Biochimica et biophysica acta. General subjects最新文献

{"title":"Enhancing soybean tolerance to drought by homologous expression of cytokinin synthase gene GmIPT10","authors":"Xuan Lan Thi Hoang ,&nbsp;Nguyen Nguyen Chuong ,&nbsp;Nguyen Cao Nguyen ,&nbsp;Nguyen Ngoc Hai ,&nbsp;Dung Tien Le ,&nbsp;Yasuko Watanabe ,&nbsp;Keiichi Mochida ,&nbsp;Tien-Dung Nguyen ,&nbsp;Henry T Nguyen ,&nbsp;Lam-Son Phan Tran ,&nbsp;Nguyen Phuong Thao","doi":"10.1016/j.bbagen.2025.130848","DOIUrl":"10.1016/j.bbagen.2025.130848","url":null,"abstract":"<div><div>Climatic change-induced osmotic stresses, especially drought and salinity, have arisen as major environmental constraints to crop productivity and sustainable agriculture. Previously, soybean <em>GmIPT10</em>, which encodes an adenine isopentenyl transferase enzyme working in the biosynthesis of cytokinin phytohormone, has been identified as a drought-responsive gene. In this study, the aim is to explore the drought-associated attributes of GmIPT10 <em>in planta</em>, by using homologous expression system. Our findings demonstrated that the transgenic plants might acquire better drought tolerance potential. Following the drought application at vegetative stage, they not only had higher drought-tolerance index by 3–4-fold but also displayed certain advantages in maintaining agronomic traits such as better plant growth, dry biomass accumulation and cellular water contents under adverse conditions than the wild-type plants. Importantly, the greater enhancement in antioxidant enzymatic activities in the transgenic plants (<em>i.e.</em> 2.4–3.8-fold increase) compared with the WT counterparts (1.2–2.3-fold increase) indicated the better defense ability towards drought-induced oxidative stress of the former group. Additional investigation on the drought effects at the reproductive stage further highlighted a less inhibition status of the photosynthetic activities in the transgenic lines, whereby they displayed more active gaseous exchange, higher chlorophyll contents and photochemical efficiency. Although there was no difference in average seed weights, the drought-treated transgenic plants could maintain higher average pod numbers by 10 %, which contributed to higher productivity. Taking these data altogether, our results demonstrated the beneficial role of soybean IPT10 and its mediating actions in alleviating the adverse drought effects on plants.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130848"},"PeriodicalIF":2.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144841908","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":"Unraveling the power of TOMM40: Driving PHB1-mediated mtDNA release and mitophagy to fuel breast cancer progression","authors":"Lei Pan,&nbsp;Feixia Ma,&nbsp;Hongchen Zhang,&nbsp;Yin Duan","doi":"10.1016/j.bbagen.2025.130851","DOIUrl":"10.1016/j.bbagen.2025.130851","url":null,"abstract":"<div><h3>Background</h3><div>In breast cancer (BRCA), mitophagy is essential for the survival and metastasis of cancer cells. However, the interaction between translocase of the outer mitochondrial membrane 40 (TOMM40) and prohibitin 1 (PHB1) in regulating mitophagy in BRCA remains poorly understood.</div></div><div><h3>Methods</h3><div>Based on bioinformatics analysis, the interaction between PHB1 and key mitophagy regulators in BRCA was explored. The effects of mitochondrial division inhibitor-1 (Mdivi-1) and Fluorizoline on mitophagy, cell viability, and sphere formation ability in MDA-MB-231 cells were assessed. In the cell model activated by carbonyl cyanide <em>m</em>-chlorophenylhydrazone (CCCP) to induce mitophagy, the effects of TOMM40 on cell viability, sphere formation ability, mitochondrial membrane potential, reactive oxygen species (ROS) levels, mitochondrial DNA (mtDNA) release, and PHB1 regulation were analyzed. In vivo, the impact of TOMM40 knockdown on tumor progression and mitophagy was also evaluated.