Cellular & Molecular Biology Letters最新文献

{"title":"Exendin-4 averts all-trans-retinal-driven damage to photoreceptors and the retina via the GLP-1R/PKA/CREB1 signaling axis.","authors":"Beiting He, Yuling Chen, Peixin Cai, Ruitong Xi, Xiaoqing Shen, Shuting Guo, Jingmeng Chen, Shiying Li, Yalin Wu","doi":"10.1186/s11658-026-00952-6","DOIUrl":"10.1186/s11658-026-00952-6","url":null,"abstract":"<p><strong>Background: </strong>Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL.</p><p><strong>Methods: </strong>Cell and animal paradigms of STGD1 and dry AMD were generated by atRAL-loaded 661W cells and light-exposed Abca4<sup>-/-</sup>Rdh8<sup>-/-</sup> mice, respectively. RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining using flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining were integrated to delineate the anti-apoptotic actions of EX-4 and to uncover its underlying protective mechanism.</p><p><strong>Results: </strong>GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element-binding protein 1 (CREB1) signaling was markedly downregulated in atRAL-challenged 661W cells and in neural retina of light-exposed Abca4<sup>-/-</sup>Rdh8<sup>-/-</sup> mice. EX-4 reinstated this pathway, suppressed caspase-3 activation and DNA damage, and curtailed apoptosis in both cell and tissue contexts. Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) abrogated EX-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation with the PKA inhibitor H-89 or the CREB1 inhibitor 666-15 largely nullified the DNA-protective and anti-apoptotic benefits conferred by EX-4 in 661W cells following atRAL exposure, suggesting that the GLP-1R/PKA/CREB1 signaling axis contributes to its cytoprotection action. More importantly, intraperitoneal injection of EX-4 significantly preserved retinal structure and function in Abca4<sup>-/-</sup>Rdh8<sup>-/-</sup> mice after exposure to light, and mitigated punctate lesions in the fundus.</p><p><strong>Conclusions: </strong>EX-4 exerted anti-apoptotic and DNA-protective effects against atRAL-induced photoreceptor loss and retinal degeneration at least partially through activating the GLP-1R/PKA/CREB1 pathway. These findings suggest that GLP-1R agonists could serve as potential preventive therapeutics for atrophic macular degeneration associated with atRAL toxicity, inclu","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OTULIN protects hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31.","authors":"Li Huang, Qing Liu, Aimin Zhang, Yanhan Liu, Furong Huang, Juanmei Wang, Manting Tan, Duane Wang, Menghua Zhao, Xu Wu","doi":"10.1186/s11658-026-00946-4","DOIUrl":"10.1186/s11658-026-00946-4","url":null,"abstract":"<p><p>The deubiquitinating enzyme OTULIN has been implicated in the development of lung injury, and regulating its expression may either exacerbate or alleviate pulmonary inflammatory damage. In this study, we aimed to investigate the role of deubiquitinating enzyme OTULIN in hyperoxia-induced lung injury and the underlying mechanisms involved. A bronchopulmonary dysplasia (BPD) model was established by exposing neonatal mice to a hyperoxic environment, and the effects of regulating OTULIN expression on mitochondrial homeostasis in pulmonary epithelial cells were further examined under hyperoxic conditions. In addition, we investigated the mechanisms through which OTULIN regulates mitochondrial-associated proteins and the ubiquitination mechanisms of differential mitochondrial protein OPA1. The results showed that hyperoxia induced significant lung injury in neonatal mice and was accompanied by upregulation of OTULIN expression. Additionally, hyperoxia disrupted mitochondrial homeostasis in neonatal mice lung tissue, as observed by a reduction in mitochondrial number and increased mitochondrial fusion and autophagy. After hyperoxia exposure, overexpression of OTULIN significantly reduced mitochondrial reactive oxygen species (ROS) levels in alveolar epithelial cells, maintained mitochondrial membrane potential, and promoted mitochondrial homeostasis. Mechanistically, OTULIN was found to directly interact with OPA1 and regulate its ubiquitination status. The E3 ubiquitin ligase RNF31 was identified as a key