Xiaojing Yuan, Qilun Zhang, Jie Li, Zichen Zhang, Shandong Ye, Wan Zhou
{"title":"Nup93-Mediated RNA Alternative Splicing Associated With Diabetic Atherosclerosis.","authors":"Xiaojing Yuan, Qilun Zhang, Jie Li, Zichen Zhang, Shandong Ye, Wan Zhou","doi":"10.1016/j.mcpro.2025.101029","DOIUrl":"10.1016/j.mcpro.2025.101029","url":null,"abstract":"<p><p>Atherosclerosis, a life-threatening complication of diabetes mellitus (DM), significantly increases the mortality risk among diabetic patients. Vascular smooth muscle cells (VSMCs) not only constitute the core of atherosclerotic lesions but also serve as primary components of plaques. Although diabetes expedites this transformation process, the specific mechanism remains elusive. Traditional proteomic approaches that analyze average signals of all cells overlook the importance of spatial information, although different cells within the same tissue exhibit distinct molecular characteristics during various stages of atherosclerosis progression. In this study, we employed spatial proteomic technology to comprehensively analyze proteins in vascular smooth muscle tissues and atherosclerotic plaques obtained from a mouse model of atherosclerosis and DM complicated with arteriosclerosis. We also employed RNA sequencing technology to further investigate the changes in RNA alternative splicing in atherosclerosis and DM complicated with arteriosclerosis in cell models. Our findings revealed the reduced expression of Nup93 within VSMCs under combined high glucose and ox-LDL stimulation, mimicking diabetic atherosclerotic stress. This reduction impairs the nuclear import of splicing regulators SRSF1 and SRSF3, leading to abnormal alternative splicing of SerpinE2, which in turn enhances its mRNA stability and promotes VSMCs' proliferation. These results reveal a novel mechanistic axis whereby diabetic atherosclerotic stress drives VSMCs dysfunction through Nup93-mediated splicing dysregulation, offering new molecular targets for the treatment of diabetes-associated atherosclerosis.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101029"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12450644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600978","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}
Juliette Dupré, Katarzyna Magdalena Dolata, Gang Pei, Aidin Molouki, Lynnette C Goatley, Richard Küchler, Timothy K Soh, Jens B Bosse, Aurore Fablet, Mireille Le Dimna, Grégory Karadjian, Edouard Hirchaud, Christopher L Netherton, Linda K Dixon, Ana Luisa Reis, Damien Vitour, Marie-Frédérique Le Potier, Axel Karger, Grégory Caignard
{"title":"Exploring Virus-Host Interactions Through Combined Proteomic Approaches Identifies BANF1 as a New Essential Factor for African Swine Fever Virus.","authors":"Juliette Dupré, Katarzyna Magdalena Dolata, Gang Pei, Aidin Molouki, Lynnette C Goatley, Richard Küchler, Timothy K Soh, Jens B Bosse, Aurore Fablet, Mireille Le Dimna, Grégory Karadjian, Edouard Hirchaud, Christopher L Netherton, Linda K Dixon, Ana Luisa Reis, Damien Vitour, Marie-Frédérique Le Potier, Axel Karger, Grégory Caignard","doi":"10.1016/j.mcpro.2025.101038","DOIUrl":"10.1016/j.mcpro.2025.101038","url":null,"abstract":"<p><p>African swine fever virus (ASFV) causes a lethal disease in pigs and represents a significant threat to the global pork industry due to the lack of effective vaccines or treatments. Despite intensive research, many ASFV proteins remain uncharacterized. This study aimed to elucidate the functions of two ASFV proteins, pMGF360-21R and pA151R, through comprehensive analysis of their interactions with host proteins. Using affinity purification-mass spectrometry and yeast two-hybrid screening approaches, we identified the host protein barrier-to-autointegration factor 1 (BANF1) as a key interactor of both viral proteins. Biochemical and colocalization assays confirmed these interactions and demonstrated that MGF360-21R and A151R expression leads to cytoplasmic relocation of BANF1. Functionally, BANF1 silencing significantly reduced ASFV replication, indicating its proviral role. Given BANF1's established function in regulating the cGAS/STING-dependent type I interferon (IFN-I) response, we postulated that