</div></div><div><h3>Results</h3><div>PHB1 interacted with TOMM40. Mdivi-1 or Fluorizoline treatment inhibited mitophagy, and significantly reduced BRCA cell viability and sphere formation. CCCP treatment induced mitophagy, increased mtDNA release and PHB1 levels, decreased mitochondrial membrane potential and ROS, and promoted cell viability and sphere formation ability, which were all reversed by TOMM40 knockdown. Additionally, TOMM40 knockdown led to decreased PHB1 levels and increased ROS accumulation in tumor tissue, thus repressing tumor progression.</div></div><div><h3>Conclusion</h3><div>This study identifies TOMM40 as a key regulator that enhances PHB1-mediated mtDNA release and induces mitophagy in BRCA cells, thus promoting breast cancer progression.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130851"},"PeriodicalIF":2.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858810","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":"Inhibition of phosphodiesterase 4 and 7 regulates breast cancer cell proliferation","authors":"Carla Mayora Justel ,&nbsp;Tamara Valladares ,&nbsp;Lucía Gargiulo ,&nbsp;Verónica González-Pardo ,&nbsp;Maximiliano De Sousa ,&nbsp;María del Carmen Esandi ,&nbsp;Carlos Davio ,&nbsp;Isabel Lüthy ,&nbsp;Ariana Bruzzone","doi":"10.1016/j.bbagen.2025.130850","DOIUrl":"10.1016/j.bbagen.2025.130850","url":null,"abstract":"<div><h3>Purpose</h3><div>cAMP regulates key processes in mammary cell biology. Previous studies suggested reduced cAMP production in more malignant cells. This study investigates the role of cAMP in mammary biology using non-tumor (MCF-10A  and HBL-100) and tumor (MCF-7 and MDA-MB-231) human breast cell lines.</div></div><div><h3>Methods</h3><div>cAMP levels were quantified using a competitive radio-binding assay. Cell proliferation and viability were assessed by cell counting and MTT assay. Gene expression was analyzed by real-time PCR and immunofluorescence. Additional assays included migration, colony formation, annexin V/IP staining, comet assay, and caspase-3 activity. Public datasets were consulted. Phosphodiesterase (PDE) inhibitors were tested: the broad-spectrum PDE inhibitor IBMX (3-Isobutyl-1-methylxanthine), the PDE4-selective inhibitor roflumilast, and the PDE7-selective inhibitor BRL-50481.</div></div><div><h3>Results</h3><div>Non-tumor cells produced more cAMP than tumor cells, with or without IBMX. IBMX decreases cell proliferation and viability in all cell lines. Gene expression data revealed higher ADCY2, 3, 4, 5, 6, and 8 expression in normal tissues. Roflumilast reduced cell viability in all tested cells, while the PDE7-specific inhibitor BRL-50481 only affected MCF-7 cells. All PDE inhibitors exhibited an additive effect with tamoxifen, reducing MCF-7 cell viability. In tumor cells roflumilast decreased cell migration. In MDA-MB-231 cells, although IBMX and roflumilast showed a trend toward further decreasing viability compared to doxorubicin or paclitaxel alone, the differences were not statistically significant.</div></div><div><h3>Conclusion</h3><div>The selective PDE4 inhibitor roflumilast demonstrated potential as a therapeutic agent when combined with specific breast cancer treatments, offering a novel approach in breast cancer therapy.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 11","pages":"Article 130850"},"PeriodicalIF":2.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858809","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":"Editorial: Nondomain biopolymers – Flexible molecular strategies for diverse biological processes","authors":"Shinichi Nakagawa","doi":"10.1016/j.bbagen.2025.130847","DOIUrl":"10.1016/j.bbagen.2025.130847","url":null,"abstract":"","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130847"},"PeriodicalIF":2.