Biochimica et biophysica acta. General subjects最新文献

{"title":"MiR-2779-x, a key microRNA that is related to the tumorigenicity of the MDCK cell line.","authors":"Di Yang, Lingwei Huang, Jiachen Shi, Zhenbin Liu, Jiamin Wang, Zhongren Ma, Ayimuguli Abudureyimu, Zilin Qiao, Jianguo Chen","doi":"10.1016/j.bbagen.2025.130843","DOIUrl":"https://doi.org/10.1016/j.bbagen.2025.130843","url":null,"abstract":"<p><p>The tumorigenicity of MDCK cell line is a major concern with respect to its safety for vaccine production, the effect of miRNAs on the tumorigenicity of MDCK cells is poorly understood. In this study, we performed miRNA-Seq on two MDCK cell lines with tumorigenic potential and their derived monoclonal cell lines that lack tumorigenicity. Through bioinformatics analysis, we identified differentially expressed miRNAs and conducted GO and KEGG pathway analyses of their target genes. Our results indicated that miR-2779-x and its target genes exhibited the most significant characteristics associated with tumorigenesis. Injection of live cells overexpressing miR-2779-x into nude mice resulted in a markedly reduced tumorigenesis rate (1/10). Overexpression of miR-2779-x significantly decreased the proliferation and migration capabilities of MDCK cells while enhancing their invasive potential. To identify and localize miR-2779-x target genes, we employed bioinformatics prediction, RT-qPCR, immunofluorescence assays (IFA), fluorescence in situ hybridization (FISH), and dual-luciferase reporter assays. We found that miR-2779-x negatively regulates the expression of PI3KR1 and Caspase 9 at both the gene and protein levels. Additionally, miR-2779-x co-localizes with PI3KR1 in the cytoplasm and directly targets the 3'UTR of PI3KR1. Overexpression of PI3KR1 in miR-2779-x-overexpressing cells restored cellular functions, leading to increased proliferation and migration but decreased invasion. Moreover, miR-2779-x modulates MDCK cell growth and tumorigenesis by influencing the expression and phosphorylation levels of proteins involved in the PI3K/AKT and apoptosis signaling pathways. We proposed the key pathways of miRNA involvement in MDCK cell tumorigenicity and initially revealed the function of miR-2779-x in MDCK cell tumorigenicity.</p>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":" ","pages":"130843"},"PeriodicalIF":2.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673880","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":"Phase separation via protein-protein and protein-RNA networks coordinates ribosome assembly in the nucleolus","authors":"Priyanka Dogra ,&nbsp;Richard W. Kriwacki","doi":"10.1016/j.bbagen.2025.130835","DOIUrl":"10.1016/j.bbagen.2025.130835","url":null,"abstract":"<div><div>The nucleolus, the largest membraneless organelle in the nucleus, functions as the site for ribosome biogenesis. While long known for its complex and dynamic structure, our mechanistic understanding of nucleolar organization has advanced dramatically in the past 15 years. The process of phase separation (PS) facilitates the compartmentalization of ribosomal components with assembly factors in the nucleolus, underlying complex ribosome biogenesis processes. Multicomponent PS creates multiple nucleolar sub-compartments that function from inside out as a ribosome assembly line. In this review, we discuss the molecular basis of nucleolar organization, including how different types of protein-protein and protein-RNA interactions create the multilayered architecture that enables ribosome biogenesis. Key proteins including nucleolin, fibrillarin, and nucleophosmin mediate nucleolar compartmentalization through their unique structural features and multivalent interactions. The processes of ribosomal RNA (rRNA) transcription, modification and splicing, and folding are spatially and temporally segregated within different regions of the nucleolus. rRNA matures and changes form along this processing continuum, continually altering its interactions with proteins, creating multiple separate liquid phases that establish sub-compartments. We highlight how both folded domains and intrinsically disordered regions (IDRs) in nucleolar proteins contribute to multivalent interactions underlying PS and nucleolar compartmentalization. We also discuss how perturbation of nucleolar PS alters nucleolar structure, dynamics, and function and contributes to a range of pathological conditions.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130835"},"PeriodicalIF":2.