Keiko Morisawa, Kazutsugu Matsukawa, Shingo Ashida, Takeshi Suzuki, Shuji Sakamoto","doi":"10.1002/2211-5463.70173","DOIUrl":"10.1002/2211-5463.70173","url":null,"abstract":"<p><p>N⁶-methyladenosine (m⁶A) modifications accelerate microRNA (miRNA) biogenesis by promoting the processing of m⁶A-modified primary miRNAs (pri-miRNAs). However, the regulatory mechanism of m⁶A modification of pri-miRNA remains unclear. Here, we found that NF90-NF45 acts as a negative regulator of the m⁶A modification of pri-miRNA by methyltransferase-like 3/14 (METTL3/14). Using overexpression constructs, METTL3/14 promoted the biogenesis of miR-7, whereas NF90-NF45 suppressed miR-7 biogenesis. METTL3/14 overexpression relieved the inhibition of miR-7 biogenesis by NF90-NF45. NF90-NF45 attenuated m⁶A modification of pri-mir-7-1 in vitro; however, it had no effect on the m⁶A modification of pri-mir-200a because of the lower binding affinity of pri-mir-200a to NF90. Furthermore, NF90-NF45 did not interact with METTL3/14, according to immunoprecipitation analysis. These findings suggest that the m⁶A modification of pri-miRNAs by METTL3/14 is regulated by NF90-NF45 competing for pri-miRNA binding.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"921-931"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RoundMi: A quantitative method to analyze mitochondrial morphology in mitotic cells.","authors":"Elmira Parvindokht Bararpour, Christine Volmert, Valentina Piano","doi":"10.1002/2211-5463.70257","DOIUrl":"https://doi.org/10.1002/2211-5463.70257","url":null,"abstract":"<p><p>Mitochondrial morphology is a key readout of cellular physiology and pathophysiology, yet its quantitative analysis in mitotic cells remains technically demanding due to their rounded, three-dimensional architecture. Volumetric imaging approaches, while comprehensive, require extensive Z-stack acquisition, high computational resources, and specialized image analysis expertise, collectively limiting throughput and accessibility. Here, we present RoundMi, a streamlined workflow for rapid, quantitative analysis of mitochondrial morphology in mitotic cells using single focal plane imaging. RoundMi integrates automated preprocessing via the Nellie plugin in Napari with downstream segmentation and quantification in MitoSkel. Focal plane selection is guided by DNA staining and mitochondrial signal to capture representative morphological features while minimizing acquisition time and phototoxicity. We validated RoundMi in mouse embryonic fibroblasts (MEFs) and HeLa cells, demonstrating robust detection of established morphological differences between wild-type and DRP1-deficient cells in both interphase and mitosis. Benchmarking against volumetric methods, including deconvolution and maximum intensity projection, confirmed that single-plane analysis provides a reliable proxy for mitochondrial morphology while avoiding projection-induced artifacts and substantially reducing computational demand. RoundMi is applicable across multiple cell types and compatible with live-cell imaging, offering a versatile, high-throughput solution for mitochondrial morphology analysis in dividing cells.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering tandem VHHs to target different epitopes to enhance antibody-dependent cell-mediated cytotoxicity.","authors":"Yuqiang Xu, Hao Jiang, Limin Chen, Fulai Zhou, Ying Jin, Mark L Chiu","doi":"10.1002/2211-5463.70166","DOIUrl":"10.1002/2211-5463.70166","url":null,"abstract":"<p><p>Engineering antibodies to elicit antibody-dependent cell-mediated cytotoxicity (ADCC) can be used to eliminate target cells. Here, we described how single domain VHH arms on a bispecific antibody (BsAb) format can be engineered to modulate cell binding and ADCC activity. The BsAbs, comprising two anti-epidermal growth factor receptor (EGFR) nanobodies, 7D12 and EGA1, were engineered onto a human IgG1 Fc domain in monovalent, bivalent, and tandem formats. While 7D12 had a stronger ADCC activity than EGA1, the tandem 7D12-EGA1 mediated a significantly stronger ADCC activity without significant changes in cell binding in numerous cancer cell lines. In addition, we present how the molecular design of the tandem 7D12 and EGA1 nanobodies could cross-link two different EGFR molecules to obtain stronger ADCC activity.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"1030-1043"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Down-regulation of Shh in the hair follicles of mice during chemotherapy-induced hair loss is mediated by the JAK/STAT1 signaling pathway.","authors":"Ruifang Fan, Jingling Huang, Xiang Lin, Tingjiao Lan, Yuli Tang, Ling Sun, Guixuan Zhou","doi":"10.1002/2211-5463.70160","DOIUrl":"10.1002/2211-5463.70160","url":null,"abstract":"<p><p>Chemotherapy-induced alopecia (CIA) is a major unresolved adverse effect in clinical oncology. We have previously shown that the Sonic hedgehog (Shh) signaling pathway is targeted by cyclophosphamide (CYP) treatment, but the detailed mechanism by which this chemotherapy drug induces alopecia still remains largely unknown. To answer this question, in the present study, we used Shh-GFP^+/- mice and analyzed Shh-expressing cells (Shh⁺ cells) in hair follicles at different times post-CYP treatment. Through flow cytometry assays, we showed that Shh⁺ cells decreased significantly after CYP treatment. To investigate the molecular events involved in this decrease, we carried out gene set enrichment analysis of RNA sequencing data of Shh⁺ cells, which revealed that the expression levels of most Janus-activated kinase/signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway-related genes were upregulated compared to the controls. Furthermore, through a chromatin immunoprecipitation assay, we showed that STAT1 could bind to the promoter of the Shh gene during CIA in hair follicles and the binding strength increased upon CYP treatment. Treatment with JAK inhibitors also rescued hair loss and upregulated Shh expression in mice with CIA, further supporting the role of the JAK/STAT1 signaling pathway in the regulation of Shh during CIA. Taken together, our results provide new insights into the molecular mechanisms of CIA.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":"966-978"},"PeriodicalIF":2.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}