Molecular & Cellular Proteomics最新文献

{"title":"Comprehensive Immunoglobulin G, A, and M Glycopeptide Profiling for Large-Scale Biomedical Research.","authors":"Bianca D M van Tol, Anna M Wasynczuk, Steinar Gijze, Oleg A Mayboroda, Jan Nouta, Radboud J E M Dolhain, Manfred Wuhrer, David Falck","doi":"10.1016/j.mcpro.2025.100928","DOIUrl":"10.1016/j.mcpro.2025.100928","url":null,"abstract":"<p><p>Glycosylation of immunoglobulin G (IgG) is recognized as a key modulator of cellular effector functions. At the same time, an increasing body of evidence underlines the importance of other antibody isotypes, especially IgA and IgM, in pathophysiological conditions. Therefore, methods to efficiently study the complex interplay between isotypes, subclasses, and glycosylation of antibodies during acute and chronic states of inflammation are needed. As a solution, we present an integrated and comprehensive method combining simultaneous affinity enrichment of IgG, IgA, and IgM with a single measurement, glycopeptide-centered LC-MS analysis of all isotypes which provides protein-specific (isotype and subclass), and site-specific N- and O-glycosylation quantitation. A two-protease approach provided individual peptides for each glycosylation site, allowing unambiguous compositional assignment and relative quantitation of glycoforms on the MS¹ level as well as structural confirmation and partial isomer assignment on the MS/MS level. We demonstrate that our methodology can be efficiently applied to large clinical studies revealing differences in antibody glycosylation in women during and after pregnancy, as well as between healthy donors and patients with rheumatoid arthritis. In addition, this showcased the advantages of our method in comprehensiveness and resolution of isotypes, subclasses, and glycosylation sites as well as its precision and robustness.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100928"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11953977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472691","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":"Multiple Classes of Antigen Contribute to the Antigenic Landscape of Mesothelioma.","authors":"Kirti Pandey, Pouya Faridi, Rochelle Ayala, Y C Gary Lee, Ebony Rouse, Sanjay S G Krishna, Ian Dick, Alec Redwood, Bruce Robinson, Jenette Creaney, Anthony W Purcell","doi":"10.1016/j.mcpro.2025.100925","DOIUrl":"10.1016/j.mcpro.2025.100925","url":null,"abstract":"<p><p>Mesothelioma is an incurable, asbestos-exposure-related cancer that typically affects the lining or pleura of the lungs. Symptoms typically develop many decades after initial asbestos exposure, leaving an enduring legacy of disease. The current disease burden is peaking worldwide and thus there is a massive unmet clinical need for curative therapies. Recently, immune checkpoint blockade-based therapy has been adopted as a first-line of treatment for mesothelioma. Vaccine-induced augmentation of immune responses unleashed during checkpoint blockade may provide further clinical benefit in mesothelioma. In this study, we explore the human leukocyte antigen class I landscape (or immunopeptidome) of mesothelioma in patient-derived cell lines and clinical material (pleural effusion samples). We identify a range of peptide antigens derived from targets including cancer testis antigens, endogenous retroviruses as well as novel post-translational modification of peptides. This information will facilitate the characterization of the immune response to these antigens to determine which class of antigen is most immunogenic and has the potential to be tested in future vaccine studies.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100925"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374170","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":"HEXB Drives Raised Paucimannosylation in Colorectal Cancer and Stratifies Patient Risk.","authors":"Rebeca Kawahara, Liisa Kautto, Naaz Bansal, Priya Dipta, The Huong Chau, Benoit Liquet-Weiland, Seong Beom Ahn, Morten Thaysen-Andersen","doi":"10.1016/j.mcpro.2025.100927","DOIUrl":"10.1016/j.mcpro.2025.100927","url":null,"abstract":"<p><p>Noninvasive prognostic markers are needed to improve the survival of colorectal cancer (CRC) patients. Toward this goal, we applied untargeted systems glycobiology approaches to snap-frozen and formalin-fixed