A151R and MGF360-21R could inhibit this pathway. Using different strategies, we showed that both A151R and MGF360-21R did indeed inhibit IFN-I induction. Generation of ASFV deficient of A151R or MGF360-21R showed that both mutant viruses enhanced the host IFN response in primary porcine macrophages compared to wild-type virus. However, their capacity to inhibit this pathway could occur through mechanisms independent of BANF1. Proteomic analysis of BANF1 interactors during ASFV infection highlighted potentially roles in chromatin remodeling, nuclear transport, and innate immune response pathways. Altogether, our data provide new insights into ASFV-host interactions, identifying BANF1 as an important new host factor required for replication and uncovering novel functions for A151R and MGF360-21R.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101038"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708169","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}
Tereza Kadavá, Jürgen Strasser, Maryam Marefat, Victor C Yin, Johannes Preiner, Leendert A Trouw, Albert J R Heck
{"title":"Structural Insights Into Complement Inhibition: Visualizing Distinct Binding Modes of C4b-Binding Protein Complexes With C4b and SAP.","authors":"Tereza Kadavá, Jürgen Strasser, Maryam Marefat, Victor C Yin, Johannes Preiner, Leendert A Trouw, Albert J R Heck","doi":"10.1016/j.mcpro.2025.101046","DOIUrl":"10.1016/j.mcpro.2025.101046","url":null,"abstract":"<p><p>C4b-binding protein (C4BP) is an innate immune inhibitor found in serum. Human C4BP adopts spider-like higher-order structures (HOS) formed by disulfide-linked C4BPα and C4BPβ chains that non-covalently bind vitamin K-dependent protein S (ProS). These spider-like structures can form even larger complexes as C4BP interacts with other, mostly complement-related, proteins. The complement inhibitory role of C4BP is primarily mediated through its interaction with C4b. C4BP also binds with high affinity to serum amyloid P component (SAP), a pentraxin family member associated with amyloidosis conditions. Here, we structurally and compositionally characterize C4BP interactions with these two natively occurring binders. To achieve this, we combine mass photometry, high-speed atomic force microscopy, and cross-linking mass spectrometry. By integrating the results, we reveal two distinct binding modes of C4BP when bound to C4b or SAP. Given the spider-like assembly of C4BP, C4b interacts with the N-terminal region of a single C4BPα leg, enabling multiple C4b molecules to bind to the C4BP HOS. Conversely, SAP engages with the entire spider-like HOS: the C4BPα-C4BPβ oligomerization core binds to SAP, and the C4BPα legs wrap around it.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101046"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775792","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}
Pedro H C Franco, Rilee Zeinert, Jakob Meier-Credo, Gisela Storz, Julian D Langer
{"title":"Detection and Quantitation of Small Proteins Using Mass Spectrometry.","authors":"Pedro H C Franco, Rilee Zeinert, Jakob Meier-Credo, Gisela Storz, Julian D Langer","doi":"10.1016/j.mcpro.2025.101052","DOIUrl":"10.1016/j.mcpro.2025.101052","url":null,"abstract":"<p><p>Small proteins or microproteins, despite long being ignored, have important roles in the regulation of larger protein complexes, metabolic pathways, and gene expression. However, these proteins remain under-represented in proteomics studies because of low detection efficiency in traditional mass spectrometry (MS) workflows. Their inherent characteristics often lead to depletion during sample preparation and a low detection efficiency in LC-MS. To improve detection and quantitation, we took advantage of the large set of documented small proteins in Escherichia coli and systematically compared and optimized different sample preparation and LC-MS approaches. We evaluated different top-down and bottom-up approaches, including data-dependent acquisition, data-independent acquisition, and parallel reaction monitoring. Our data highlight the benefit of top-down proteomics for identifying new small proteins and bottom-up preparation coupled with parallel reaction monitoring acquisition for quantitation of protein levels in different growth conditions. Our systematic comparison can serve as a guideline for MS detection of small proteins in all organisms.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101052"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862334","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}