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633262","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":"Pharmacological role of MLN4924 in cisplatin-induced acute kidney injury","authors":"Feng Chen ,&nbsp;Ayinigaer Yusufu ,&nbsp;Gang Li ,&nbsp;Xueyun Gao ,&nbsp;Danqin Lu ,&nbsp;Xiaoyan Wu ,&nbsp;Lihua Ni","doi":"10.1016/j.bbagen.2025.130842","DOIUrl":"10.1016/j.bbagen.2025.130842","url":null,"abstract":"<div><h3>Background</h3><div>Cisplatin-induced acute kidney injury (Cis-AKI) is a major complication that limits the clinical use of cisplatin, largely due to its cytotoxic effects on renal tubular epithelial cells. Recent studies have shown that MLN4924, a NEDD8-activating enzyme inhibitor, can modulate key cellular processes such as apoptosis, autophagy, and DNA damage repair. However, its precise role and regulatory mechanisms in the context of Cis-AKI remain largely undefined.</div></div><div><h3>Purpose</h3><div>This study aimed to elucidate the renoprotective mechanisms of MLN4924 in Cis-AKI.</div></div><div><h3>Materials and methods</h3><div>A cisplatin-induced nephrotoxicity mouse model and a human renal tubular epithelial (HK−2) damage cellular model were established. Kidney injury was evaluated by histopathology and RNA-sequencing. To explore whether MLN4924 alleviates Cis-AKI via modulation of the p53 and MAPK pathways, we analyzed pathway-specific regulatory changes in response to MLN4924 treatment.</div></div><div><h3>Results</h3><div>Compared to the group exposed to cisplatin, MLN4924 mitigated the pathological alterations and reduced the expression of molecules associated with renal injury. RNA-sequencing analysis indicated that the p53 and MAPK signaling pathways were inhibited by MLN4924 treatment compared to the cisplatin-exposed group. Moreover, silencing p53 or p38 exacerbates the renal protection conferred by MLN4924 in cisplatin-treated HK-2 cells, while their activation abolishes this effect. Mechanically, p38 activity promoted p53-dependent nephrotoxicity by increasing p53 expression.</div></div><div><h3>Conclusions</h3><div>MLN4924 exhibits a protective effect against Cis-AKI, as evidenced by inhibition of p53 and MAPK signaling pathways. These results suggest that MLN4924 holds potential as an adjuvant therapeutic agent in the treatment of kidney diseases associated with chemotherapy.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130842"},"PeriodicalIF":2.8,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633598","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":"Gamma radiation assisted green synthesis of spirulina-reduced graphene oxide and its anti-inflammatory effect against renal injury induced by gamma irradiation via IRE1α -TRAF2 pathway","authors":"M.M. Atta ,&nbsp;Marwa A. Mohamed ,&nbsp;Aliaa Mazhar ,&nbsp;Fatma Y. Abdou ,&nbsp;E.O. Taha ,&nbsp;Mahmoud E. Habieb","doi":"10.1016/j.bbagen.2025.130840","DOIUrl":"10.1016/j.bbagen.2025.130840","url":null,"abstract":"<div><h3>Background</h3><div>Combining gamma rays with natural antioxidants leads to the formation of reduced graphene oxide (RGO) biocomposites from graphene oxide (GO) in a way that is both incredibly safe and environmentally friendly, unlocking new possibilities for medical use.</div></div><div><h3>Methods</h3><div>In the present study, spirulina-reduced graphene oxide nanocomposites (SRGOs) were fabricated by gamma rays as a one-step and straightforward technique.The loading and reduction of graphene oxide in the presence of different spirulina ratios (25, 50, 100, and 200 wt%) under gamma irradiation were verified by diverse characterization apparatuses, including XRD, FTIR, HRTEM, and XPS. Moreover, in vivo studies are conducted to investigate the anti-inflammatory properties of the selected SRGO nanocomposite in preventing kidney injury caused by gamma irradiation.</div></div><div><h3>Results</h3><div>SRGO amended the renal levels of interleukin-6 (IL-6), IL-8, Inositol requirement enzyme 1α (IRE1α), and TNF receptor-associated factor 2 (TRAF2), the protein expression of NF-κB p65, and the levels of GSH, MDA, serum urea, and creatinine. In the context of oxidative stress and inflammatory biomarkers, the histopathological study results of kidney tissue concurred with those of the molecular biochemical examinations.</div></div><div><h3>Conclusion</h3><div>The findings endorsed SRGO biocomposite as a promising antioxidant, radioprotector, and anti-inflammatory agent in mitigating kidney damage caused by γ-radiation via significant inhibition of the IRE1α-TRAF2 signaling pathway.