Critical reviews in eukaryotic gene expression最新文献

{"title":"LncRNA MANCR Acts as a ceRNA to Sponge MicroRNA-20a-5p and Upregulate GCNT4 to Suppress Angiogenesis in Colorectal Cancer.","authors":"Wei Zheng, ShuRong Huang, YangQiang Wang, ShiYang Zhan, Zongda Cai, JinPing Chen","doi":"10.1615/CritRevEukaryotGeneExpr.2026061564","DOIUrl":"10.1615/CritRevEukaryotGeneExpr.2026061564","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is ranked among the most prevalent digestive system malignancies worldwide. Its progression is closely associated with angiogenesis, which not only supplies nutrients and oxygen to tumors but also facilitates metastasis. Dysregulation of lncRNA MANCR (MANCR) in multiple cancers influences tumorigenesis and development. However, the function and molecular mechanism of MANCR in CRC angiogenesis remain unclear.</p><p><strong>Methods: </strong>This study constructed a MANCR/miR-20a-5p/GCNT4 axis using TCGA, starBase, and TargetScan Human databases. Expression of MANCR, microRNA-20a-5p, and GCNT4 in CRC was analyzed using the TCGA database, with validation performed in cell lines. In vitro functional assays (CCK-8, colony formation, transwell migration/invasion, tube formation, and Western blotting) were conducted to evaluate the impact of MANCR on CRC cell proliferation, migration, invasion, and angiogenesis. Bioinformatics analysis was used to analyze the Pearson correlation between MANCR and microRNA-20a-5p, and between microRNA-20a-5p and GCNT4. Functional interactions of MANCR and microRNA-20a-5p, and ceRNA regulatory mechanisms were verified via dual-luciferase reporter assays, RNA pull-down, and RNA immunoprecipitation, with further exploration of GCNT4's role in angiogenesis regulation conducted.</p><p><strong>Results: </strong>Significant downregulation of MANCR expression was observed in CRC tissues and cell lines. Overexpression of MANCR robustly inhibited CRC cell proliferation, migration, invasion, and angiogenesis. Significant negative correlations were observed between MANCR and microRNA-20a-5p, and between microRNA-20a-5p and GCNT4. MANCR sponged microRNA-20a-5p to downregulate its expression, while microRNA-20a-5p repressed GCNT4 expression by binding to the 3'UTR of GCNT4 mRNA. Overexpression of microRNA-20a-5p reversed MANCR-mediated suppression of angiogenesis.</p><p><strong>Conclusion: </strong>LncRNA MANCR sponges microRNA-20a-5p, relieves the suppression of GCNT4 expression caused by microRNA-20a-5p, and elevates GCNT4 expression, ultimately inhibiting tumor growth and angiogenesis in CRC.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 1","pages":"51-65"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Study of the Pink1/Parkin Signaling Pathway in Mitochondrial Dysfunction and Podocyte Injury.","authors":"Shengyou Yu, Qingke Xie, Li Yu","doi":"10.1615/CritRevEukaryotGeneExpr.2026061692","DOIUrl":"10.1615/CritRevEukaryotGeneExpr.2026061692","url":null,"abstract":"<p><p>PTEN-Induced Putative Kinase 1 (Pink1) is a key regulatory protein in mitochondrial autophagy: upon mitochondrial damage, Pink1 selectively binds to the mitochondrial outer membrane, thereby recruiting and phosphorylating Parkin. However, the mechanism by which the Pink1/Parkin signaling pathway functions in podocytes remains unclear, and this study aimed to investigate the role of this pathway in mitochondrial dysfunction associated with glomerular podocyte injury. For this purpose, flow cytometry was used to detect podocyte apoptosis rate; transmission electron microscopy was employed to observe the quantity and morphological changes of podocyte mitochondrial autophagosomes; and reverse transcription-polymerase chain reaction (RT-PCR) and western blot were performed to quantify the mRNA and protein expression levels of Pink1, Parkin, and LC3-II, respectively. The results showed that compared with the Control and Pink1 groups, the PAN group exhibited a significantly increased podocyte apoptosis rate; in the Pink1 group, mitochondria gradually became swollen and rounded, with disordered arrangement. These findings confirmed that PAN can induce podocyte injury and that this process is associated with the Pink1/Parkin pathway. In conclusion, the Pink1/Parkin signaling pathway plays a crucial role in mitochondrial dysfunction during glomerular podocyte injury, and these results provide a new perspective for the potential clinical application of the Pink1/Parkin signaling pathway in podocyte injury and future related research.