regulator of OPA1 stability, with knockdown of RNF31 reducing OPA1 levels. Moreover, OTULIN regulated the expression of both OPA1 and RNF31 and affected the stability of OPA1 and mitochondrial function through RNF31-dependent mechanisms. In vivo experiments further showed that knockdown of OTULIN aggravated hyperoxia-induced lung injury in neonatal mice, characterized by alveolar simplification, increased fibrosis, and further impairment of mitochondrial function, whereas overexpression of OTULIN alleviated these pathological changes. In conclusion, deubiquitinating enzyme OTULIN protected hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31. These findings provide new insights into the pathogenesis of BPD and highlight the therapeutic potential of targeting the OTULIN/RNF31-OPA1 axis.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148101153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AARS1 promotes diabetic kidney disease through rewiring Akt and NF-κB signaling to suppress autophagy and sustain inflammation.","authors":"Lei Tian, Yumeng Wang, Chen Guan, Ewud Agborbesong, Julie Xia Zhou, Shan Mou, Xiaogang Li","doi":"10.1186/s11658-026-00953-5","DOIUrl":"10.1186/s11658-026-00953-5","url":null,"abstract":"<p><strong>Background: </strong>Diabetic kidney disease (DKD) is characterized by metabolic reprogramming, autophagy impairment, and chronic inflammation, but the molecular mechanisms linking these processes are not fully understood. Lactylation has emerged as an important metabolic-epigenetic regulatory mechanism in diabetic tissues. Alanyl-tRNA synthetase 1 (AARS1) has recently been identified as a lactyltransferase, but whether and how AARS1-mediated lactylation contributes to tubular stress responses and DKD progression remains unclear.</p><p><strong>Methods: </strong>Kidney-specific Aars1 knockout mice and β-alanine treatment were used in streptozotocin-induced and db/db diabetic mouse models. Human proximal tubular epithelial cells cultured under high-glucose conditions, including CRISPR/Cas9-mediated AARS1 knockout cells, were used for mechanistic studies. AARS1-dependent transcriptional programs were analyzed by CUT and Tag, ChIP assays, and luciferase reporter assays.</p><p><strong>Results: </strong>AARS1 was upregulated in diabetic kidneys and directly lactylated Akt and the NF-κB subunit p65, enhancing their phosphorylation and activation. This modification promoted autophagy impairment, inflammatory cytokine expression, tubular injury, and macrophage accumulation. CUT and Tag analysis further revealed AARS1-dependent transcriptional control of HK2, PFKP, ZEB1, and PPP6C, linking AARS1 to glycolytic reprogramming and fibrotic signaling. Mechanistically, AARS1 operated within a glycolysis-lactate-NF-κB feedback circuit, in which glycolysis-driven lactate increased the lactylation and activation of NF-κB, promoting AARS1 transcription and reinforcing glycolytic reprogramming and chronic tubular stress. Genetic deletion of Aars1 or pharmacological inhibition with β-alanine reduced protein lactylation, restored autophagy, attenuated inflammation, and significantly slowed DKD progression in both diabetic mouse models.</p><p><strong>Conclusions: </strong>These findings identify AARS1 as a metabolic-epigenetic amplifier that rewires Akt- and NF-κB-dependent signaling to sustain chronic tubular stress and fibrotic remodeling in DKD, highlighting the AARS1-lactylation axis as a potential therapeutic target.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRAS^G12V/A146T mutations are associated with nCRT resistance via enhanced DNA double-strand break repair and support a deep learning prediction framework in LARC.","authors":"Hengchang Liu, Dechao Bu, Guanhua Yu, Ran Wei, Hui Jin, Yixiao Liu, Xu Guan, Zhixun Zhao, Haipeng Chen, Yi Zhao, Zheng Jiang","doi":"10.1186/s11658-026-00947-3","DOIUrl":"10.1186/s11658-026-00947-3","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer (LARC), yet clinically validated biomarkers for predicting response remain lacking. This study aimed to identify candidate molecular events associated with nCRT response and to develop a pretreatment prediction framework integrating genomic and pathological information.