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130840"},"PeriodicalIF":2.8,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633597","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":"Mechanism of alkaloid-based inhibition of aldose reductase: Computational perspectives and experimental validations","authors":"Emadeldin M. Kamel ,&nbsp;Saleh Maodaa ,&nbsp;Sarah I. Othman ,&nbsp;Adil Abalkhail ,&nbsp;Faris F. Aba Alkhayl ,&nbsp;Al Mokhtar Lamsabhi","doi":"10.1016/j.bbagen.2025.130841","DOIUrl":"10.1016/j.bbagen.2025.130841","url":null,"abstract":"<div><div>Excessive aldose reductase activity drives the polyol-pathway damage that underlies diabetic cataract, neuropathy and nephropathy, yet few safe, potent AR inhibitors have reached the clinic. Here we integrated virtual screening, atomistic simulation and enzymology to evaluate six natural alkaloids—calycanthine, rutaecarpine, glaucine, sparteine, berbamine and tetrandrine—as prospective AR antagonists. A 2500-compound AutoDock Vina screen singled out these scaffolds for high predicted affinity (≤ − 7.0 kcal mol⁻¹), chemotype diversity and favorable <em>in silico</em> developability. Docking located all ligands within the catalytic cleft; 200-ns MD trajectories plus free-energy landscapes revealed that rutaecarpine and the bis-benzylisoquinolines tetrandrine and berbamine clamp the anion-binding and specificity pockets simultaneously, collapsing conformational space into a single deep basin. MM/PBSA analysis ranked tetrandrine highest (ΔG_total = −35.8 ± 2.5 kcal mol⁻¹) followed by rutaecarpine (−23.0 ± 1.3 kcal mol⁻¹) and berbamine (−19.4 ± 2.7 kcal mol⁻¹); per-residue decomposition highlighted Phe122, Trp219 and Leu300 as recurring hot-spots. <em>In vitro</em>, the same hierarchy emerged: tetrandrine inhibited recombinant human AR with an IC₅₀ of 1.56 ± 0.23 μM, outperforming quercetin (2.37 ± 0.27 μM), while rutaecarpine and berbamine yielded IC₅₀ values of 4.84 ± 0.81 and 7.35 ± 0.78 μM, respectively. Lineweaver–Burk and Michaelis–Menten plots demonstrated non-competitive inhibition, aligning with the MD-inferred pocket-clamping mechanism. ADMET profiling identified rutaecarpine as the most balanced lead (Lipinski-compliant, moderate hERG/CYP risk), whereas tetrandrine's hERG liability and low solubility call for scaffold refinement. This study validates bis-benzylisoquinoline and indolo-quinazolinone frameworks as privileged AR inhibitory chemotypes and showcases an end-to-end computational–experimental pipeline that rapidly converts ethnopharmacological molecules into mechanistically characterized leads for managing diabetic complications.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 9","pages":"Article 130841"},"PeriodicalIF":2.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605004","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":"Neu1 sialidase regulates heterospecific social interaction in zebrafish via D1 dopamine receptor","authors":"Sumomo Tsuji ,&nbsp;Asami Ikeda ,&nbsp;Yurina Kubo ,&nbsp;Toshiki Hyodo ,&nbsp;Mika Ishii ,&nbsp;Masaharu Komatsu ,&nbsp;Kazuhiro Shiozaki","doi":"10.1016/j.bbagen.2025.130839","DOIUrl":"10.1016/j.bbagen.2025.130839","url":null,"abstract":"<div><div>Neu1 sialidase catalyzes the removal of sialic acids from oligosaccharides and glycoproteins in lysosomes and plasma membranes. Recently, the association between Neu1 and psychiatric disorders, such as manic depression and schizophrenia, has attracted attention. <em>neu1</em>^−/− zebrafish (Neu1-KO) exhibit low anxiety, low aggressiveness, and increased social interaction with unfamiliar conspecific and heterospecific groups; however, the underlying mechanisms of action remain unclear. This study investigated alterations in monoamine levels in the Neu1-KO zebrafish brain and their significance in the unique behavioral response toward heterospecifics. The dopamine (DA) and serotonin (5-HT) levels were significantly elevated in the brains of Neu1-KO zebrafish compared with those of wild-type (WT) zebrafish, accompanied by a decrease in noradrenaline (NE). Immunohistochemical (IHC) analysis revealed increased numbers of DA and 5-HT neurons in the Neu1-KO zebrafish brain. Behavioral analysis revealed that treatment with a D1 receptor antagonist significantly suppressed heterospecific interactions in Neu1-KO zebrafish, whereas treatment with D2 and 5-HT receptor antagonists did not. IHC showed that polysialic acid (PSA), a known regulator of DA neuronal function, was predominantly distributed in the hypothalamus of zebrafish, with markedly enhanced signals in Neu1-KO zebrafish. These findings elucidate the role of Neu1 sialidase in regulating social interaction behaviors via DA neurons, potentially as a mechanism for mitigating risks in social environments.