paraffin-embedded tumor tissues and peripheral blood mononuclear cells from CRC patients spanning different disease stages and matching controls to faithfully uncover molecular changes associated with CRC. Quantitative glycomics and immunohistochemistry revealed that noncanonical paucimannosidic N-glycans are elevated in CRC tumors relative to normal adjacent tissues. Cell origin-focused glycoproteomics enabled using the well-curated Human Protein Atlas combined with immunohistochemistry of CRC tumor tissues recapitulated these findings and indicated that the paucimannosidic proteins were in part from tumor-infiltrating monocytes (e.g., MPO, AZU1) and of CRC cell origin (e.g., LGALS3BP, PSAP). Biosynthetically explaining these observations, N-acetyl-β-D-hexosaminidase (Hex) subunit β (HEXB) was found to be overexpressed in CRC tissues relative to normal adjacent colorectal tissues and colocalization and enzyme inhibition studies confirmed that HEXB facilitates paucimannosidic protein biosynthesis in CRC cells. Employing a sensitive, quick, and robust enzyme activity assay, we then showed that Hex activity was elevated in plasma and peripheral blood mononuclear cells from patients with advanced CRC relative to controls and those with early-stage disease. Surveying a large donor cohort, the plasma Hex activity was found to be raised in CRC patients relative to normal controls and correlated with the 5-year survival of CRC patients indicating that elevated plasma Hex activity is a potential disease risk marker for patient outcome. Our glycoproteomics-driven findings open avenues for better prognostication and disease risk stratification in CRC.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100927"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414100","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":"Causal Inference and Annotation of Phosphoproteomics Data in Multiomics Cancer Studies.","authors":"Qun Dong, Minjia Tan, Yingchun Zhou, Yue Zhang, Jing Li","doi":"10.1016/j.mcpro.2025.100905","DOIUrl":"10.1016/j.mcpro.2025.100905","url":null,"abstract":"<p><p>Protein phosphorylation plays a crucial role in regulating diverse biological processes. Perturbations in protein phosphorylation are closely associated with downstream pathway dysfunctions, whereas alterations in protein expression could serve as sensitive indicators of pathological status. However, there are currently few methods that can accurately identify the regulatory links between protein phosphorylation and expression, given issues like reverse causation and confounders. Here, we present Phoslink, a causal inference model to infer causal effects between protein phosphorylation and expression, integrating prior evidence and multiomics data. We demonstrated the feasibility and advantages of our method under various simulation scenarios. Phoslink exhibited more robust estimates and lower false discovery rate than commonly used Pearson and Spearman correlations, with better performance than canonical instrumental variable selection methods for Mendelian randomization. Applying this approach, we identified 345 causal links involving 109 phosphosites and 310 proteins in 79 lung adenocarcinoma (LUAD) samples. Based on these links, we constructed a causal regulatory network and identified 26 key regulatory phosphosites as regulators strongly associated with LUAD. Notably, 16 of these regulators were exclusively identified through phosphosite-protein causal regulatory relationships, highlighting the significance of causal inference. We explored potentially druggable phosphoproteins and provided critical clues for drug repurposing in LUAD. We also identified significant mediation between protein phosphorylation and LUAD through protein expression. In summary, our study introduces a new approach for causal inference in phosphoproteomics studies. Phoslink demonstrates its utility in potential drug target identification, thereby accelerating the clinical translation of cancer proteomics and phosphoproteomic data.