{"title":"UPF1 promotes wound healing in diabetic foot ulcer by reducing CYP1A1-induced oxidative stress through enhancing EGR1 degradation.","authors":"Zhi-Yang Qiu, Yun-Lei Ma, Yao-Xue Zhang, Jia Fu, Wei-Cheng Xu, Shao-Jia Kuang, Jia-Qin Xu, Zun-Hong Liang","doi":"10.1007/s00438-026-02432-0","DOIUrl":"https://doi.org/10.1007/s00438-026-02432-0","url":null,"abstract":"<p><p>Diabetic foot ulcer (DFU) is a severe and debilitating complication of diabetes with limited effective therapeutic strategies, and persistent oxidative stress and inflammation are the core pathological factors leading to its impaired wound healing. RNA-binding protein UP frameshift 1 (UPF1) is implicated in modulating oxidative stress pathways, yet its regulatory role and underlying mechanism in DFU-associated oxidative stress remain largely unelucidated. This study aims to explore the function of UPF1 in oxidative stress during DFU pathogenesis and identify its related molecular regulatory axis, so as to provide novel therapeutic targets for DFU management. Human dermal fibroblasts (HDFs) were exposed to 30 mM high glucose (HG) to simulate diabetic conditions. The results showed that HG stimulation increased cytochrome P450 family 1 subfamily A member 1 (CYP1A1) and early growth response 1 (EGR1) expression, exacerbating oxidative stress and inflammation in HDFs. EGR1 knockdown or CYP1A1 inhibition attenuated these effects. Mechanistically, EGR1 transcriptionally activated CYP1A1, while UPF1 bound to and destabilized EGR1 mRNA. As expected, UPF1 upregulation rescued HG-induced inflammation and oxidative stress in HDFs, whereas concurrent EGR1 overexpression abolished this protective effect. In conclusion, UPF1 exerts a protective role in HG-stressed HDFs by degrading EGR1 mRNA, which in turn suppresses the transcriptional activation of CYP1A1 and subsequent CYP1A1-mediated oxidative stress and inflammation, thus uncovering a novel UPF1-EGR1-CYP1A1 regulatory axis in DFU pathogenesis. These core findings not only enrich the molecular understanding of oxidative stress regulation in DFU but also provide promising novel therapeutic targets for DFU management.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"SETDB1 induces H3K9me3 methylation modification of RASSF2 to inhibit PTEN and facilitate ovarian cancer progression.","authors":"Jing Wang, Xinyu Li, Jianmiao Chang, Xiaoxue Hou, Lijia Sun, Yanan Yan, Lisha Shu, Xin Wu","doi":"10.1007/s00438-026-02424-0","DOIUrl":"https://doi.org/10.1007/s00438-026-02424-0","url":null,"abstract":"<p><p>Ovarian cancer (OV) is one of the deadliest gynecological malignancies, and its high heterogeneity significantly impacts treatment efficacy. Against this background, the molecular mechanisms underlying the pathogenesis of this lethal disease have attracted extensive research attention. However, the pathogenic mechanisms of OV remain incompletely understood. Therefore, this study systematically investigates the pathogenesis of OV. This study collected 20 paired clinical samples comprising OV tissues and benign ovarian tissues to investigate RASSF2 expression. The biological effects of RASSF2 were investigated using both in vitro and in vivo models, including assessments of proliferation and migration. The impact of RASSF2 on PTEN protein stability was examined through co-immunoprecipitation and cycloheximide (CHX) chase assays. Additionally, chromatin immunoprecipitation (ChIP) was performed to investigate the SETDB1/RASSF2 interaction and H3K9me3 modifications on the chromatin of RASSF2. OV tissues exhibited significantly lower RASSF2 expression compared to normal tissues, and this reduction was associated with poorer patient survival. Overexpression of RASSF2 inhibited the proliferation and migration of OV cells. Additionally, RASSF2 inhibited OV growth in vivo. Mechanistically, RASSF2 stabilized PTEN expression to inhibit the activation of PI3K/AKT pathway. In addition, SETDB1 drove OV progression by increasing H3K9me3 enrichment at the RASSF2 promoter to negatively regulate RASSF2 expression. H3K9me3‑modified RASSF2 promotes ovarian cancer metastasis by regulating PTEN expression, which may offer a potential therapeutic target to counteract distant dissemination of OV.