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 1","pages":"37-50"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Biomarkers and Regulatory Mechanisms Associated with the Innate Immune Cell Barrier in Pulmonary Tuberculosis Using Bioinformatics and Machine Learning.","authors":"Qin Zhu, Cheng Peng, Qiong Zhou, Zhengfeng Hang","doi":"10.1615/CritRevEukaryotGeneExpr.2026063297","DOIUrl":"https://doi.org/10.1615/CritRevEukaryotGeneExpr.2026063297","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary tuberculosis (PTB) development is linked to dysregulated immune responses, with the innate immune cell barrier playing a crucial role in both disease initiation and progression.</p><p><strong>Methods: </strong>The acquisition of transcriptomic datasets pertaining to PTB was conducted using the GEO database. Modules associated with the innate immune cell barrier were identified using weighted gene co-expression network analysis. The intersection of the differentially expressed genes and the module genes yielded a set of overlapping genes. Biological pathways were characterized and candidate genes were screened through functional enrichment analyses and protein-protein interaction network modeling. Key genes were identified through the application of machine-learning algorithms and further confirmed via qPCR using clinical samples. Diagnostic models were developed and independently evaluated. Multiple analytical approaches were employed to explore the biological mechanisms and therapeutic potential. These included gene set enrichment analysis, immune cell infiltration profiling, regulatory network analysis, and molecular docking.</p><p><strong>Results: </strong>A total of 360 overlapping genes were identified, enriched in immune activation and inflammatory pathways. Nineteen candidates were screened, and five key genes-OAS1, STAT2, IFITM1, CCR7, and CD19-were prioritized through machine learning. qPCR validation confirmed consistent expression trends for all genes except CD19. These genes were enriched in lysosomal and ribosomal pathways, with aberrant neutrophil and monocyte infiltration strongly correlating with gene expression. Molecular docking identified peginterferon-alfa-2a and isotretinoin as potential therapeutic agents.</p><p><strong>Conclusion: </strong>This study identified five key genes and two potential drug candidates associated with innate immune dysregulation in PTB, providing new insights into disease mechanisms and supporting their potential value in PTB diagnosis and therapy.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 2","pages":"49-64"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIS/HA Loaded with BMSC-Exo Enhances the Osseointegration after Tooth Defect.","authors":"Kaiyang Zhang, Guolin Liu","doi":"10.1615/CritRevEukaryotGeneExpr.2026062593","DOIUrl":"https://doi.org/10.1615/CritRevEukaryotGeneExpr.2026062593","url":null,"abstract":"<p><p>Tooth tissue loss hinders full regeneration. Small intestinal submucosa (SIS) coated with hydroxyapatite (HA) possesses biocompatibility, biodegradability, and osseointegration properties. This study aimed to investigate the effects of SIS/HA on tooth defect. Herein, we used SIS/HA for tooth tissue engineering. Bone marrow mesenchymal stem cell (BMSC)-derived exosomes were inserted into SIS/HA. Histological analysis was detected using HE staining and ALP staining. Gene expression was analyzed by qRT-PCR and Western blot. Osteogenesis was analyzed by alizarin red staining. Cellular mineralization was analyzed by ALP staining. Cell viability was detected by CCK-8 assay. Angiogenesis was analyzed by tube formation assay. We found that SIS/HA effectively showed high cell viability. SIS/HA loaded with BMSC-Exo enhanced the effects of SIS/HA and promoted angiogenesis of RAOECs. Moreover, SIS/HA loaded with BMSC-Exo enhanced the effects of SIS/HA and mediated osteogenesis in vitro. BMSC-Exo-loaded SIS/HA enhanced new bone regeneration in vivo. In summary, BMSC-Exo-coated SIS/HA mediates osseointegration after tooth defect.