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100905"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965955","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":"Ciliopathy-Associated Missense Mutations in IFT140 are Tolerated by the Inherent Resilience of the IFT Machinery.","authors":"Tina Beyer, Gaurav D Diwan, Tobias Leonhard, Katrin Dahlke, Franziska Klose, Isabel F Stehle, Marian Seda, Sylvia Bolz, Franziska Woerz, Robert B Russell, Dagan Jenkins, Marius Ueffing, Karsten Boldt","doi":"10.1016/j.mcpro.2025.100916","DOIUrl":"10.1016/j.mcpro.2025.100916","url":null,"abstract":"<p><p>Genotype-phenotype correlations of rare diseases are complicated by low patient number, high phenotype variability, and compound heterozygosity. Mutations may cause instability of single proteins, and affect protein complex formation or overall robustness of a specific process in a given cell. Ciliopathies offer an interesting case for studying genotype-phenotype correlations as they have a spectrum of severity and include diverse phenotypes depending on different mutations in the same protein. For instance, mutations in the intraflagellar transport protein IFT140 cause a vast spectrum of ciliopathies ranging from isolated retinal dystrophy to severe skeletal abnormalities and multi-organ diseases such as Mainzer-Saldino and Jeune syndrome. Here, the quantitative effects of 23 missense mutations in IFT140, which forms part of the crucial IFT-A complex of the ciliary machinery, were analyzed using affinity purification coupled with mass spectrometry (AP-MS). A subset of 10 mutations led to a significant and domain-specific reduction in IFT140-IFT-A complex interaction indicating complex formation issues and potentially hampering its molecular function. Knockout of IFT140 led to loss of cilia, as shown before. However, phenotypically only mild effects concerning cilia assembly were observed for two out of four tested IFT140 missense mutations. Therefore, our results demonstrate the utility of AP-MS in discerning pathogenic MMs from polymorphisms, and we postulate that reduced function is tolerated by the evolutionarily highly conserved IFT-A system.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100916"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066765","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":"Glycoproteoforms of Osteoarthritis-associated Lubricin in Plasma and Synovial Fluid.","authors":"Ali Reza Afshari, Vincent Chang, Kristina A Thomsson, Jennifer Höglund, Elizabeth N Browne, George Karadzhov, Keira E Mahoney, Taryn M Lucas, Valentina Rangel-Angarita, Henrik Ryberg, Kamlesh Gidwani, Kim Pettersson, Ola Rolfson, Lena I Björkman, Thomas Eisler, Tannin A Schmidt, Gregory D Jay, Stacy A Malaker, Niclas G Karlsson","doi":"10.1016/j.mcpro.2025.100923","DOIUrl":"10.1016/j.mcpro.2025.100923","url":null,"abstract":"<p><p>Lubricin/proteoglycan-4 (PRG-4) is a mucinous glycoprotein that lubricates cartilage and maintains normal tissue function and cell homeostasis. Altered O-glycoproteforms of lubricin have been found in osteoarthritis (OA) synovial fluid (SF), which could ostensibly be used to diagnose early onset OA. However, SF is invasive to obtain and generally would not be surveyed from otherwise healthy individuals. Thus, a plasma-based OA screening tool focused on lubricin glycosylation could be a less invasive method to aid in early-stage OA diagnosis. In this report, we used glycomics and glycoproteomics to characterize glycoproteoforms of OA lubricin in SF and plasma. We obtained near-complete sequence coverage of lubricin's mucin domain and its glycosylation using matched SF and plasma from patients with OA (N = 5). From SF lubricin we observed a spectrum of O-glycans ranging from a single GalNAcα1-Ser/Thr monosaccharide up to branched pentasaccharides. In contrast, plasma based lubricin was predominantly decorated with sialylated Galβ1-3GalNAcα1-Ser/Thr (Sialyl T). To explain the glycosylation differences observed between SF and plasma lubricin, we present splice variant-specific peptides found within the non-glycosylated region, revealing that that the longest spliceoform of lubricin was present exclusively in SF, while additional shorter splice variants could only be detected in plasma. Based on our glycoproteomic data, we developed and validated a lectin assay for lubricin, and applied this on a larger cohort of matched SF/plasma (N = 19) to confirm the glycosylation differences between SF and plasma proteoforms. Next, we leveraged our assay to screen over 100 patient with OA samples (OA patients N = 108/controls N = 38) to probe plasma lubricin as an OA biomarker. Here, we detected a decrease in α2,6 linked sialic acid in patients with OA and further show that the extent of α2,6 and α2,3 sialylation on plasma-associated lubricin correlated with patient characteristics, especially Body Mass Index (BMI).