Lizhuo Ai, Aleksandra Binek, Vladimir Zhemkov, Jae Hyung Cho, Ali Haghani, Simion Kreimer, Edo Israely, Madelyn Arzt, Blandine Chazarin, Niveda Sundararaman, Jesse G Meyer, Arun Sharma, Eduardo Marbán, Clive N Svendsen, Jennifer E Van Eyk
{"title":"Single-Cell Proteomics Reveals Specific Cellular Subtypes in Cardiomyocytes Derived From Human iPSCs and Adult Hearts.","authors":"Lizhuo Ai, Aleksandra Binek, Vladimir Zhemkov, Jae Hyung Cho, Ali Haghani, Simion Kreimer, Edo Israely, Madelyn Arzt, Blandine Chazarin, Niveda Sundararaman, Jesse G Meyer, Arun Sharma, Eduardo Marbán, Clive N Svendsen, Jennifer E Van Eyk","doi":"10.1016/j.mcpro.2025.100910","DOIUrl":"10.1016/j.mcpro.2025.100910","url":null,"abstract":"<p><p>Single-cell proteomics was performed on human induced pluripotent stem cells (iPSCs), iPSC-derived cardiomyocytes, and adult cardiomyocytes. More than 700 proteins could be simultaneously measured in each cell revealing unique subpopulations. A subset of iPSCs expressed higher levels of Lin28a and Tra-1-60 towards the outer edge of cell colonies. In the cardiomyocytes, two distinct populations were found that exhibited complementary metabolic profiles. Cardiomyocytes from iPSCs showed a glycolysis profile while adult cardiomyocytes were enriched in proteins involved with fatty acid metabolism. Interestingly, rare single cells also co-expressed markers of both cardiac and neuronal lineages, suggesting there may be a novel hybrid cell type in the human heart.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100910"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040243","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":"From Vision to Reality: A Perspective on the Innovative and Collaborative Forces That Evolved Proximity Labeling.","authors":"Tess C Branon, Wei Qin, Namrata D Udeshi","doi":"10.1016/j.mcpro.2025.101045","DOIUrl":"10.1016/j.mcpro.2025.101045","url":null,"abstract":"<p><p>Proximity labeling coupled with mass spectrometry is a powerful method for studying living systems with high spatial and temporal resolution. This perspective aims to provide a history of how APEX- and TurboID-based proximity labeling technologies were developed through dedication, innovation, and, most importantly, collaboration. We share our candid guidance on how to execute a successful proximity labeling experiment and comments on future developments in this field.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101045"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794899","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}
Anouk M D Becker, Bob J Ignacio, Jelmer J Dijkstra, Alexander R Ziegler, Iván Ramos-Tomillero, Floris J van Dalen, Laura E Edgington-Mitchell, Michiel Vermeulen, Kimberly M Bonger, I Jolanda M de Vries, Martijn Verdoes
{"title":"Proteome and Secretome Profiling of the Melanoma-Induced Transition Toward Immune Incompetent Dendritic Cells Reveals Enhanced IDO1, Cathepsin, and Legumain Activity.","authors":"Anouk M D Becker, Bob J Ignacio, Jelmer J Dijkstra, Alexander R Ziegler, Iván Ramos-Tomillero, Floris J van Dalen, Laura E Edgington-Mitchell, Michiel Vermeulen, Kimberly M Bonger, I Jolanda M de Vries, Martijn Verdoes","doi":"10.1016/j.mcpro.2025.101048","DOIUrl":"10.1016/j.mcpro.2025.101048","url":null,"abstract":"<p><p>Dendritic cells (DCs) are professional antigen-presenting cells endowed with the capacity to initiate strong antitumor immune responses. This function is critical for effective DC-based immunotherapies but is often hampered by tumor-derived immunosuppressive factors, as is observed for CD14<sup>+</sup>CD163<sup>+</sup> tumor-induced DC3s (ti-DC3s). ti-DC3s are increased in cancer patients where they display an immunosuppressive phenotype, accompanied by weak antigen-specific CD8 T cell-activating capacities. While tumor-derived interleukin-6, macrophage colony-stimulating factor, and