Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Prostaglandin E2 alleviates inflammatory response and lung injury through EP4/cAMP/IKK/NF-κB pathway","authors":"Yelin Tang ,&nbsp;Weiting Pan ,&nbsp;Wenting Ding ,&nbsp;Xingye Pan ,&nbsp;Junyi Zhu ,&nbsp;Huiwen Chen ,&nbsp;Xiaona Zhu ,&nbsp;Jingyi Chen ,&nbsp;Zijun Cheng ,&nbsp;Yali Zhang ,&nbsp;Bing Zhang","doi":"10.1016/j.bbadis.2025.167801","DOIUrl":"10.1016/j.bbadis.2025.167801","url":null,"abstract":"<div><h3>Purpose</h3><div>Prostaglandin E2 (PGE2), a pivotal lipid metabolite, plays a dual role in inflammation, manifesting both pro-inflammatory and anti-inflammatory effects, which are significantly influenced by the cellular microenvironment and receptor subtype. Although recent studies have highlighted the anti-inflammatory potential of PGE2, its role in toll-like receptor (TLR)-associated inflammation and the underlying mechanisms have not fully elucidated. Consequently, the primary aim of this study was to assess the anti-inflammatory efficacy of PGE2 in TLR-related inflammation and to elucidate the associated mechanisms.</div></div><div><h3>Methods</h3><div>In vitro, the anti-inflammatory effect of PGE2 on TLR-related inflammation were investigated by measuring pro-inflammatory cytokine protein and gene levels using ELISA and RT-qPCR, respectively. Western blot analysis was used to explore the corresponding anti-inflammatory signaling pathways. In vivo, the anti-inflammatory effects of PGE2 were further validated using ALI and sepsis models, employing the PGE2 analog 16,16-dimethyl prostaglandin E2 (dmPGE2).</div></div><div><h3>Results</h3><div>The findings revealed that PGE2 inhibited the LPS-induced inflammatory response and activation of the IKK/NF-κB signaling pathway via the EP4 receptor-mediated downstream cAMP/PKA pathway. Additionally, PGE2 analog, dmPGE2, effectively mitigated pathological injury and the inflammatory response in lung tissue of mice subjected to LPS-induced ALI and sepsis. Notably, dmPGE2 suppressed LPS-induced activation of the IKK/NF-κB signaling pathway in lung tissue.</div></div><div><h3>Conclusion</h3><div>This study demonstrated that PGE2 can inhibit the IKK/NF-κB signaling pathway through the EP4/cAMP/PKA pathway, thereby alleviating the LPS-induced inflammatory response and providing a protective effect against LPS-induced ALI and sepsis. Consequently, PGE2 holds promise as a candidate for drug development aimed at preventing ALI and sepsis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167801"},"PeriodicalIF":4.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis, necroptosis, and pyroptosis in calcium oxalate crystal-induced kidney injury","authors":"Kun Tang ,&nbsp;Tao Ye ,&nbsp;Yu He ,&nbsp;Xiaozhuo Ba ,&nbsp;Ding Xia ,&nbsp;Ejun Peng ,&nbsp;Zhiqiang Chen ,&nbsp;Zhangqun Ye ,&nbsp;Xiaoqi Yang","doi":"10.1016/j.bbadis.2025.167791","DOIUrl":"10.1016/j.bbadis.2025.167791","url":null,"abstract":"<div><div>Kidney stones represent a highly prevalent urological disorder worldwide, with high incidence and recurrence rates. Calcium oxalate (CaOx) crystal-induced kidney injury serves as the foundational mechanism for the formation and progression of CaOx stones. Regulated cell death (RCD) such as ferroptosis, necroptosis, and pyroptosis are essential in the pathophysiological process of kidney injury. Ferroptosis, a newly discovered RCD, is characterized by its reliance on iron-mediated lipid peroxidation. Necroptosis, a widely studied programmed necrosis, initiates with a necrotic phenotype that resembles apoptosis in appearance. Pyroptosis, a type of RCD that involves the gasdermin protein, is accompanied by inflammation and immune response. In recent years, increasing amounts of evidence has demonstrated that ferroptosis, necroptosis, and pyroptosis are significant pathophysiological processes involved in CaOx crystal-induced kidney injury. Herein, we summed up the roles of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury. Furthermore, we delved into the curative potential of ferroptosis, necroptosis, and pyroptosis in CaOx crystal-induced kidney injury.