</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100923"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374164","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":"Identifying Receptor Kinase Substrates Using an 8000 Peptide Kinase Client Library Enriched for Conserved Phosphorylation Sites.","authors":"Daewon Kim, Gabriel Lemes Jorge, Chunhui Xu, Lingtao Su, Sung-Hwan Cho, Nagib Ahsan, Dongqin Chen, Lijuan Zhou, Marina A Gritsenko, Mowei Zhou, Jinrong Wan, Ljiljana Pasa-Tolic, Dong Xu, Laura E Bartley, Jay J Thelen, Gary Stacey","doi":"10.1016/j.mcpro.2025.100926","DOIUrl":"10.1016/j.mcpro.2025.100926","url":null,"abstract":"<p><p>In eukaryotic organisms, protein kinases regulate diverse protein activities and signaling pathways through phosphorylation of specific protein substrates. Isolating and characterizing kinase substrates is vital for defining downstream signaling pathways. The kinase-client (KiC) assay is an in vitro synthetic peptide LC-MS/MS phosphorylation assay that has enabled identification of protein substrates (i.e., clients) for various protein kinases. For example, previous use of a 2100-member (2k) peptide library identified substrates for the extracellular ATP receptor-like kinase, P2K1. Many P2K1 clients were confirmed by additional in vitro and in planta studies, including integrin-linked kinase 4, for which we provide the evidence herein. In addition, we developed a new KiC peptide library containing 8000 (8k) peptides based on phosphorylation sites primarily from Arabidopsis thaliana datasets. The 8k peptides are enriched for sites with conservation in other angiosperm plants, with the paired goals of representing functionally conserved sites and usefulness for screening kinases from diverse plants. Screening the 8k library with the active P2K1 kinase domain identified 177 phosphopeptides, including calcineurin B-like protein and G protein alpha subunit 1, which functions in cellular calcium signaling. We confirmed that P2K1 directly phosphorylates calcineurin B-like protein and G protein alpha subunit 1 through in vitro kinase assays. This expanded 8k KiC assay will be a useful tool for identifying novel substrates across diverse plant protein kinases, ultimately facilitating the exploration of previously undiscovered signaling pathways.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100926"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382916","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":"Proteomic Diversity in Bacteria: Insights and Implications for Bacterial Identification.","authors":"Miriam Abele, Armin Soleymaniniya, Florian P Bayer, Nina Lomp, Etienne Doll, Chen Meng, Klaus Neuhaus, Siegfried Scherer, Mareike Wenning, Nina Wantia, Bernhard Kuster, Mathias Wilhelm, Christina Ludwig","doi":"10.1016/j.mcpro.2025.100917","DOIUrl":"10.1016/j.mcpro.2025.100917","url":null,"abstract":"<p><p>Mass spectrometry-based proteomics has revolutionized bacterial identification and elucidated many molecular mechanisms underlying bacterial growth, community formation, and drug resistance. However, most research has been focused on a few model bacteria, overlooking bacterial diversity. In this study, we present the most extensive bacterial proteomic resource to date, covering 303 species, 119 genera, and five phyla with over 636,000 unique expressed proteins, confirming the existence of over 38,700 hypothetical proteins. Accessible via the public resource ProteomicsDB, this dataset enables quantitative exploration of proteins within and across species. Additionally, we developed MS2Bac, a bacterial identification algorithm that queries NCBI's bacterial proteome space in two iterations. MS2Bac achieved over 99% species-level and 89% strain-level accuracy, surpassing methods like MALDI-TOF and FTIR, as demonstrated with food-derived bacterial isolates. MS2Bac also effectively identified bacteria in clinical samples, highlighting the potential of MS-based proteomics as a routine diagnostic tool.