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 2","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JMJD6 Inhibits the Ferroptosis of Neurons in Alzheimer's Disease through Driving H4R3 Symmetrical Dimethylation of GPX4.","authors":"Lexuan Gu, Dongmei Sun, Luxiang Sun, Tianqi Ma, Qiulu Wang, Xiaoli Hou, Hong Cheng","doi":"10.1615/CritRevEukaryotGeneExpr.2026064685","DOIUrl":"https://doi.org/10.1615/CritRevEukaryotGeneExpr.2026064685","url":null,"abstract":"<p><p>Histone methylation is a key hallmark of Alzheimer's disease (AD). JMJD6 functions in a neuro-protective role. The purpose of this study is to explore the role of JMJD6 in AD. Neurons are exposed to Aβ1-42 to establish in vitro AD model. Neurons are treated with RSL3 to induce neuronal ferroptosis. mRNA expression is detected using qRT-PCR. Protein expression is determined using Western blot. The levels of ROS, GSH, MDA, ferrous iron, and C11-BODIPY are analyzed. Neuronal death is detected using PI staining. H4R3 symmetrical dimethylation of GPX4 is analyzed using ChIP and luciferase assays. We found that Aβ1-42 exposure promotes iron overload and lipid peroxidation, driving neuronal ferroptosis. Aβ1-42 exposure inhibits the expression of JMJD6. However, overexpression of JMJD6 reverses Aβ1-42 exposure-induced neuronal ferroptosis. Moreover, JMJD6 promotes H4R3 symmetrical dimethylation and upregulation of GPX4, driving the release of anti-oxidant GSH. Furthermore, JMJD6 overexpression alleviated cognitive impairment and neuronal ferroptosis in AD mouse models. However, downregulation of GPX4 mediates neuronal ferroptosis. In conclusion, JMJD6 protects against neuronal ferroptosis in AD via upregulating GPX4.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 3","pages":"47-57"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PFKFB2-Induced Glycolysis and Ferroptosis in Diabetic Nephropathy by HIF-1α.","authors":"Yayin Tan, Jiajun Zhou, Yong Liu","doi":"10.1615/CritRevEukaryotGeneExpr.2025062419","DOIUrl":"10.1615/CritRevEukaryotGeneExpr.2025062419","url":null,"abstract":"<p><p>In recent years, the prevalence of diabetic nephropathy (DN) has been increasing year by year. Here, this experiment investigated the effects of PFKFB2 in DN and its molecular mechanisms of DN. DN mice were fed a high-fat diet for 12 weeks, and then injected with STZ. DN mice were transfected with negative or sh-DPP9 lentivirus using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA). Human proximal tubular HK-2 cells stimulated with 20 mmol/L d-glucose. Analysis revealed a significant downregulation of PFKFB2 expression in DN patients. PFKFB2 was expression in renal cell of DN model using single-cell RNA sequencing. Sh-PFKFB2 aggravated DN in mice model. PFKFB2 up-regulation reduced oxidative stress and glycolysis in model of DN. The inhibition of PFKFB2 aggravated mitochondria-dependent ferroptosis in model of DN. Ferroptosis inhibitor reduced the effects of PFKFB2 down-regulation in mitochondria-dependent ferroptosis in model of DN. PFKFB2 suppressed HIF-1α expression in model of DN by the inhibition of HIF-1α ubiquitination. HIF-1α inhibitor reduced the effects of PFKFB2 down-regulation in mitochondria-dependent ferroptosis in model of DN. In conclusion, PFKFB2 reduced oxidative stress and glycolysis of DN through the inhibition of HIF-1α signaling pathway by the induction of Nrf2 ubiquitination, further elucidating the role of PFKFB2 regulated mitochondrial ROS-induced ferroptosis for DN. Targeting PFKFB2 is thus a potentially effective therapeutic strategy for DN.