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167791"},"PeriodicalIF":4.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing RGS7 attenuates atrial fibrillation progression by activating the cGMP-PKG signaling pathway","authors":"Hao Huang ,&nbsp;Yan Xiong ,&nbsp;Jie Zeng","doi":"10.1016/j.bbadis.2025.167786","DOIUrl":"10.1016/j.bbadis.2025.167786","url":null,"abstract":"<div><h3>Background</h3><div>Atrial fibrillation (AF) is a common diagnosed heart disease that needs novel managements. This study aimed to seek potential biomarkers and underlying regulatory pathways associated with AF.</div></div><div><h3>Methods</h3><div>Differential expressed genes (DEGs) were identified from the Gene Expression Omnibus database, followed by a protein-protein interaction (PPI) network to discover hub genes. Principal components analysis (PCA) and receiver operating characteristic (ROC) curves were performed to evaluate the ability of hub genes to discriminate between AF and control. RGS7 was selected as a key hub gene, and genes co-expressed with RGS7 were identified for functional enrichment analysis. Further in vivo and in vitro experiments were conducted to investigate the effects of silencing RGS7 on AF and the potential pathway.</div></div><div><h3>Results</h3><div>We identified top 5 hub genes (RGS7, EGFR, RGS4, GNA13 and RGS11) from the PPI network. PCA showed these genes could distinguish between AF and control samples, with 100 % of the area under curve (AUC) values. Silencing RGS7 inhibited cell apoptosis, inflammation and oxidative stress, and increased mitochondrial membrane potential in angiotensin II (AngII)-treated HL-1 cells, while overexpression of RGS7 reversed the inhibitory effects of silencing RGS7 on AF. Additionally, silencing RGS7 improved cardiac function and decreased cardiac fibrosis in AF rats. The cGMP-PKG signaling pathway was screened as a potential signal transduction pathway, and silencing RGS7 increased the expression of PKG1, while KT5823 blocked the process.</div></div><div><h3>Conclusion</h3><div>Silencing RGS7 attenuates AF by activating the cGMP-PKG signaling pathway, which may offer directions for selecting biomarkers and regulatory pathways for AF.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167786"},"PeriodicalIF":4.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAT2 activity increases cytotoxicity of anthracycline antibiotics and HDAC inhibitors","authors":"Natallia Rameika ,&nbsp;Ioanna Tsiara ,&nbsp;Xiaonan Zhang ,&nbsp;Wawrzyniec Haberek ,&nbsp;Verónica Rendo ,&nbsp;Snehangshu Kundu ,&nbsp;Mario S.P. Correia ,&nbsp;Ivaylo Stoimenov ,&nbsp;Daniel Globisch ,&nbsp;Tobias Sjöblom","doi":"10.1016/j.bbadis.2025.167755","DOIUrl":"10.1016/j.bbadis.2025.167755","url":null,"abstract":"<div><div>The Arylamine-<em>N</em>-acetyltransferase-2 (NAT2) enzyme is involved in metabolism of commonly used drugs driving differences in efficacy and tolerability of treatments. To bridge the current knowledge gap on metabolism of cytotoxic drugs by NAT2, and identify anticancer agents whose effects depend on NAT2 activity, we assessed 147 clinically used drugs. Hit compounds were evaluated for metabolic conversion by acetylation in presence of recombinant NAT2. Among those 147 drugs we found doxorubicin, daunorubicin, epirubicin, valrubicin, teniposide, afatinib, carmustine, vincristine, panobinostat, and vorinostat to have increased toxicity to cancer cells expressing the rapid <em>NAT2</em> allele. Additionally, we report NAT2-mediated acetylation of idarubicin, daunorubicin, doxorubicin, vorinostat, and CUDC-101. These findings have implications for pharmacogenomics and cancer precision medicine using conventional chemotherapeutic drugs, as improving their efficacy and safety may affect &gt;4 million cancer patients worldwide that receive these drugs as standard of care.