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

{"title":"PIM1 protects pancreatic ductal cancer cells from glucose deprivation-induced oxidative stress via OXR1 phosphorylation","authors":"Jinjing Wang ,&nbsp;Weidong Yu ,&nbsp;Shuxin Cai ,&nbsp;Huanxin Wei ,&nbsp;Bilu Peng ,&nbsp;Jiazi Qian ,&nbsp;Yu Chen ,&nbsp;Fulong Zheng ,&nbsp;Huihui Jiang ,&nbsp;Qipeng Xie ,&nbsp;Huaibin Zhou ,&nbsp;Hezhi Fang ,&nbsp;Jianxin Lyu","doi":"10.1016/j.bbadis.2025.168031","DOIUrl":"10.1016/j.bbadis.2025.168031","url":null,"abstract":"<div><div>Limited nutrient availability in pancreatic ductal adenocarcinoma (PDAC), due to its dense extracellular matrix, presents a significant metabolic challenge that tumor cells must overcome to survive oxidative stress-induced cell death. Here, we found that PIM1, a serine/threonine kinase, is upregulated in PDAC tumors and serves as a poor prognostic indicator. Although PIM1 does not significantly affect PDAC cell proliferation, it is essential for protecting cells from glucose deprivation-induced cell death. Mechanistically, PIM1 interacts with the antioxidant protein OXR1 (oxidation resistance protein 1) and promotes its phosphorylation at serine 91. This modification mitigates oxidative stress, preserves mitochondrial morphology, and ultimately protects PDAC cells from glucose deprivation-induced cell death. Moreover, glucose deprivation activates AMPK, which in turn stabilizes PIM1 by protecting it from ubiquitin-mediated protein degradation. In contrast, AMPK inhibition reduces PIM1 level and abolishes the survival difference between cells with and without PIM1 depletion. Collectively, our findings reveal a critical role of PIM1 in PDAC cell survival under nutrient stress and identify PIM1 as a potential therapeutic target for PDAC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168031"},"PeriodicalIF":4.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994671","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":"m6A mRNA methylation initiated by METTL14 promotes STK11 translation and increases STK11 activity to induce anti-HER2 therapy resistance in breast cancer","authors":"Fan Yang ,&nbsp;Pei Ma ,&nbsp;Yaozhou He ,&nbsp;Yongfei Li ,&nbsp;Yan Liang ,&nbsp;Wei Li ,&nbsp;Xiang Huang ,&nbsp;Chunxiao Sun ,&nbsp;Xueqi Yan ,&nbsp;Yijia Hua ,&nbsp;Jue Gong ,&nbsp;Tianyu Zeng ,&nbsp;Yongmei Yin","doi":"10.1016/j.bbadis.2025.168029","DOIUrl":"10.1016/j.bbadis.2025.168029","url":null,"abstract":"<div><div>Resistance to HER2-targeted therapies presents a major challenge in the treatment of patients with HER2-positive breast cancer. N(6)-methyladenosine (m6A) modification plays a critical role in tumor progression; however, its role in mediating resistance to anti-HER2 therapy remains poorly defined. In trastuzumab-resistant HER2-positive breast cancer tissues, METTL14 expression is significantly upregulated and correlates with poor trastuzumab response. Moreover, our data suggest that the transcription factor RAD21 directly regulates METTL14 expression by binding to its promoter region. Elevated METTL14 expression enhances resistance to HER2-targeted therapies, while METTL14 knockdown restores trastuzumab sensitivity in resistant breast cancer cells. Mechanistically, METTL14 facilitates m6A methylation of STK11 mRNA, increasing its stability in an m6A-dependent manner, thereby contributing to resistance. Taken together, our findings define a novel RAD21-METTL14-STK11 axis that drives trastuzumab resistance in HER2-positive breast cancer and highlight potential therapeutic targets for overcoming treatment failure.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168029"},"PeriodicalIF":4.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982331","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":"Polyphyllin I inhibits glioblastoma progression by initiating ferroptosis via the Sirt1/Nrf2/HO-1/GPX4 signaling cascade","authors":"Anhui Fu ,&nbsp;Hao Feng ,&nbsp;Mou Sun ,&nbsp;Xiaoquan Luo ,&nbsp;Zhou Li ,&nbsp;Hui Tang ,&nbsp;Fei Qiao","doi":"10.1016/j.bbadis.2025.168028","DOIUrl":"10.1016/j.bbadis.2025.168028","url":null,"abstract":"<div><h3>Rationale</h3><div>Glioblastoma is a fast-growing, invasive brain tumor with poor prognosis. Polyphyllin I, a saponin from Liliaceae plants, shows anti-tumor, anti-inflammatory effects, and induces ferroptosis, but its impact on glioblastoma and underlying mechanisms are not well understood.