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803357","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":"IRF1 transcriptionally activates ALOX15B to enhance ferroptosis sensitivity in triple-negative breast cancer","authors":"Wei Peng,&nbsp;Yi Xie,&nbsp;Bofeng Duan,&nbsp;Fuyong Qian,&nbsp;Zhifeng Fan,&nbsp;Wei Zheng","doi":"10.1016/j.bbagen.2025.130846","DOIUrl":"10.1016/j.bbagen.2025.130846","url":null,"abstract":"<div><div>This study focused on the transcriptional activation of arachidonate 15-lipoxygenase type B (ALOX15B) by interferon regulatory factor 1 (IRF1) to promote ferroptosis in triple-negative breast cancer (TNBC) cells. In this study, TNBC and adjacent non-cancerous tissues were collected to detect ALOX15B expression. Functional studies were conducted by overexpressing or knocking down ALOX15B in TNBC cells treated with erastin (a ferroptosis inducer). The role of IRF1 as a potential transcriptional regulator of ALOX15B was explored using bioinformatics tools, dual-luciferase reporter gene assays, electrophoretic mobility shift assays (EMSA), and chromatin immunoprecipitation (ChIP) followed by quantitative polymerase chain reaction (qPCR). Our results revealed that ALOX15B expression was significantly lower in TNBC tissues compared to adjacent non-cancerous tissues. Functionally, ALOX15B overexpression inhibited ferroptosis-related proteins SLC7A11 and GPX4, decreased cell viability and glutathione levels, and increased malondialdehyde levels, reactive oxygen species levels, and lipid oxidation. Conversely, knocking down ALOX15B had the opposite effect. Bioinformatics analysis predicted IRF1 as a potential transcriptional regulator of ALOX15B, which was confirmed using dual-luciferase reporter gene assays, EMSA, and ChIP-qPCR. IRF1 overexpression increased ALOX15B expression and promoted ferroptosis in TNBC cells, while IRF1 knockdown had the opposite effect. Importantly, knocking down IRF1 and overexpressing ALOX15B simultaneously demonstrated that IRF1 enhanced TNBC cell ferroptosis sensitivity by promoting ALOX15B expression. Collectively, our study suggests that IRF1 transcriptionally activates ALOX15B to enhance ferroptosis sensitivity in TNBC cells. These findings provide new insights into the molecular mechanisms underlying TNBC progression and suggest potential therapeutic targets for TNBC treatment.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130846"},"PeriodicalIF":2.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757771","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":"Nitrosative stress affects mitochondrial respiratory chain complex II and complex IV assemblies in Saccharomyces cerevisiae: S-nitrosylation of complex II","authors":"Sanchita Biswas ,&nbsp;Ayantika Sengupta ,&nbsp;Shubhojit Das ,&nbsp;Chirandeep Dey ,&nbsp;Rajib Sengupta ,&nbsp;Alok Ghosh ,&nbsp;Sanjay Ghosh","doi":"10.1016/j.bbagen.2025.130845","DOIUrl":"10.1016/j.bbagen.2025.130845","url":null,"abstract":"<div><div>The elevated level of nitric oxide (NO) and reactive nitrogen species (RNS) induce nitrosative stress in cells and inhibit mitochondrial respiration. Reports showed that RNS rapidly inactivate complex I, followed by inhibition of complex II, III and IV in isolated mitochondria. However, the mechanism(s) by which NO and RNS inhibit these complexes still unclear. In this study facultative anaerobic yeast <em>Saccharomyces cerevisiae</em> has been used for investigating mitochondrial respiratory dysfunction under nitrosative stress, as four out of five mitochondrial oxidative phosphorylation complexes i.e. complexes II, III, IV and V are structurally conserved from yeast to human. Using microbiological growth assays, we showed that <em>S. cerevisiae</em> wild type W3O3 cells treated with graded concentration of sodium nitroprusside (SNP) and S-Nitrosoglutathione (GSNO) induce nitrosative stress, and cell growth was severely compromised under the respiratory proficient rich glycerol-ethanol media. Both the whole cell and the mitochondrial oxygen consumption rates were also significantly compromised under nitrosative stress. Surprisingly, mitochondrial respiratory chain complex II succinate dehydrogenase (SDH) of <em>S. cerevisiae</em> was found S-nitrosylated and therefore inactivated under nitrosative stress. Endogenous RNS produced by S-nitrosoglutathione reductase mutant cells of <em>S. cerevisiae</em> also showed increased S-nitrosylation of SDH. Complex