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167755"},"PeriodicalIF":4.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The IGF2BP2-circ-DAPK1 axis promotes high-glucose-induced ferroptosis of HUVECs by decreasing NQO1 expression","authors":"Chenyang Qiu ,&nbsp;Xiangtao Zheng ,&nbsp;Xiaoxiang Zhou ,&nbsp;Bing Wang ,&nbsp;Tianchi Chen ,&nbsp;Yiting Xu ,&nbsp;Xinyu Yu ,&nbsp;Wei Lu ,&nbsp;Ziheng Wu","doi":"10.1016/j.bbadis.2025.167797","DOIUrl":"10.1016/j.bbadis.2025.167797","url":null,"abstract":"<div><div>Circular RNAs (circRNAs) are non-coding RNAs with covalently closed loop structures that participate in various biological processes. However, the functions of many circRNAs remain unclear. Endothelial cell dysfunction, which involves abnormal ferroptosis, a unique form of regulated cell death, is a characteristic of various diseases. However, the mechanisms governing ferroptosis in endothelial cells are not fully understood. Here, we investigated the impact of a novel circRNA, circ-DAPK1, on ferroptosis in human umbilical vein endothelial cells (HUVECs) under high-glucose conditions. Our data showed that high-glucose conditions upregulate circ-DAPK1 expression in HUVECs. Overexpression of circ-DAPK1 induced ferroptosis in HUVECs, whereas depletion of circ-DAPK1 mitigated the ferroptosis triggered by high-glucose treatment. Inhibition of ferroptosis reversed the decrease in cell viability induced by high glucose or circ-DAPK1 overexpression. Using RNA immunoprecipitation analyses, we identified several ferroptosis-regulating proteins, including NAD(<em>P</em>)H dehydrogenase [quinone] 1 (NQO1) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Mechanistically, circ-DAPK1 interacts with NQO1, enhancing its ubiquitination and accelerating its degradation. NQO1 overexpression partially rescues HUVECs from high-glucose-induced ferroptosis. We also found that IGF2BP2 binds to the m⁶A site on circ-DAPK1. Depletion of IGF2BP2 in HUVECs reduced circ-DAPK1 expression and inhibited high-glucose-induced ferroptosis. These findings reveal the effects of the IGF2BP2-circ-DAPK1 axis in regulating ferroptosis in HUVECs under high-glucose conditions and extend our understanding of the mechanisms controlling ferroptosis in endothelial cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167797"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MBD2 promotes epithelial-to-mesenchymal transition (EMT) and ARDS-related pulmonary fibrosis by modulating FZD2","authors":"Yang Zhou ,&nbsp;Guifang Yang ,&nbsp;Jiqiang Liu ,&nbsp;Shuo Yao ,&nbsp;Jingsi Jia ,&nbsp;Xianming Tang ,&nbsp;Xun Gong ,&nbsp;Fang Wan ,&nbsp;Ren Wu ,&nbsp;Zhenyu Zhao ,&nbsp;Hengxing Liang ,&nbsp;Linxia Liu ,&nbsp;Qimi Liu ,&nbsp;Shanshan Xie ,&nbsp;Xian Long ,&nbsp;Xudong Xiang ,&nbsp;Guyi Wang ,&nbsp;Bing Xiao","doi":"10.1016/j.bbadis.2025.167798","DOIUrl":"10.1016/j.bbadis.2025.167798","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis.</div></div><div><h3>Methods</h3><div>Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell sequencing data and Human pulmonary fibrosis samples were analyzed.</div></div><div><h3>Results</h3><div>Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis.</div></div><div><h3>Conclusion</h3><div>Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167798"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AAV8-mediated silencing of Atad3 prevents the progression from simple steatosis to MASH in mice by reduced IL6 secretion","authors":"Liting Chen ,&nbsp;Yuchang Li ,&nbsp;Rahil Nitinkumar Patel ,&nbsp;Chantal Sottas ,&nbsp;Mahima Chandrakant Raul ,&nbsp;Nrupa Dinesh Patel ,&nbsp;Alexander Zambidis ,&nbsp;Meng Li ,&nbsp;Shefali Chopra ,&nbsp;Vassilios Papadopoulos","doi":"10.1016/j.bbadis.2025.167792","DOIUrl":"10.1016/j.bbadis.2025.167792","url":null,"abstract":"<div><div>ATAD3A deficiency in hepatocytes has been shown to promote simple steatosis (SS). ATAD3 is upregulated in MCD diet-induced MASH. Since the MCD diet is commonly used to induce liver