</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) was performed on pretreatment tumors from 67 patients with LARC, and an additional 22 published WES cases were integrated to compare genomic differences between responders (R) and nonresponders (NR). Using histopathological whole-slide images (WSIs; n = 106) and genome-derived features, a weakly supervised, multimodal deep learning fusion model was developed to predict nCRT response. Multiomics profiling was used for exploratory pathway characterization, and functional assays were conducted in colorectal cancer cell lines and mouse models harboring KRAS^G12V or KRAS^A146T.</p><p><strong>Results: </strong>WES identified 41 response-associated hotspot codon events. KRAS^G12V and KRAS^A146T were detected in the NR group in this cohort and were directionally aligned with poor response, indicating an association with nCRT resistance. Because these events are low-frequency alterations, and the study is a single-center retrospective cohort with limited numbers of carriers, multivariable adjustment for key covariates (including stage and T/N status) was not feasible; thus, these findings should be interpreted as exploratory candidate signals. The multimodal fusion model showed good discrimination within the cohort (AUC = 0.882). Mechanistically, exploratory multiomics analyses and orthogonal functional assays were consistent with KRAS variants being associated with altered DNA damage repair signaling and increased repair capacity, with the functional assays providing the main support for this interpretation.</p><p><strong>Conclusions: </strong>The proposed genome-pathology fusion model provides a research-oriented framework for pretreatment prediction and risk stratification of nCRT response in LARC. KRAS^G12V and KRAS^A146T are presented as candidate molecular events aligned with poor response, but their independent predictive value and the clinical usability of the model require validation in larger, multicenter prospective cohorts that include external WSI data, together with systematic evaluation of thresholding and calibration before clinical translation.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omic screening identifies RBMXL3 as a primate-specific RNA-binding protein and candidate regulator of RNA metabolism in human spermatogenesis.","authors":"Agata J Barszcz, Katarzyna Tutak, Joanna Zyprych-Walczak, Erik Dassi, Erkut Ilaslan, Małgorzata Dąbrowska, Agnieszka Malcher, Marta Olszewska, Dominik Cysewski, Agnieszka Nadel, Tomasz Kolanowski, Zofia E Madeja, Michał Hrab, Alexander N Yatsenko, Maciej Kurpisz, Zbigniew Warkocki, Natalia Rozwadowska","doi":"10.1186/s11658-026-00959-z","DOIUrl":"10.1186/s11658-026-00959-z","url":null,"abstract":"<p><strong>Background: </strong>RBMXL3 is a primate-specific gene localized on the X chromosome, of which the expression is detectable mainly in the male gonad. So far, very little is known about the RBMXL3 protein function and its molecular interactions. However, recent reports mention the RBMXL3 gene in the context of human spermatogenesis, cancer, and a breathing disorder that affects newborns. In this study, we investigate the RBMXL3's molecular network on a genome-wide scale using the human seminoma cell line (TCam-2) as a male germline in vitro model.</p><p><strong>Methods: </strong>By using transcriptomic (RNA sequencing [RNA-seq] and enhanced crosslinking and immunoprecipitation [eCLIP]) and proteomic (co-immunoprecipitation coupled with mass spectrometry, (Co-IP-MS)) approaches, we show RBMXL3's importance in RNA metabolism. In addition, western blot, quantitative polymerase chain reaction with reverse transcription (qRT-PCR), immunostaining, and confocal imaging were used to investigate the function of RBMXL3. Finally, we used a plasmid-based L1 retrotransposition assay to demonstrate the suppressive effect of RBMXL3 on human Long Interspersed Nuclear Element-1 (LINE-1, L1) retrotransposition.</p><p><strong>Results: </strong>Our RNA-seq data show that RBMXL3 expression drives gene expression changes and influence alternative splicing in human cells. Moreover, by performing eCLIP, we provide proof that RBMXL3 binds to a wide range of RNA transcripts. In addition, we confirmed the nuclear localization of RBMXL3 in TCam-2 cells and its presence in spermatogonia and spermatocytes within the human testis. Finally, we report for the first time that RBMXL3 restricts human LINE-1 retrotransposition.