III and IV activities were irreversibly inhibited in <em>S. cerevisiae</em> under nitrosative stress. Interestingly, protein tyrosine nitration was also enhanced in mitochondria in a dose dependent manner upon SNP treatment. Reduced expressions of both Sdh2 (succinate dehydrogenase subunit-2) and Cox2 (mitochondrial complex IV subunit) were observed at the transcription and translation level in <em>S. cerevisiae</em> under nitrosative stress. Blue Native-PAGE followed by Western blotting analysis, further revealed significantly reduced native complex II and the complex III and IV containing super-complexes assemblies in consequences of nitrosative stress in <em>S. cerevisiae</em>. Henceforth, the present in vivo study provides for the first-time novel information on the modification of mitochondrial complexes under nitrosative stress which in turn regulates the mitochondrial respiratory chain complexes assembly in <em>S. cerevisiae</em>.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130845"},"PeriodicalIF":2.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764457","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":"Coupling of muscarinic receptors to protein kinase C underlies a feedback regulation of cell responsiveness to acetylcholine","authors":"Ekaterina A. Dymova,&nbsp;Olga A. Rogachevskaja,&nbsp;Vladislav V. Sokolov,&nbsp;Elizaveta Е. Kopylova,&nbsp;Natalia V. Kabanova,&nbsp;Stanislav S. Kolesnikov","doi":"10.1016/j.bbagen.2025.130844","DOIUrl":"10.1016/j.bbagen.2025.130844","url":null,"abstract":"<div><div>Acetylcholine (ACh)-induced Ca²⁺ signaling was analyzed in HEK-293 (WT-HEK) cells and their derivatives, IP3R1-HEK, IP3R2-HEK, and IP3R3-HEK with a single functional IP₃ receptor isoform, IP₃R1, IP₃R2, or IP₃R3, respectively. The initial stimulation of WT-HEK cells triggered a prolonged feedback process that diminished their responsiveness to ACh. Inhibition of protein kinase C (PKC) with Gö 6983 or calphostin C prevented the decline of ACh responsivity, indicating that PKC was involved. Using IP3R1-HEK, IP3R2-HEK, and IP3R3-HEK cells, it was shown that PKC was capable of regulating Ca²⁺ release through each IP₃R isoform. While in control, IP₃ uncaging triggered Ca²⁺ transients in ∼15 % of cells loaded with caged-Ins(145)P3/PM, PKC inhibition enlarged this fraction nearly twofold. These observations suggested that in ACh transduction machinery, PKC targeted primarily IP₃-driven Ca²⁺ release. ADP and 5-HT triggered Ca²⁺ transients in WT-HEK cells and CHO cells expressing endogenous P2Y and recombinant 5HT2C receptors, respectively. The responsiveness of WT-HEK cells to ADP and CHO cells to 5-HT applied serially declined after the initial cell stimulation but PKC inhibition precluded this phenomenon almost completely. The coupling of GPCRs to PKC in living cells, muscarinic and P2Y receptors in WT-HEK cells and 5HT2C receptors in CHO cells, was demonstrated for the first time using real-time fluorescence imaging and sapphireCKAR, a genetically encoded sensor of PKC activity. Altogether, our findings suggest that a PKC-based feedback regulation of agonist-induced Ca²⁺ release might be a common attribute of transduction of various agonists involving GPCRs coupled to the phosphoinositide cascade.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130844"},"PeriodicalIF":2.2,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717301","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":"MiR-2779-x, a key microRNA that is related to the tumorigenicity of the MDCK cell line","authors":"Di Yang ,&nbsp;Lingwei Huang ,&nbsp;Jiachen Shi ,&nbsp;Zhenbin Liu ,&nbsp;Jiamin Wang ,&nbsp;Zhongren Ma ,&nbsp;Ayimuguli Abudureyimu ,&nbsp;Zilin Qiao ,&nbsp;Jianguo Chen","doi":"10.1016/j.bbagen.2025.130843","DOIUrl":"10.1016/j.bbagen.2025.130843","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":8800,"journal":{"name":"Biochimica et biophysica acta. General subjects","volume":"1869 10","pages":"Article 130843"},"PeriodicalIF":2.2,"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}