fibrosis, which is related to HSCs activation, we are prompted to investigate the functions of ATAD3 in these two cell types and their mediated transition from SS to MASH. To investigate the role of ATAD3A in HSCs, human LX-2 cells were treated with TGFβ. The results showed that ATAD3A expression was linked to the fibrotic markers ACTA2 and COL1A1. Knockdown of <em>ATAD3A</em> reversed TGFβ-induced HSC activation by downregulating both canonical (SMAD2/3) and non-canonical (ERK1/2 and p38 MAPK) TGFβ signaling pathways. To examine the effect of ATAD3 on the transition from SS to MASH, MASH was induced in mice using the GAN diet for 24 weeks. After 12 weeks, AAV8-conjugated <em>Atad3</em> shRNA was administered to knock down <em>Atad3</em> in the liver. This intervention suppressed steatosis and fibrosis while enhancing insulin sensitivity. Further analysis using conditioned medium (CM) from WT and <em>ATAD3A KO</em> Huh7 cells treated with LPS and PA revealed that IL-6 secretion from Huh7 hepatocytes activated HSCs. However, IL-6 secretion was diminished in <em>ATAD3A KO</em> CM. CM from <em>ATAD3A KO</em> cells also suppressed expression of fibrotic markers ACTA2, P<img>P38, and P-SMAD3 compared to WT cells under MASH conditions. These data suggest that AAV8-mediated <em>Atad3</em> silencing in hepatocytes prevents the transition from SS to MASH, at least in part, by downregulating IL-6 secretion to suppress HSC activation in MASH.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167792"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircPICALM promotes neonatal acute kidney injury triggered by hypoxia/reoxygenation via sponging microRNA-204-5p","authors":"Yang Yang ,&nbsp;Jing-jing Pan ,&nbsp;Xiao-qing Chen ,&nbsp;Jia Shi ,&nbsp;Mu-zi Wang ,&nbsp;Tian-yu Liu ,&nbsp;Xiao-guang Zhou","doi":"10.1016/j.bbadis.2025.167795","DOIUrl":"10.1016/j.bbadis.2025.167795","url":null,"abstract":"<div><h3>Background</h3><div>Circular RNAs (circRNAs) have been documented to regulate neonatal acute kidney injury (AKI). Based on previous RNA-sequence findings, circPICALM exhibited significantly disparate expression between AKI newborns and Controls. This study aimed to provide further insights into the regulatory mechanism of circPICALM in neonatal AKI.</div></div><div><h3>Methods</h3><div>C57BL/6 mice born 7 days were divided into Control group and hypoxia groups (11%O₂ and 8%O₂ groups). Human tubule epithelial cells (HK-2) were stimulated with hypoxia/reoxygenation (H/R) to establish an AKI cell model. Through overexpression and knockdown techniques, the regulatory role of circPICALM in H/R-induced kidney injury was explored. Inflammatory cytokines, cell apoptosis, and oxidative stress were also detected to confirm the regulatory function of circPICALM in neonatal AKI.</div></div><div><h3>Results</h3><div>RT-qPCR confirmed that circPICALM was highly expressed in the serum of AKI newborns, neonatal I/R mice and H/R-treated HK-2 cells. Functionally, circPICALM exacerbated H/R-induced HK-2 cell injury by aggravating apoptosis and mitochondrial oxidative stress, increasing the expression of inflammatory factors, including IL-6, IL-1β, and TNF-α. Conversely, inhibition of circPICALM alleviated H/R injury in the HK-2 cell line. The interaction between circPICALM and miR-204-5p was validated through RNA immunoprecipitation and luciferase assay. Finally, circPICALM functioned as a molecular sponge of miR-204-5p and promoted the upregulation of downstream IL-1β expression.</div></div><div><h3>Conclusion</h3><div>CircPICALM plays a critical role in H/R-induced neonatal AKI by sponging miR-204-5p and then activating the downstream IL-1β signaling axis. The inhibition of circPICALM and subsequent suppression of pro-inflammatory factors could serve as a promising biomarker and therapeutic target for early intervention in neonatal AKI.