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 9","pages":"Article 130839"},"PeriodicalIF":2.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574769","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":"EP300-mediated H3K18la regulation of METTL3 promotes macrophage ferroptosis and atherosclerosis through the m6A modification of SLC7A11","authors":"Jingquan Chen ,&nbsp;Zongrong Liu ,&nbsp;Zhujun Yue ,&nbsp;Qiang Tan ,&nbsp;Hongshun Yin ,&nbsp;Haifei Wang ,&nbsp;Zhilong Chen ,&nbsp;Yanbing Zhu ,&nbsp;Jianghua Zheng","doi":"10.1016/j.bbagen.2025.130838","DOIUrl":"10.1016/j.bbagen.2025.130838","url":null,"abstract":"<div><div>Macrophages, as the primary immune cell population in atherosclerosis (AS), exhibit complex pathogenic mechanisms that are not fully elucidated. This study aims to explore the interplay between histone lactylation and methyltransferase-like protein 3 (METTL3)-mediated m6A modification and their potential mechanisms in AS. We demonstrate that METTL3 is highly expressed in macrophages in both in vivo and in vitro models of atherosclerosis, and myeloid cell-specific deletion of METTL3 attenuates the progression of atherosclerosis. Furthermore, the accumulation of lactate levels in macrophages promotes METTL3 expression through EP300-mediated histone H3 lysine 18 lactylation (H3K18la) binding to the METTL3 promoter site. We found that METTL3-mediated m6A modifications are enriched in solute carrier family 7 member 11 (SLC7A11) and accelerate its mRNA degradation in a YTH domain family member 2 (YTHDF2)-dependent manner, thereby promoting ferroptosis in macrophages. Additionally, lactate stimulation downregulates SLC7A11 through the METTL3/YTHDF2 pathway, further promoting ferroptosis. Overall, during AS, lipid peroxidation induces an increase in lactate levels within macrophages, which enhances METTL3 expression through EP300-mediated H3K18la. This further accelerates the degradation of SLC7A11 mRNA via the YTHDF2-dependent m6A modification pathway, inducing ferroptosis in macrophages. This discovery provides new insights into the mechanisms of macrophage function in AS and offers a theoretical basis for the development of therapies for AS.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 9","pages":"Article 130838"},"PeriodicalIF":2.8,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526253","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":"Drought stress induces variation in DNA methylation pattern in a genotype-dependent manner in chickpea","authors":"Khushboo Gupta,&nbsp;Rohini Garg","doi":"10.1016/j.bbagen.2025.130836","DOIUrl":"10.1016/j.bbagen.2025.130836","url":null,"abstract":"<div><div>When plants are exposed to harsh environmental conditions, such as extreme temperatures or drought, certain genes are turned on or off. This process can be controlled by a chemical modification to their DNA called methylation. Here, we examined the impact of DNA methylation during drought stress on two chickpea genotypes, ICC 1882 (drought sensitive, DS) and ICC 4958 (drought tolerant, DT) chickpea genotypes via whole-genome bisulfite sequencing. A higher degree of hypomethylation in the DT genotype and more hypermethylation in the DS genotype were observed. A positive correlation was observed between CG methylation with genes and CHH methylation with TEs. Functional annotation of differentially methylated regions associated with differentially expressed genes revealed distinct pathways enriched in DS, such as enrichment of genes involved in root development, telomere maintenance, ion transport, and regulation of gene expression, while pathways like apoptosis, silencing by miRNAs, programmed cell death and carotenoid metabolic processes were enriched in DT genotype. Further, small RNA distribution and non-CWA context methylation density in TEs suggested the role of the RdDM pathway in mediating CHH hypermethylation in transposable elements. Overall, we observed distinct genes are differentially expressed and differentially methylated under drought stress in sensitive and tolerant genotypes.