</div></div><div><h3>Methods</h3><div>Tumor malignancy was evaluated using assays such as scratch assays, CCK-8, clonogenic analyses, transwell experiments, along with EdU incorporation staining. Quantification for relevant molecules was performed using WB and RT-qPCR experiments. Ferroptosis in cells was quantified using JC-1, Boodipy, and TME assays. Lastly, the in vivo anti-tumor effects and mechanisms of Polyphyllin I were examined using a mouse xenograft model.</div></div><div><h3>Results</h3><div>This study reveals how PPI significantly inhibits GBM growth and spread while simultaneously improving the efficacy of chemotherapy drugs. In addition, the anti-tumor properties of PPI are linked to ferroptosis, and its effect is significantly diminished when ferroptosis is inhibited. Specifically, PPI binds directly to SIRT1, reducing its levels, which subsequently promotes oxidative cell death via the SIRT1/Nrf2/GPX4/HO-1 signaling pathway, thus suppressing glioblastoma. Furthermore, overexpression of SIRT1 can negate the therapeutic effects of PPI. The mouse xenograft model further supported the anti-tumor efficacy of PPI and provided deeper insights into its underlying mechanism.</div></div><div><h3>Conclusions</h3><div>Additionally, through regulating the SIRT1/Nrf2/GPX4/HO-1 axis, PPI induces iron-dependent cell death, contributing to its inhibition of glioblastoma. According to this research, PPI could serve as a superior treatment approach for GBM patients and holds promise for its combination with chemotherapy drugs in GBM treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168028"},"PeriodicalIF":4.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982294","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":"Remote ischemic preconditioning enhances antioxidant capacity in cerebral ischemia–reperfusion injured rats via the ARE pathway","authors":"Liang-Yi Chen ,&nbsp;Shih-Huang Tai ,&nbsp;Sheng-Yang Huang ,&nbsp;Kai-Wen Lo ,&nbsp;Ai-Hua Lee ,&nbsp;Yu-Ning Chen ,&nbsp;Ai-Chiang Lee ,&nbsp;Chen-Sheng Tseng ,&nbsp;E-Jian Lee","doi":"10.1016/j.bbadis.2025.168010","DOIUrl":"10.1016/j.bbadis.2025.168010","url":null,"abstract":"<div><h3>Background</h3><div>Remote ischemic preconditioning (RIPC) is a protective strategy in which transient ischemia and reperfusion in one organ confers protection to another. This can be mediated by humoral responses, transcriptional processes, or both. These protective effects are hypothesized to result from enhanced cellular tolerance to ischemia. Herein, we investigated the protective effects of RIPC in middle cerebral artery occlusion (MCAO) rats.</div></div><div><h3>Methods</h3><div>RIPC was performed by applying an elastic rubber tourniquet to the right hindlimb to induce transient ischemia. This involved tightening and releasing the tourniquet for 15 min per cycle (2 cycles for 30 min or 4 for 60 min). MCAO was then induced 12 or 24 h post-limb ischemia and maintained for 90 min. Seven days after MCAO, neurobehavioral outcomes and brain infarction volumes were evaluated. Oxidative stress markers, including malondialdehyde, myeloperoxidase, and dihydroethidium, alongside antioxidant parameters such as glutathione (GSH), the GSH/GSSG ratio, and γ-glutamyl cysteine ligase (GCS), were assessed. The expression levels of Nrf-1 and Nrf-2 were analyzed by western blotting and immunofluorescence.</div></div><div><h3>Results</h3><div>RIPC for 60 min (4 cycles), but not for 30 min, significantly reduced infarct volumes and improved behavioral outcomes. In addition, reductions in neutrophil infiltration, lipid peroxidation, and neuronal degeneration were observed. Nrf1 and Nrf2 levels and GSH, HO-1, and GCS activities were significantly elevated after RIPC for 60 min compared to the control.</div></div><div><h3>Conclusion</h3><div>RIPC in the hind limbs for 60 min leads to neuroprotection in a rat MCAO model. RIPC may be a potential adjunctive strategy for clinical stroke management.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168010"},"PeriodicalIF":4.