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exosomal miR-27a-3p promotes osteosarcoma lung metastasis by negatively regulating TNFAIP3 to form a premetastatic niche.","authors":"Yuxin Jiang, Changcheng Fan, Qiuyu Tan, Ying Wang, Jinwen Xu, Xiaoxuan Zuo, Xiaojian Li, Xu Wu, Jinzhu Ma, Liang Yan","doi":"10.1007/s00438-026-02431-1","DOIUrl":"https://doi.org/10.1007/s00438-026-02431-1","url":null,"abstract":"<p><p>Osteosarcoma (OS) is a highly aggressive primary bone malignancy with a strong predilection for lung metastasis, and the formation of a lung pre-metastatic niche represents a key early event driving OS distant dissemination. Elucidating the molecular mechanisms of pre-metastatic niche establishment is therefore critical for developing novel anti-metastatic therapies for OS. However, the mechanisms by which OS cells initiate the formation of a lung pre-metastatic niche remain poorly understood. Exosomes, as key mediators of intercellular communication, play a pivotal role in promoting tumor metastasis by shuttling functional biomolecules to remodel the microenvironment of distant target organs. In this study, we found that MG63 OS cells secreted exosomal miR-27a-3p, which targeted TNFAIP3 in lung fibroblasts, resulting in decreased TNFAIP3 protein expression. This downregulation enhanced the metastatic potential of OS cells toward lung fibroblasts. TNFAIP3 was identified as a direct target of miR-27a-3p, and TNFAIP3-Mut abrogated the regulatory effect of miR-27a-3p on TNFAIP3 expression, confirming the specific targeting relationship. Mechanistically, miR-27a-3p-mediated suppression of TNFAIP3 abrogated its negative regulation of the NF-κB pathway, leading to increased transcription of downstream inflammatory cytokines IL-1β, IL-6, and IL-8. The resulting pro-inflammatory microenvironment contributed to the establishment of a lung pre-metastatic niche, thereby promoting OS lung metastasis. These findings underscore the critical role of OS-derived exosomes in lung metastasis and suggest that exosomal miR-27a-3p may serve as a promising therapeutic target in OS lung metastasis.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Focus on M2-TAMs and gastric cancer: a Mendelian randomization and bioinformatics analysis.","authors":"GuangTao Min, Hao Tang, GuangNing Min, YuMin Li","doi":"10.1007/s00438-026-02422-2","DOIUrl":"https://doi.org/10.1007/s00438-026-02422-2","url":null,"abstract":"<p><p>Gastric cancer (GC), a highly aggressive and heterogeneous malignancy, remains challenging in immunotherapy despite recent advancements. This study aims to identify novel biomarkers and construct a prognostic model to improve outcome prediction and therapeutic strategies. Mendelian randomization (MR) analysis identified immune cell subtypes linked to GC using FinnGen and GWAS cohorts. CIBERSORT and WGCNA algorithms were applied to define M2 tumor-associated macrophage (TAM)-related gene modules. Key prognostic genes were selected via Lasso-Cox regression to establish a risk model, validated using GEO datasets. Biological function disparities, tumor microenvironment heterogeneity, and therapeutic sensitivities were assessed via GSEA and immune infiltration analysis. Protein-level validation was performed using TCGA, HPA, and Western blot. MR analysis revealed 26 immune cell subtypes associated with GC. WGCNA identified 20 gene modules, with the most M2 TAM-correlated module prioritized. A prognostic signature incorporating SEC61G, BGN, and STC1 was developed, stratifying patients into distinct risk groups with divergent survival outcomes (1-/3-/5-year, all P < 0.05). High-risk patients exhibited enriched calcium signaling pathways, reduced immunotherapy responsiveness, and increased sensitivity to veriparib and palbociclib. Protein overexpression of key genes was validated in GC tissues. This integrated bioinformatics-MR framework establishes a TAM-driven prognostic model for GC, demonstrating clinical utility in survival prediction, immunotherapy efficacy evaluation, and personalized therapeutic targeting. The findings provide actionable insights for advancing precision immunotherapy in GC.