</p><p><strong>Conclusions: </strong>Our findings for the first time identify primate-specific RBMXL3 protein as a new upstream regulator of RNA metabolism, characterized by broad RNA-binding activity in human TCam-2 cells. Finally, we show that RBMXL3 expression heavily reduces LINE-1 retrotransposition in human cells, underlying RBMXL3 importance in maintaining genome integrity. Our data suggest that RBMXL3 may contribute to the regulation of transcriptome dynamics in male germ cells, while its broader functional implications remain to be determined.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HucMSC-mediated stromal metabolic reprogramming in reactivating aged ovaries: a single-cell transcriptomic perspective.","authors":"Ying-Yi Zhang, Yuqing Mei, Weijie Yang, Hanjing Zhou, Yan Zhou, Yingyan Chen, Yi Zhang, Jianmin Chen, Jiamin Jin, Xiaomei Tong, Libing Shi, Dong Huang, Guoji Guo, Yin-Li Zhang, Songying Zhang","doi":"10.1186/s11658-026-00919-7","DOIUrl":"10.1186/s11658-026-00919-7","url":null,"abstract":"<p><strong>Background: </strong>Aging-induced decline in ovarian function and oocyte quality contributes to female infertility. However, the mechanisms underlying human umbilical cord-derived mesenchymal stem cell (HucMSC)-mediated rejuvenation of aged ovaries remain poorly understood. This study aimed to systematically investigate whether and how HucMSCs restore ovarian function and oocyte quality and elucidate the potential pathways involved.</p><p><strong>Methods: </strong>Aged mice received in situ ovarian injections of HucMSCs. Ovarian follicular development and fertility outcomes were assessed. Low-input RNA-seq and single-cell RNA sequencing (scRNA-seq) were applied to evaluate transcriptomic heterogeneity in oocytes and somatic cells separately. Additionally, the molecular change and function of HucMSC-primed stromal cells (SCs) in aged ovaries were assessed to validate SCs' functional roles in ovarian microenvironment improvement.</p><p><strong>Results: </strong>HucMSC treatment enhanced follicular development, increased antral follicle numbers, and partially restored fertility in aged mice. Oocyte transcriptomes in HucMSC-treated mice resembled those of young mice, with 75% of aging-dysregulated genes (notably mitochondrial respiratory chain complex assembly-related genes) reverting to youthful expression patterns. scRNA-seq revealed upregulated transcription and glycolysis in granulosa cells (GCs), alongside stromal cell fate redirection toward steroidogenesis and folliculogenesis instead of fibrosis. Transplantation of HucMSC-primed SCs replicated these restorative effects. Mechanistically, HucMSCs promoted pregnenolone synthesis in stromal cells, facilitating follicular development.</p><p><strong>Conclusions: </strong>HucMSCs reactivate aged ovaries by inducing metabolic reprogramming in both oocytes and somatic cells, enhancing mitochondrial function in oocytes, and redirecting stromal cells toward steroidogenic and folliculogenic pathways. These findings underscore stromal cell functional modulation as a critical mechanism in counteracting ovarian aging and revealing the potential of stromal cells as therapeutic targets.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enolase 2-mediated lactylation-dependent disruption of the GNL3-MDM2-p53 axis in age-related osteoarthritis.","authors":"Feng Hua, Jiangyu Nan, Rong Wu, Bin Zhang, Qimeng Liu, Tianliang Ma, Zheyu Zhang, Yihe Hu, Jie Xie, Yute Yang","doi":"10.1186/s11658-026-00960-6","DOIUrl":"10.1186/s11658-026-00960-6","url":null,"abstract":"<p><strong>Background: </strong>Age-related osteoarthritis (OA) involves metabolic dysregulation and chondrocyte senescence. This study examined the nonmetabolic role of enolase 2 (ENO2) in OA pathogenesis and its therapeutic potential.