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886733","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":"Prospect of Newcastle disease virus in clinical neurological tumour diseases","authors":"Yuxin Chen ,&nbsp;Zecheng Yu ,&nbsp;Huazhong Ying ,&nbsp;Fangwei Dai ,&nbsp;Wei Han","doi":"10.1016/j.bbadis.2025.168025","DOIUrl":"10.1016/j.bbadis.2025.168025","url":null,"abstract":"<div><div>Newcastle disease virus (NDV) can activate an anti-tumour immune response, and the virus has tumour-lysing properties and can induce apoptosis in tumour cells. NDV is used as a vector in oncolytic virus therapy, which has the unique advantage of tumour-specific inflammation activation, and drug resistance avoidance, resulting in the killing of tumour cells and induction of systemic anti-tumour immunity. NDV uses cancer signalling pathways to transform the immune-desert and microenvironment and immune-rejecting tumours into immunoinflammatory tumours, activating innate and adaptive anti-tumour immune responses to kill tumour cells, and its clinical application is one of the emerging cancer therapies focused on by researchers with good prospects for translational applications. The article reviews the mechanisms of NDV infection and oncolysis, and the clinical applications and safety of tumour oncolysis in nervous system tumours. This may contribute to enhancing further intervention and treatment of neurological tumours with NDV and lay the foundation for the widespread clinical use of NDV as a neoadjuvant therapeutic treatment.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168025"},"PeriodicalIF":4.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922303","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":"Platycodin D attenuates diabetic renal ischemia/reperfusion injury by enhancing mitophagy and suppressing MAPK/NF-κB signaling activation","authors":"Xuke Qin ,&nbsp;Jin Liu ,&nbsp;Xiaojie Zhao ,&nbsp;Lei Wang ,&nbsp;Xiuheng Liu ,&nbsp;Zhiyuan Chen","doi":"10.1016/j.bbadis.2025.168026","DOIUrl":"10.1016/j.bbadis.2025.168026","url":null,"abstract":"<div><div>The global incidence of diabetes mellitus (DM) is rapidly rising, and DM worsens renal ischemia/reperfusion (I/R) injury, a major cause of high-mortality acute kidney injury (AKI). Therefore, preventing renal I/R injury in DM is crucial. Platycodin D (PD), a compound from <em>Platycodon grandiflorum</em> roots, is known to activate AMP-activated protein kinase (AMPK).</div><div>Numerous studies have demonstrated that AMPK activation has protective effects in diabetes mellitus (DM) and ischemia/reperfusion (I/R) injury. However, the impact of PD on renal I/R injury in DM and its underlying mechanisms remain unclear. Our experiments revealed that PD treatment via gavage significantly alleviated kidney tissue damage and cell apoptosis in diabetic renal I/R injury. Additionally, PD reduced reactive oxygen species (ROS) levels, and transmission electron microscopy (TEM) indicated a notable discovery in mitophagosome formation. The expression levels of P-AMPK, light chain 3B (LC3B)-II, PTEN-induced putative protein kinase 1 (PINK1) and Parkin all increased under PD treatment, while sequestosome 1 (P62) level decreased. Importantly, AMPK antagonist Compound C (CC) abolished these effects. Additionally, our transcriptomic profiling revealed that PD treatment significantly suppressed MAPK/NF-κB signaling activation. Through functional rescue experiments, we mechanistically demonstrated that PD-mediated AMPK phosphorylation governs this regulatory axis. AMPK inhibition abolished PD's effects on both MAPK/NF-κB suppression, establishing AMPK activation as the upstream modulator. Overall, PD may reduce renal I/R injury in DM through AMPK/PINK1/Parkin-mediated mitophagy and inhibiting MAPK/NF-κB pathway.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168026"},"PeriodicalIF":4.