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuroprotective role of Curcuma amada evidenced from pesticide-induced stressed Drosophila melanogaster: insights from RNAseq and gut microbiome analyses.","authors":"Nikita Bindal, Sujata Mohanty","doi":"10.1007/s00438-026-02418-y","DOIUrl":"https://doi.org/10.1007/s00438-026-02418-y","url":null,"abstract":"<p><p>Prolonged exposure to pesticides is linked to neurodegenerative disorders through mechanisms involving oxidative stress, inflammation, and neuronal signaling. Therapeutic plants may offer a promising and natural alternative for protecting against such damage. Hence, the present study aims to understand the role of Curcuma amada in mitigating pesticide-induced neurotoxicity and its molecular mechanism in Drosophila. The pesticidal stress was induced in Drosophila through oral feed of ethion and its action was confirmed through behavioural assay. The stressed flies were treated with C. amada rhizome and the effect of both ethion and ethion + C. amada was assessed through RNA profiling and gut microbiome analysis. Decrease in locomotory activity on exposure to ethion represents the induced neuronal stress and an increase was seen after C. amada was fed to the stressed flies. Many DEGs were identified through RNAseq results of stressed and C. amada treated which were further analysed using Cytoscape. In ethion and ethion + C. amada treated flies, the upregulated and downregulated genes were found to be associated with neuronal signal processing and mitochondrial function [MRPs, Dop2R, 5-HT1A, aminoacyl-tRNA synthetase (AARs), ND-B17]. A significant change in the gut microbial population (especially decrease in Lactiplantibacillus species) was observed in stressed flies. But the restoration of healthy bacterial population such as Lactiplantibacillus in C. amada treated flies evidencing the crucial role of gut microbiome in neuronal health. This study highlights the beneficial effects of C. amada from pesticidal stress which needs to be further researched to understand the underlying molecular mechanisms.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Scarlet A Shifflett, Esther Weyer, Madolyn L MacDonald, Vincenzo A Ellis
{"title":"Assembled and annotated reference genome and demographic history of the eastern chipmunk (Tamias striatus).","authors":"Scarlet A Shifflett, Esther Weyer, Madolyn L MacDonald, Vincenzo A Ellis","doi":"10.1007/s00438-026-02427-x","DOIUrl":"10.1007/s00438-026-02427-x","url":null,"abstract":"<p><p>The eastern chipmunk (Tamias striatus) is an abundant North American sciurid rodent and the only extant member of the subgenus Tamias. Despite its abundance, a reference genome has not been produced for this species. Here we present an assembled and annotated reference genome for the eastern chipmunk using PacBio HiFi long read sequencing data. We sequenced the genome of a vouchered male eastern chipmunk collected in Maine and stored at the National Museum. We compared the eastern chipmunk's genome with the genome of the Siberian chipmunk (Tamias sibiricus; subgenus Eutamias), the only other species in the Tamias genus with an annotated reference genome. The genomes were similar with 55.45% of genes showing collinearity and chromosomal rearrangements only occurring between chromosomes 4 and 8. We identified 219 genes under positive selection in the eastern chipmunk relative to the Siberian chipmunk. A coalescent analysis inferred the effective population size of the Maine eastern chipmunk may have steadily decreased through the Pleistocene epoch, consistent with a reduction in available habitat. We also generated short-read Illumina sequencing data from two additional eastern chipmunks collected in New Castle County, Delaware and Carbon County, Pennsylvania. We calculated nucleotide diversity over 10 kb windows across the genome (mean = 0.0014 ± 0.0012 s.d.) and identified genes with high nucleotide diversity. The eastern chipmunk reference genome will facilitate future population genetic and evolutionary studies including those investigating its role as a reservoir host for the bacterium that causes Lyme disease.