</p><p><strong>Methods: </strong>Human aged and OA cartilage (n = 3 per group) underwent ¹⁸F-FDG positron emission tomography (PET)-computed tomography (CT) imaging, proteomic profiling, and immunohistochemistry. In vitro chondrocyte senescence models were generated by inducing doxorubicin-induced stress and serial passaging. Protein-protein interactions (ENO2-GNL3-MDM2) were validated by co-immunoprecipitation (IP), GST pull-down, and site-directed mutagenesis (E4A-ENO2 and K5R-GNL3 mutants). Lactylation was assessed using lactylomics and immunoprecipitation. The therapeutic effect of the ENO2-specific inhibitor POMHEX was evaluated in C57BL/6 J mice (n = 6 per group) via intra-articular injection for 16 weeks. Outcomes included histology, micro-CT, pain behavior, and gait analysis.</p><p><strong>Results: </strong>Proteomics revealed ENO2 upregulation in aged human cartilage. In vitro, ENO2 overexpression promoted extracellular matrix catabolism, senescence, and glycolysis, whereas ENO2 knockdown attenuated these processes. Mediated by its Glu-4 residue, nuclear ENO2 bound GNL3 lactylated at Lys-5. This interaction displaced MDM2 from GNL3, resulting in MDM2 destabilization, impaired ubiquitination, p53 accumulation, and persistent senescence. Moreover, p53 transcriptionally activated ENO2, establishing a pathological positive feedback loop. Pharmacological inhibition of ENO2 with POMHEX disrupted ENO2-GNL3 binding, restored p53 degradation, reduced senescence markers in vitro, and mitigated cartilage degradation, subchondral bone sclerosis, and pain in aged mice.</p><p><strong>Conclusions: </strong>ENO2 promotes OA progression through a lactate-dependent, lactylation-mediated disruption of the GNL3-MDM2-p53 axis, leading to a senescent feedback loop. Targeting ENO2 may represent a novel disease-modifying therapeutic approach for age-related OA.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148027405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPR161 contributes to macrophage glycolytic reprogramming via targeting C5aR1 in acute lung injury.","authors":"Yu-Huan Li, Xue Yang, Ying Chen, Miao Wang, Han Shu, Ke Wan, Dan-Tong Sun, Ning Yao, Ying-Li Yang, Fei Zhao, Bo-Bo Han, Chao Yao, Biao Song, Jing Bao, Geng-Yun Sun, Jun Li, Xiao-Feng Li","doi":"10.1186/s11658-026-00955-3","DOIUrl":"10.1186/s11658-026-00955-3","url":null,"abstract":"<p><p>Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are severe respiratory disorders characterized by a dysregulated and excessive inflammatory response within the pulmonary system. Recent studies have underscored the pivotal role of macrophage activation in driving inflammatory processes, with glycolytic reprogramming emerging as a critical regulator of macrophage function. In this study, we observed significantly elevated expression levels of G protein-coupled receptor 161 (GPR161) in peripheral circulating monocytes from patients with ARDS, with GPR161 expression positively correlating with disease severity. Utilizing genetically engineered mouse models, including global and macrophage-specific conditional knockout mice, we demonstrated that GPR161 deficiency attenuated pulmonary inflammatory damage in lipopolysaccharide-induced and sepsis-associated ALI mice. In vitro experiments further elucidated the essential role of GPR161 in macrophage activation and glycolytic reprogramming. Mechanistic investigations, integrating RNA sequencing with co-immunoprecipitation and surface plasmon resonance assays, identified complement component 5a receptor 1 (C5aR1) as a downstream target of GPR161 and showed that GPR161 promotes glycolytic reprogramming in macrophages by suppressing C5aR1 expression. Collectively, these findings demonstrate that GPR161 enhances macrophage activation and glycolytic reprogramming in ALI/ARDS through a C5aR1-dependent mechanism. These results establish macrophage GPR161 as a promising therapeutic target for the treatment of ALI/ARDS.