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144914006","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 impact of p53 on the urea cycle and nitrogen metabolism enzymes: Mechanisms and implications for cancer development","authors":"Santhanagopalakrishnan Rajesh Iyer ,&nbsp;Beata Schlichtholz","doi":"10.1016/j.bbadis.2025.168024","DOIUrl":"10.1016/j.bbadis.2025.168024","url":null,"abstract":"<div><div>The tumour suppressor protein p53, encoded by the TP53 gene, is widely celebrated as the “guardian of the genome,” yet its role in metabolic reprogramming, particularly nitrogen metabolism, remains underappreciated. This review highlights the emerging nexus between p53 and the urea cycle, a key pathway responsible for ammonia detoxification and the generation of biosynthetic precursors. By regulating the expression and activity of urea cycle enzymes, p53 exerts profound control over interconnected metabolic pathways, including the metabolism of polyamine, methionine, glutathione, and proline. Cancer cells, with their voracious nitrogen demand, co-opt urea cycle dysregulation to fuel tumour growth and survival. Here, we synthesise the latest insights into p53's role in nitrogen homeostasis, delineating its broader implications for cellular metabolism and carcinogenesis. Additionally, we propose the strategic targeting of urea cycle enzymes as novel prognostic biomarkers and therapeutic vulnerabilities in cancer. This work not only redefines the metabolic scope of p53 but also positions nitrogen metabolism at the forefront of cancer research, offering transformative avenues for therapeutic innovation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168024"},"PeriodicalIF":4.2,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916896","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":"Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration","authors":"Anna Fernàndez-Bernal ,&nbsp;Natàlia Mota ,&nbsp;Reinald Pamplona ,&nbsp;Estela Area-Gómez ,&nbsp;Manuel Portero-Otin","doi":"10.1016/j.bbadis.2025.168021","DOIUrl":"10.1016/j.bbadis.2025.168021","url":null,"abstract":"<div><div>Cholesterol is a central determinant of membrane architecture, signaling, and cellular homeostasis in the central nervous system (CNS). While historically viewed as a structural component, emerging evidence highlights its dynamic regulatory role in neuronal function, particularly through its compartmentalized synthesis, trafficking, and turnover. This review examines the complex landscape of cholesterol metabolism in the CNS, emphasizing the cooperative roles of astrocytes and neurons, the partitioning of biosynthetic pathways, and the barriers that distinguish brain cholesterol pools from peripheral sources. We focus on mitochondria-associated endoplasmic reticulum membranes (MAMs) as key regulatory platforms for cholesterol sensing, esterification, and signaling, underscoring their emerging role in neurodegenerative diseases. Disruptions in MAM integrity, lipid raft composition, and transcriptional regulation of cholesterol-handling genes have been linked to pathologies such as amyotrophic lateral sclerosis (ALS), particularly through the actions of TDP-43. By consolidating recent findings from lipidomics, cell biology, and disease models, we propose that cholesterol dyshomeostasis constitutes a shared mechanistic axis across diverse neurodegenerative conditions. Understanding this axis offers novel insights into the metabolic vulnerability of neurons and highlights cholesterol metabolism as a promising target for therapeutic intervention.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168021"},"PeriodicalIF":4.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890369","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":"Mechanistic and target study of anthraquinone modifier KA-4c triggering endoplasmic reticulum stress to inhibit triple-negative breast cancer cells","authors":"Yingying Yang ,&nbsp;Shumei Xu ,&nbsp;Qiangjian Chen ,&nbsp;Yingdan Zhao ,&nbsp;Xinxiao Li ,&nbsp;Junying Li ,&nbsp;Huaxin Hou ,&nbsp;Danrong Li","doi":"10.1016/j.bbadis.2025.168020","DOIUrl":"10.1016/j.bbadis.2025.168020","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is associated with poor prognosis and high rates of metastasis and recurrence owing to lack of targeted therapies. Therefore, identifying effective targets for TNBC therapy remains an important clinical challenge. In this study, we examined the potential anticancer mechanisms and targets of the anthraquinone modifier KA-4c. Hematoxylin/eosin (HE), ER-Tracker™ Red, and Mito-Tracker™ Green staining followed by transmission electron microscopy (TEM) were performed to study the effect of KA-4c on TNBC cell morphology. KA-4c-induced apoptosis was detected using flow cytometry, and apoptosis-related proteins were analyzed using western blotting. Drug affinity-responsive target stability (DARTS), liquid chromatography tandem mass spectrometry (LC-MS/MS), bioinformatics, cell thermal shift analysis (CETSA), and RNA interference were used to identify the target protein of KA-4c. The results revealed increased cytoplasmic vacuolation from the endoplasmic reticulum and mitochondria in MDA-MB231 and MDA-MB468 cells treated with KA-4c. Furthermore, KA-4c enhanced MDA-MB231 and MDA-MB468 cell apoptosis by upregulating CHOP and caspase7 expression, and inducing PARP cleavage. DARTS results revealed that KA-4c activates the ER protein-processing signaling pathway by binding to ATF6 and rendering it resistant to protease hydrolysis. CETSA results demonstrated that KA-4c enhances ATF6 protein expression in a concentration-dependent manner. The results of RNA interference indicated that silencing ATF6 could effectively inhibit the upregulation of CHOP. In conclusion, KA-4c activates the ER protein-processing signaling pathway by targeting ATF6, damaging mitochondria, and inducing TNBC cell apoptosis. Thus, ATF6 represents a potential target of KA-4c, and a therapeutic target for TNBC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168020"},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867033","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":"Inhibition of ELOVL6 activity impairs mitochondrial respiratory function and inhibits tumor progression in FGFR3-mutated bladder cancer cells","authors":"Erika Matsuda ,&nbsp;Shiho Hasebe ,&nbsp;Takashi Matsuzaka ,&nbsp;Akio Hayashi ,&nbsp;Hiroshi Ohno ,&nbsp;Kaori Motomura ,&nbsp;Shotaro Sakka ,&nbsp;Susumu Kohno ,&nbsp;Hayato Muranaka ,&nbsp;Minako Yamamura ,&nbsp;Asuka Suzuki ,&nbsp;Yoshinori Takeuchi ,&nbsp;Yoshinori Osaki ,&nbsp;Takafumi Miyamoto ,&nbsp;Motohiro Sekiya ,&nbsp;Hirohito Sone ,&nbsp;Naoya Yahagi ,&nbsp;Yoshimi Nakagawa ,&nbsp;Satoshi Nitta ,&nbsp;Shuya Kandori ,&nbsp;Hitoshi Shimano","doi":"10.1016/j.bbadis.2025.168023","DOIUrl":"10.1016/j.bbadis.2025.168023","url":null,"abstract":"<div><h3>Objective</h3><div>Increased de novo fatty acid (FA) synthesis is a hallmark of cancer. ELOVL FA elongase 6 (ELOVL6) catalyze chain elongation of C16 saturated and monounsaturated FAs into C18 species and has been implicated in several cancers. This study investigated the role of ELOVL6 in bladder cancer (BC).</div></div><div><h3>Methods</h3><div>ELOVL6 expression was compared between BC and nontumor tissues. Human BC cell lines with ELOVL6-knockdown were assessed for proliferation and tumor growth. Metabolic and molecular alterations induced by ELOVL6 inhibition were analyzed using lipidomics and transcriptomics.</div></div><div><h3>Results</h3><div>ELOVL6 expression was significantly higher in BC tissues than in controls. In fibroblast growth factor receptor 3 (FGFR3)-mutant BC cell lines, ELOVL6 knockdown suppressed cell growth in vitro and tumor progression in vivo. Lipidomic analysis showed a marked reduction in phosphatidylethanolamine following ELOVL6 knockdown, which was accompanied by lower mitochondrial complex I and II protein levels and impaired mitochondrial oxidative phosphorylation (OXPHOS). RNA sequencing revealed that mitochondrial dysfunction resulting from ELOVL6 knockdown triggered changes in extracellular matrix (ECM) remodeling gene expression and activation of the ECM-integrin-focal adhesion kinase (FAK) pathway, likely as a compensatory response to reduced cell proliferation.</div></div><div><h3>Conclusion</h3><div>ELOVL6 regulates lipid composition to preserve mitochondrial function, supporting cell growth and tumorigenesis in FGFR3-mutated BC. Targeting ELOVL6 may represent a novel therapeutic strategy for treating BC, particularly in tumors driven by FGFR3 mutations.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 168023"},"PeriodicalIF":4.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867034","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}