prostaglandin E2 have been identified as factors inducing the transition from DC2s to ti-DC3s, a comprehensive unbiased profiling of the resulting changes in secretome and proteome has not been reported. Here, we characterized by tandem LC-MS/MS the proteomic changes in conventional DCs during their transition into CD14<sup>+</sup> ti-DC3s in vitro, using conditioned medium from the melanoma cell line BLM. This revealed 157 differentially expressed proteins, including upregulated indoleamine-2,3-dioxygenase 1 and legumain, which we confirmed to be functionally active. Next, we profiled the newly synthesized secretome in human DCs with THRONCAT metabolic labeling. We detected 17 differentially secreted proteins between DC2s and ti-DC3s, which included six cathepsins and tumor-associated transforming growth factor-β-induced protein. Cathepsin activity was validated in peripheral blood and tumor tissue of melanoma patients. We detected the highest cathepsin activity in ti-DC3s, surpassing DC2s and tumor-associated macrophages. Together, our findings represent the first characterization of the proteome and secretome of human melanoma-induced DC3s. This revealed several protein-driven protumor mechanisms active in ti-DC3s that potentially contribute to creating an immune environment favorable for tumor progression.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101048"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822017","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}
Tereza Kozelková, Martin Horn, Daniel Sojka, Stephen Lu, Jana Pytelková, Veronika Urbanová, Filip Dyčka, Michael Mareš, Petr Kopáček
{"title":"Proteomic Insight Into the Ontogeny of Blood-Meal Digestion in the Tick Ixodes ricinus.","authors":"Tereza Kozelková, Martin Horn, Daniel Sojka, Stephen Lu, Jana Pytelková, Veronika Urbanová, Filip Dyčka, Michael Mareš, Petr Kopáček","doi":"10.1016/j.mcpro.2025.101054","DOIUrl":"10.1016/j.mcpro.2025.101054","url":null,"abstract":"<p><p>Ticks are important ectoparasites and vectors of a variety of pathogens in both animals and humans, and their increasing global distribution poses a growing health risk. Unlike other blood-feeding vectors, ticks feed for an extended period at each life stage and rely exclusively on blood for development and reproduction. Blood digestion in ticks is mediated by a complex multienzyme network within the endolysosomal system of the midgut (MG) epithelial cells. Previous studies have focused largely on protein digestion during the slow feeding phase. However, the processing of the blood meal after the mating-induced rapid engorgement (\"big sip\") remains unclear, although the rapid turnover of proteins from host blood proteins into yolk proteins in fully fed females is a crucial step for tick reproduction. In this study, we performed a label-free quantitative proteomic analysis of MG tissue extracts and MG contents of the hard tick Ixodes ricinus to characterize proteases and protease inhibitors expressed during selected timepoints of female feeding and off-host digestion. In addition, we analyzed the distribution of digestive enzymes by activity profiling in MG extracts and contents with specific diagnostic substrates. Our results show that the multienzyme network, mainly based on aspartic acid and cysteine cathepsins and complemented by specific types of serine proteases and metalloproteases, is involved in the intracellular and probably also in the luminal digestion of blood meal proteins in fully engorged female ticks. We also detected different types of protease inhibitors and proposed their regulatory role in controlling both endogenous (tick-derived) and host protease activities in the MG tissue and luminal contents storing ingested blood. These results provide comprehensive insights into the physiology of the tick MG and offer new opportunities for the development of future control strategies against ticks and tick-borne diseases.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101054"},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961611","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}
Chunyan Hou, Hemeng Zhang, Jingtao Deng, Xiaoxin Wang, Stephen Byers, Moshe Levi, Daniel T S Pak, Kelley W Moremen, Huadong Pei, Gerald W Hart, Junfeng Ma