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophils blend innate and adaptive immunity in early breast milk.","authors":"Gema Gomez-Casado, Natalia Saldaña-García, Antonio Cantarero-Cuenca, Andrés Gonzalez-Jimenez, Guillermo Paz-López, Patricia Garcia-Hurtado, Francisco J Tinahones, Ernesto González-Mesa, Almudena Ortega-Gomez","doi":"10.1186/s11658-026-00920-0","DOIUrl":"10.1186/s11658-026-00920-0","url":null,"abstract":"<p><strong>Background: </strong>Breast milk not only is the most optimal source of nutrition for newborns but also provides crucial immune support. While there is extensive evidence highlighting the health benefits of breastfeeding, the scientific understanding behind many of these advantages remains limited. The immune cell fraction of breast milk has been poorly studied, and characterization of this essential component may be crucial to shed light on the subject. Here, we investigate the population of neutrophils in breast milk to unveil their phenotype and functions.</p><p><strong>Methods: </strong>Neutrophils in human breast milk were characterized by flow cytometry, and their phenotype was contrasted with that of their circulating counterparts using a paired approach. Transmission electron microscopy (TEM), intracellular granule immunocytochemistry, and Giemsa staining were employed to reveal their intracellular structure. In vitro neutrophil incubations were performed to assess the phenotypic modifications of circulating neutrophils in a breast milk environment. Functional assays were carried out to assess the activity of neutrophils and their potential impact on adaptive immunity. Finally, a proteomic approach was used on isolated neutrophils and their supernatant after cultivation to define the protein-based mechanisms involved in their biology. Paired t-tests and one- and two-way analysis of variance (ANOVA) were used for statistical analyses.</p><p><strong>Results: </strong>In the breast milk from the first 5 days (known as colostrum), neutrophils represent most of the cellular compartment. Colostrum neutrophils present a cell surface signature markedly different from circulating neutrophils with a clear CXCR4⁺CD62L^-CXCR2^mid phenotype and important differences in other markers. These differences are partially phenocopied upon incubation of blood neutrophils with colostrum whey, implying that cell transition occurs owing to the niche environment. Additionally, colostrum neutrophils exhibit reduced cytoplasmic granule content and altered canonical functions. Proteomic analyses reveal that the most important processes in colostrum neutrophils are related to antigen binding and humoral response pathways.</p><p><strong>Conclusions: </strong>This study provides evidence of a unique population of neutrophils in early breast milk connected to adaptive immunity, which may hold the key to understanding the mechanisms behind the immunological benefits of breastfeeding.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13308176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic context of mutations in MIR142 in blood cancers: summary and integrative analysis.","authors":"Wladyslaw Wegorek, Adrian Tire, Daniel Kuznicki, Julia Richter, Maciej Giefing, Wolfram Klapper, Piotr Kozlowski, Paulina Galka-Marciniak","doi":"10.1186/s11658-026-00933-9","DOIUrl":"10.1186/s11658-026-00933-9","url":null,"abstract":"<p><p>MIR142 is the most frequently mutated microRNA (miRNA) gene in cancer, with recurrent alterations observed particularly in hematologic malignancies of lymphoid origin. It is expressed at very high levels in blood cells and plays an essential role in the development, differentiation, and maturation of various lymphopoietic and hematopoietic lineages. To gain a deeper understanding of MIR142 mutations, we summarize all data on these mutations, including their frequency in different cancers, their location within the miR-142 precursor, and their functional consequences. We also analyzed MIR142 mutations within a broader genomic context in thousands of cancers, including hundreds of blood neoplasms. Our results show that the most prevalent mutations in the MIR142 gene originate from a clearly distinct hotspot in hematologic malignancies, concentrated mainly within the sequence of the secondary miR-142 precursor. We found substantial differences in mutation frequency and distribution across cancer types. This indicates that MIR142 alterations are not random consequences of an increased mutational load but are likely subject to positive selection, underscoring their biological and clinical significance.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}