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 9","pages":"Article 130836"},"PeriodicalIF":2.8,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473877","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":"Nitric oxide in plant stress: Rewilding and restoring signaling for enhancing plant growth and development","authors":"Sumreen Amin Shah ,&nbsp;Awdhesh Kumar Mishra ,&nbsp;Abdul Rehaman ,&nbsp;Sumit G. Gandhi ,&nbsp;Arif Tasleem Jan","doi":"10.1016/j.bbagen.2025.130837","DOIUrl":"10.1016/j.bbagen.2025.130837","url":null,"abstract":"<div><div>Plants, represented as a complex system, are continuously exposed to environmental conditions that affect their growth and development, and sometimes their survival. Being sessile, they complete their life cycle under the influence of varied environmental constraints (biotic and abiotic), that adversely affect the produce's quality and productivity. Plants have evolved several defense strategies orchestrated through phytohormones that play a pivotal role in conferring resistance to stress. Nitric oxide (NO), an endogenously produced gaseous hormone, has emerged as a saviour in plant's response to different stresses. It plays an active role in the growth and development of plants, from seed dormancy and germination to growth, differentiation, flowering, fruiting, and ripening, besides affecting key metabolic processes such as photosynthesis. Endogenous production of NO and its interaction with phytohormones across different signaling cascades helps in alleviating the cellular damage caused by free radicals during drought, salinity, and other stresses. It contributes to stress resilience by inducing the synthesis of stress hormones such as ethylene (ET), which help plants to withstand adverse environmental constraints by minimizing the damage caused by different stresses. Exogenous application of NO exerts protective effects against different stresses by breaking seed dormancy and modulating germination, enhancing acquisition of mineral nutrients, photosynthetic functioning, production of antioxidant enzymes capable of neutralizing free radicals, and maintaining membrane integrity. These multifaceted roles of NO underscore its significance in plant stress tolerance. The present study offers valuable insights into NO production methods, involvement in growth and development, and a mechanistic view of its role in alleviating different stresses. In the current scenario, continued research into NO signaling mechanisms and cross-talk with other pathways seems essential for harnessing its potential in developing crops with enhanced resilience to environmental challenges.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 9","pages":"Article 130837"},"PeriodicalIF":2.8,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366653","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":"USP33-mediated stabilization of c-Myc drives glycolytic reprogramming and promotes ovarian cancer progression","authors":"Dejia Chen ,&nbsp;Yue Zhao ,&nbsp;Xiaobo Zhang ,&nbsp;Xiaocheng Shi ,&nbsp;Yiming Liu ,&nbsp;Ge Lou","doi":"10.1016/j.bbagen.2025.130830","DOIUrl":"10.1016/j.bbagen.2025.130830","url":null,"abstract":"<div><div>Ovarian cancer (OC) is one of the most lethal gynecological malignancies, characterized by late-stage presentation, high recurrence rates, and a lack of effective early diagnostic markers. Recent evidence suggests that deubiquitinating enzymes (DUBs) play pivotal roles in tumor development and metabolic reprogramming. Here, we identify and characterize the function of the deubiquitinase USP33 in regulating c-Myc stability and glycolytic metabolism in OC. Through quantitative PCR (qPCR) and Western blot analyses, we show that USP33 is significantly upregulated in both OC tissues and cell lines compared to normal controls. Functional assays reveal that USP33 knockdown markedly inhibits cell proliferation, migration, and invasion while promoting apoptosis. Metabolically, USP33 silencing reduces glucose uptake, lactate production, and the extracellular acidification rate, consistent with downregulation of key glycolytic enzymes (LDHA, GLUT1, and PKM2). Mechanistically, co-immunoprecipitation and ubiquitination assays demonstrate that USP33 interacts with and deubiquitinates c-Myc at K48-linked chains, thereby stabilizing c-Myc protein levels and enhancing its transcriptional activity. Moreover, c-Myc overexpression rescues the inhibitory effects of USP33 knockdown on both glycolysis and malignant phenotypes. Clinically, high USP33 expression correlates with poor prognosis, suggesting that the USP33–c-Myc axis may serve as both a prognostic biomarker and a potential therapeutic target. Taken together, our findings highlight a critical role for USP33 in OC pathogenesis by mediating c-Myc-driven glycolytic reprogramming, and they provide new insights for developing targeted treatment strategies aimed at disrupting this pathway.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 9","pages":"Article 130830"},"PeriodicalIF":2.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324394","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}