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100917"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066455","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":"Quantitative Chromatin Protein Dynamics During Replication Origin Firing in Human Cells.","authors":"Sampath Amitash Gadi, Ivo Alexander Hendriks, Christian Friberg Nielsen, Petya Popova, Ian D Hickson, Michael Lund Nielsen, Luis Toledo","doi":"10.1016/j.mcpro.2025.100915","DOIUrl":"10.1016/j.mcpro.2025.100915","url":null,"abstract":"<p><p>Accurate genome duplication requires a tightly regulated DNA replication program that relies on the fine regulation of origin firing. While the molecular steps involved in origin firing have been determined predominantly in budding yeast, the complexity of this process in human cells has yet to be fully elucidated. Here, we describe a straightforward proteomics approach to systematically analyze protein recruitment to the chromatin during induced origin firing in human cells. Using a specific inhibitor against CHK1 kinase, we induced a synchronized wave of dormant origin firing (DOF) and assessed the S phase chromatin proteome at different time points. We provide time-resolved loading dynamics of 3269 proteins, including the core replication machinery and origin firing factors. This dataset accurately represents known temporal dynamics of proteins on the chromatin during the activation of replication forks and the subsequent DNA damage due to the hyperactivation of excessive replication forks. Finally, we used our dataset to identify the condensin II subunit NCAPH2 as a novel factor required for efficient origin firing and replication. Overall, we provide a comprehensive resource to interrogate the protein recruitment dynamics of replication origin firing events in human cells.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100915"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066463","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":"Integrated Analysis of Proteome and Transcriptome Profiling Reveals Pan-Cancer-Associated Pathways and Molecular Biomarkers.","authors":"Guo-Sheng Hu, Zao-Zao Zheng, Yao-Hui He, Du-Chuang Wang, Rui-Chao Nie, Wen Liu","doi":"10.1016/j.mcpro.2025.100919","DOIUrl":"10.1016/j.mcpro.2025.100919","url":null,"abstract":"<p><p>Understanding dysregulated genes and pathways in cancer is critical for precision oncology. Integrating mass spectrometry-based proteomic data with transcriptomic data presents unique opportunities for systematic analyses of dysregulated genes and pathways in pan-cancer. Here, we compiled a comprehensive set of datasets, encompassing proteomic data from 2404 samples and transcriptomic data from 7752 samples across 13 cancer types. Comparisons between normal or adjacent normal tissues and tumor tissues identified several dysregulated pathways including mRNA splicing, interferon pathway, fatty acid metabolism, and complement coagulation cascade in pan-cancer. Additionally, pan-cancer upregulated and downregulated genes (PCUGs and PCDGs) were also identified. Notably, RRM2 and ADH1B, two genes which belong to PCUGs and PCDGs, respectively, were identified as robust pan-cancer diagnostic biomarkers. TNM stage-based comparisons revealed dysregulated genes and biological pathways involved in cancer progression, among which the dysregulation of complement coagulation cascade and epithelial-mesenchymal transition are frequent in multiple types of cancers. A group of pan-cancer continuously upregulated and downregulated proteins in different tumor stages (PCCUPs and PCCDPs) were identified. We further constructed prognostic risk stratification models for corresponding cancer types based on dysregulated genes, which effectively predict the prognosis for patients with these cancers. Drug prediction based on PCUGs and PCDGs as well as PCCUPs and PCCDPs revealed that small molecule inhibitors targeting CDK, HDAC, MEK, JAK, PI3K, and others might be effective treatments for pan-cancer, thereby supporting drug repurposing. We also developed web tools for cancer diagnosis, pathologic stage assessment, and risk evaluation. Overall, this study highlights the power of combining proteomic and transcriptomic data to identify valuable diagnostic and prognostic markers as well as drug targets and treatments for cancer.</p>","PeriodicalId":18712,"journal":{"name":"Molecular & Cellular Proteomics","volume":" ","pages":"100919"},"PeriodicalIF":6.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066048","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}