{"title":"Comprehensive Evaluation of Cleavable Bioorthogonal Probes for Site-Specific O-GlcNAc Proteomics.","authors":"Chunyan Hou, Hemeng Zhang, Jingtao Deng, Xiaoxin Wang, Stephen Byers, Moshe Levi, Daniel T S Pak, Kelley W Moremen, Huadong Pei, Gerald W Hart, Junfeng Ma","doi":"10.1016/j.mcpro.2025.101064","DOIUrl":"10.1016/j.mcpro.2025.101064","url":null,"abstract":"<p><p>O-linked β-N-acetylglucosamine (O-GlcNAc) modification (i.e., O-GlcNAcylation) on proteins is an essential modification in physiology and pathology. Although O-GlcNAcylation is functionally critical, its analysis has been challenging. Despite the existence of a number of methods developed in the past years, which one(s) might have the best performance is largely unclear. To that end, we conducted a rigorous comparison of several cleavable bioorthogonal biotin-alkyne probes which showed promise for sensitive O-GlcNAc proteomics. In brief, we developed chemoenzymatic labeling/click chemistry-based analytical workflows for O-GlcNAc proteomics by utilizing four cleavable bioorthogonal probes, including photocleavabe-biotin-alkyne (PC-biotin-alkyne), dialkoxydiphenylsilane-biotin-alkyne (DADPS-biotin-alkyne); 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl-biotin-alkyne (Dde-biotin-alkyne), and diazobenzene-biotin-alkyne (Diazo-biotin-alkyne). The analytical performance of these probes was evaluated with synthetic O-GlcNAc peptides and then benchmarked by using mouse brain lysates for O-GlcNAc proteomics. Besides providing valuable technical insights into O-GlcNAc proteomics methods, our work yielded an unprecedented O-GlcNAc proteome depth in the mouse brain. In total, 2906 O-GlcNAc sites were unambiguously assigned on 878 proteins. Among them, 1611 sites were newly identified, including 138 O-GlcNAcylated tyrosine residues. Our work will help guide the selection/development of O-GlcNAc proteomics methods for future studies, provide an invaluable resource for functional elucidation of protein O-GlcNAcylation in brain biology, and yield critical insights into tyrosine O-GlcNAcylation.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101064"},"PeriodicalIF":5.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961631","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}
Mingjie Gao, Weiyi Hu, Delan Meng, Pengju Yao, Siqi Yang, Yuanpeng Tong, Lei Wang, Ya Zhang, Qingsong Wang, Jianguo Ji, Wenyuan Zhu
{"title":"Jolkinolide B Activates Mitophagy to Exhibit Antipancreatic Cancer Activity and Alleviate Cognitive Deficits in Alzheimer's Disease.","authors":"Mingjie Gao, Weiyi Hu, Delan Meng, Pengju Yao, Siqi Yang, Yuanpeng Tong, Lei Wang, Ya Zhang, Qingsong Wang, Jianguo Ji, Wenyuan Zhu","doi":"10.1016/j.mcpro.2025.101060","DOIUrl":"10.1016/j.mcpro.2025.101060","url":null,"abstract":"<p><p>Dysfunctional mitophagy leads to the pathological accumulation of damaged mitochondria, which is closely associated with the development of human diseases such as cancer and Alzheimer's disease. The identification of safer and more effective mitophagy regulators may provide a novel approach for treating mitochondrial diseases. Covalent-binding drugs have attracted substantial attention due to their high specificity, selectivity, and low resistance potential. In this study, we demonstrated that the natural epoxide compound jolkinolide B (JB) specifically induces mitophagy both in vitro and in vivo. Mass spectrometry analysis confirmed that JB directly binds to the outer mitochondrial membrane translocase protein TOM40, leading to autophagic cell death in pancreatic cancer. As a mitophagy enhancer, JB also ameliorates mitochondrial dysfunction and mitigates cognitive deficits in the 5×FAD mouse model of Alzheimer's disease. The findings indicate that JB selectively targets mitochondria to enhance mitophagy while exhibiting minimal toxicity in pancreatic cancer and Alzheimer's disease mouse models, highlighting its potential as a therapeutic agent for mitochondrial diseases.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"101060"},"PeriodicalIF":5.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961677","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}