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"XAF1 nonsense mutation rs117407731 enhances lung adenocarcinoma susceptibility via apoptosis suppression.","authors":"Guanxin Xu, Hang Zhang, Sai Zhang, Danqing Yu","doi":"10.1007/s00438-026-02421-3","DOIUrl":"https://doi.org/10.1007/s00438-026-02421-3","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, the leading cause of global cancer-related mortality. Genetic mutations play critical roles in LUAD pathogenesis. This study aims to investigate the role of XIAP-associated factor 1 (XAF1) rs117407731, a nonsense mutation in certain splice variants (p.22W>*, TGG to TGA), in LUAD susceptibility and cellular function. Genotyping of XAF1 rs117407731 was conducted using blood samples of 103 LUAD patients and 229 healthy individuals. Multivariate logistic regression analysis was carried out to identify independent factors associated with LUAD risk. Immunofluorescence staining showed the expression of XAF1 and XIAP in LUAD tissues. TUNEL staining was employed for cell apoptosis analysis in patient LUAD tissues or mouse tumors. A549 cells were transduced with lentiviral vectors carrying wild-type or mutant XAF1 (XAF1-WT or XAF1-MUT) for functional experiments. XAF1 rs117407731 significantly increased susceptibility to LUAD. XAF1 protein expression was reduced, XIAP expression was elevated, and cell apoptosis was decreased in LUAD tissues from rs117407731 carriers. Overexpressing XAF1-MUT abated XAF1-mediated impairment of A549 cell proliferation and enhancement of apoptosis in vitro. XAF1-MUT overexpression impaired tumor suppression in the xenograft mouse model. XAF1 rs117407731 contributes to LUAD risk by impairing XAF1-mediated apoptosis.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pangenomic and functional domain comparison of enterotoxigenic Escherichia coli isolated from humans and swine: insights into host specificity.","authors":"Gabriela Merker Breyer, Juliana Silva Bernardes, Márcio Dorn, Franciele Maboni Siqueira","doi":"10.1007/s00438-026-02412-4","DOIUrl":"https://doi.org/10.1007/s00438-026-02412-4","url":null,"abstract":"<p><p>Diarrhea caused by enterotoxigenic Escherichia coli (ETEC) is a common threat to humans and animals. Clinical ETEC strains display host tropism, usually driven by adherence and toxin-host interactions in the gut. Other virulence factors, metal acquisition mechanisms, and immune evasion strategies may also influence host specificity. Using publicly available genomes, we performed a pangenomic and functional comparison of 77 human- and swine-derived ETEC strains. Sequence types ST10 and ST4 found in both hosts, suggesting potential cross-host transmission. Phylogenetic analyses showed clustering mainly by ST, regardless of host or geography. Additionally, most functional domains were shared between hosts; however, human-derived strains carried exclusive domains related to adhesion, transposition, and toxins, whereas swine-derived strains harbored domains linked to stress response and metal binding. Notably, the PF09075 domain from the STb enterotoxin occurred only in swine-derived strains, despite previous reports in humans. Comparative analyses of STa (PF02048) and STb revealed no structural or functional homology but confirmed the swine-specific association of STb and greater sequence STa variability in human-derived strains. These findings indicate that sequence and functional differences in these enterotoxins contribute to ETEC host tropism, while ST patterns reveal possible epidemiological links between human and swine infections.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}