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167795"},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CNC-family transcription factor NRF3: A crucial therapeutic target for cancer treatment","authors":"Liangwen Yan ,&nbsp;Xinyan Li ,&nbsp;Jiayi Xu ,&nbsp;Shenkang Tang ,&nbsp;Gang Wang ,&nbsp;Mengjiao Shi ,&nbsp;Pengfei Liu","doi":"10.1016/j.bbadis.2025.167794","DOIUrl":"10.1016/j.bbadis.2025.167794","url":null,"abstract":"<div><div>The CNC-bZIP family member NRF3 (NFE2L3) has received limited attention since its discovery. However, recent research has gradually revealed its biological functions, such as involvement in the regulation of cell differentiation, lipid metabolism, and malignant cell proliferation. Under physiological conditions, NRF3 is anchored to the endoplasmic reticulum within the cytoplasm and is biologically inactive. Upon cellular exposure to microenvironmental stresses such as oxidative stress, NRF3 translocates to the nucleus, binds to DNA, and acts as a transcription factor by inducing or repressing the expression of various genes. In terms of tumor regulation, NRF3 exhibits a dual role. It can function as a tumor suppressor to prevent the malignant progression of tumor tissues, protecting the organism from harm. Conversely, current research indicates that NRF3 plays a tumor-promoting role in most tumor tissues. NRF3 enhances the proliferation, migration and invasion of tumor cells by regulating cell cycle-related proteins and enhancing proteasome assembly to degrade tumor suppressors. Studies correlating NRF3 expression with clinical tumor features have found that elevated NRF3 expression is often associated with poor prognoses in various cancers, with patients exhibiting higher NRF3 expression typically having lower survival rates. Several studies suggest that NRF3 could serve as a clinical diagnostic and prognostic marker for tumors. Finally, from the clinical perspective, exploring the feasibility of inhibiting NRF3 activity in tumor treatment provides new insights for the development of NRF3-targeted oncological therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167794"},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells","authors":"Congyu Wang ,&nbsp;Siwen Wang ,&nbsp;Guowei Zhang ,&nbsp;Haihong Shi,&nbsp;Pengfei Li,&nbsp;Sijie Bao,&nbsp;Lihua Kang,&nbsp;Min Ji,&nbsp;Huaijin Guan","doi":"10.1016/j.bbadis.2025.167796","DOIUrl":"10.1016/j.bbadis.2025.167796","url":null,"abstract":"<div><div>Mitochondrial dysfunction, resulting from a diminished oxidative damage repair capacity of mitochondrial DNA (mtDNA) in peripheral lens epithelial cells (LECs), is a key pathogenic mechanism in age-related cortical cataract (ARCC). This study aims to investigate the potential role of the E3 ligase HUWE1 and its ubiquitination substrate, the oxidative damage repair gene ATM, in the pathogenesis of ARCC. Our findings reveal that ATM protein expression is downregulated in human peripheral lens epithelial cells and the turbid cortex, correlating with increased expression of HUWE1. Overexpression of ATM is shown to repair damaged mtDNA, protect mitochondria in LECs from oxidative damage, inhibit mitochondrial fission, enhance mitochondrial biogenesis and mitophagy, and prevent LECs apoptosis. Conversely, overexpression of HUWE1 may negate the protective effects of ATM via the ubiquitination pathway, promote oxidative stress-induced mitochondrial damage, increase the expression of mitochondrial fission proteins Drp1/Fis1, lead to mitochondrial network fragmentation and LECs apoptosis. In a SD rat lens model ex vitro, the ATM inhibitor AZD0156 exacerbated lens opacity, whereas the mitochondrial fission inhibitor Mdivi-1 restored lens transparency. These results suggest that modulating key molecules involved in oxidative damage repair and mitochondrial fission pathways could enhance mitochondrial quality control, paving the way for the development of targeted molecular therapies for the prevention and treatment of ARCC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167796"},"PeriodicalIF":4.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}