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 1","pages":"67-84"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydroartemisinin Suppresses Esophageal Squamous Cell Carcinoma by Downregulating COX-2 through the ROS/MAPK/Sp1 Pathway.","authors":"Chongbo Liao, Xingyao Zhu, Yong Yang, Jiang Zhu, Xiao Liu, Maoju Tang, Man Luo, Xiaowu Zhong, Lei Xu, Hebin Liao, Lin Xiao, Feng Gong, Qiang Ma, Xiaolan Guo","doi":"10.1615/CritRevEukaryotGeneExpr.2026064579","DOIUrl":"https://doi.org/10.1615/CritRevEukaryotGeneExpr.2026064579","url":null,"abstract":"<p><strong>Background: </strong>Esophageal squamous cell carcinoma (ESCC) has a poor prognosis due to its aggressiveness and chemoresistance, necessitating novel therapeutic strategies. Dihydroartemisinin (DHA), an artemisinin derivative, exhibits broad anticancer activity, but its mechanism in ESCC remains incompletely understood.</p><p><strong>Methods: </strong>Transcriptomic sequencing identified differentially expressed genes upon DHA treatment. The regulation of COX-2 by DHA was validated via RT-qPCR and Western blot. Gain- and loss-of-function assays assessed COX-2 and Sp1 effects on ESCC proliferation and migration. Dual-luciferase reporter assays confirmed Sp1-driven COX-2 transcription. ROS levels and MAPK pathway protein expression were measured by flow cytometry and Western blot, respectively. A xenograft model evaluated in vivo effects of Sp1 overexpression and DHA.</p><p><strong>Results: </strong>DHA downregulated COX-2 in a time- and dose-dependent manner, inhibiting ESCC cell proliferation and migration. Sp1 directly bound the COX-2 promoter and positively regulated its expression, thereby promoting malignant phenotypes. DHA triggered ROS accumulation and downregulated the protein levels of MAPK (ERK/MSK), Sp1, and COX-2. Both NAC (an antioxidant) and Sp1 overexpression reversed these effects. In vivo, DHA significantly suppressed tumor growth via the Sp1/COX-2 axis without detectable toxicity.</p><p><strong>Conclusion: </strong>This study establishes that DHA inhibits ESCC proliferation and metastasis through the ROS-MAPK(ERK/MSK)-Sp1-COX-2 axis, highlighting DHA as a promising repurposed agent and identifying Sp1/COX-2 as novel therapeutic targets for ESCC.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 3","pages":"59-77"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD58: A Promising Diagnostic and Prognostic Biomarker for Hepatocellular Carcinoma.","authors":"Rong Cui, Yanmei Gu, Yingying Wang, Gangli Liu, Xiaomei Li, Puyi He, Yujie Wei, Yumin Li","doi":"10.1615/CritRevEukaryotGeneExpr.2026063933","DOIUrl":"https://doi.org/10.1615/CritRevEukaryotGeneExpr.2026063933","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) remains a global health challenge due to the lack of reliable early diagnostic markers and therapeutic targets. While CD58 is implicated in immune modulation and cancer progression, its role in HCC has not been fully explored.</p><p><strong>Methods: </strong>Bioinformatics analysis was performed to assess CD58 expression and its clinical significance. Immunohistochemistry was conducted on tissue microarrays to validate CD58 expression, while enzyme-linked immunosorbent assay was used to measure soluble CD58 levels in HCC serum. A nomogram was constructed to predict overall survival, and decision curve analysis along with area under the ROC curve were applied to evaluate its diagnostic value. Additionally, serum trace elemental levels were analyzed using inductively coupled plasma atomic emission spectroscopy to explore their relationship with sCD58.</p><p><strong>Results: </strong>CD58 was overexpressed in human HCC tissues and its expression was associated with age and hepatitis status. For HCC patients, CD58 was identified as an independent prognostic factor. Furthermore, CD58 was positively correlated with T cell infiltration in HCC tissues. The levels of sCD58 were elevated in HCC serum and showed significant diagnostic potential. Notably, sCD58 correlated with copper levels, providing new insights into its role in HCC progression.</p><p><strong>Conclusion: </strong>CD58 is a promising diagnostic and prognostic biomarker for HCC, and targeting CD58 may offer novel therapeutic strategies. The correlation between sCD58 and copper levels suggests that copper could play a key role in HCC pathogenesis.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 3","pages":"29-45"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Lack of Association between Vitamin D Receptor Gene Polymorphisms with Colorectal Cancer: A Comprehensive Meta-Analysis and Power Assessment.","authors":"Anu Shibi Anilkumar, Sheena Mariam Thomas, Ramakrishnan Veerabathiran","doi":"10.1615/CritRevEukaryotGeneExpr.2025062255","DOIUrl":"10.1615/CritRevEukaryotGeneExpr.2025062255","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) remains a major global health burden, and genetic factors such as vitamin D receptor (VDR) polymorphisms have been implicated in its pathogenesis. However, the translational relevance of these variants in clinical risk stratification remains unclear.</p><p><strong>Methods: </strong>We conducted a comprehensive meta-analysis of case-control studies assessing the association between four common VDR single-nucleotide polymorphisms (Fok1, Apa1, Bsm1, and Taq1) and CRC risk, integrating data from PubMed, Embase, Google Scholar, and other sources through 2024. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated under multiple genetic models. Heterogeneity, publication bias, and sensitivity analyses were performed. Statistical power was evaluated using G*Power 3.1.</p><p><strong>Results: </strong>Across 24 datasets from diverse ethnic populations, no significant associations were observed for any of the four VDR variants in allelic, dominant, recessive, or overdominant models. Statistical power exceeded 0.99 for all variants, indicating that the null results were unlikely due to sample size limitations.</p><p><strong>Conclusion: </strong>This study provides robust evidence that these common VDR polymorphisms are not clinically functional as biomarkers for CRC susceptibility. Eliminating these variants from biomarker panels can help redirect resources toward more promising genetic or molecular predictors. These findings also reinforce the need for integrative studies exploring gene-environment interactions, particularly vitamin D status, diet, and lifestyle, to clarify the role of vitamin D pathways in CRC prevention and treatment.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 1","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DPP9 Expression in a PDTX Model of Undifferentiated Pleomorphic Sarcoma Reduced Mitochondrial Damage-Induced Ferroptosis for Diagnosis and Guidance for Individualized Clinical Treatment.","authors":"Jing Zhang, Yinjuan Shang, Peng Fang, Lei Zhang, Tianting Bai, Xiaozhou Liu","doi":"10.1615/CritRevEukaryotGeneExpr.2026063409","DOIUrl":"https://doi.org/10.1615/CritRevEukaryotGeneExpr.2026063409","url":null,"abstract":"<p><p>This study aims to screen for and target DPP9 expression in patient-derived tumor xenografts (PDTX) of Undifferentiated Pleomorphic Sarcoma (UPS) to advance personalized therapeutic strategies. We found that DPP9 mRNA expression is significantly upregulated in UPS patients. Single-cell RNA sequencing (scRNA-seq) further confirmed elevated DPP9 levels within the UPS tumor microenvironment. Functional studies demonstrated that shRNA-mediated knockdown of DPP9 suppressed tumor growth in UPS mouse models. Mechanistically, DPP9 promotes UPS cell proliferation by inhibiting mitochondria-dependent ferroptosis. Specifically, DPP9 reduces intracellular reactive oxygen species (ROS) accumulation and confers resistance to ferroptosis. Conversely, DPP9 downregulation induces ferroptosis by enhancing ROS production and mitochondrial dysfunction. Moreover, N6-methyladenosine (m6A) methylation enhances DPP9 mRNA stability in UPS, contributing to its overexpression. DPP9 also activates the NRF2 signaling axis by suppressing KEAP1-mediated ubiquitination and subsequent degradation of NRF2. This stabilization of NRF2 underlies DPP9's ability to inhibit mitochondria-dependent ferroptosis. Collectively, our findings identify DPP9 as a critical regulator of ferroptosis resistance in UPS and suggest that targeting DPP9 may represent a promising therapeutic strategy-not only for UPS, but potentially for other malignancies driven by dysregulated ferroptosis.</p>","PeriodicalId":521156,"journal":{"name":"Critical reviews in eukaryotic gene expression","volume":"36 2","pages":"27-47"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}