{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:09:08Z","timestamp":1788775748928,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chronic infection with Helicobacter pylori (H. pylori) is a major environmental risk factor for gastric carcinogenesis. Malignancy is largely driven by variations within the virulence factor CagA, with East Asian lineages exhibiting higher oncogenic potential than Western ones. However, how these variants modulate cellular crosstalk remains poorly understood. We integrated molecular dynamics (MD) simulations with single-cell transcriptomics across progressive disease stages, including chronic atrophic gastritis, intestinal metaplasia, and gastric cancer. Local niche remodeling was evaluated via cell\u2013cell communication profiling among epithelial, stromal, and immune circuits, while simulations of MARK2 kinase bound to distinct CagA lineages determined binding affinities. Single-cell analysis revealed that H. pylori toxicity progressively dampens epithelial\u2013stromal crosstalk, marked by severe epithelial polarity aberrations that disrupt neuroendocrine-like secretory and synaptic pathways during malignant transformation. Mechanistically, MD simulations and MM\/GBSA calculations demonstrated that East Asian CagA lineages exhibit higher binding affinity toward host MARK2 than Western lineages. Specific East Asian amino acid substitutions dramatically tighten the protein interface, driving stronger signaling perturbations. This study bridges atomistic structural virulence with microenvironmental shifting, establishing geographic CagA toxicity divergence as a critical determinant for pathogen-driven gastric cancer risk.<\/jats:p>","DOI":"10.3390\/molecules31173118","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:23:37Z","timestamp":1788773017000},"page":"3118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lineage-Specific CagA Binding Mechanics and Microenvironmental Rewiring in East Asian Gastric Carcinogenesis"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7916-7038","authenticated-orcid":false,"given":"Hongbo","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2064-6912","authenticated-orcid":false,"given":"Denan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Qing","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2423-8569","authenticated-orcid":false,"given":"Xiujie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13045-024-01654-2","article-title":"Helicobacter pylori and gastric cancer: Mechanisms and new perspectives","volume":"18","author":"Duan","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S2468-1253(23)00070-5","article-title":"Global prevalence of Helicobacter pylori infection between 1980 and 2022: A systematic review and meta-analysis","volume":"8","author":"Li","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41572-023-00431-8","article-title":"Helicobacter pylori infection","volume":"9","author":"Malfertheiner","year":"2023","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2314201","DOI":"10.1080\/19490976.2024.2314201","article-title":"The Helicobacter pylori cag pathogenicity island as a determinant of gastric cancer risk","volume":"16","author":"Tran","year":"2024","journal-title":"Gut Microbes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1053\/j.gastro.2015.09.004","article-title":"Pathobiology of Helicobacter pylori-Induced Gastric Cancer","volume":"150","author":"Amieva","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1056\/NEJMoa2211807","article-title":"Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer","volume":"388","author":"Usui","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1038\/s41564-019-0441-6","article-title":"VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1","volume":"4","author":"Capurro","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s10120-025-01677-9","article-title":"Burden of gastric cancer attributable to Helicobacter pylori in 27 countries from seven geographic regions in 2022","volume":"29","author":"Collatuzzo","year":"2026","journal-title":"Gastric Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1146\/annurev-med-042220-020814","article-title":"Diagnosis and Treatment of Helicobacter pylori Infection","volume":"73","author":"Lee","year":"2022","journal-title":"Annu. Rev. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Park, J.Y., Forman, D., Waskito, L.A., Yamaoka, Y., and Crabtree, J.E. (2018). Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer. Toxins, 10.","DOI":"10.3390\/toxins10040163"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101470","DOI":"10.1016\/j.jcmgh.2025.101470","article-title":"Decoding the Ability of Helicobacter pylori to Evade Immune Recognition and Cause Disease","volume":"19","author":"Sirit","year":"2025","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1158\/2159-8290.CD-23-1529","article-title":"MARK2\/MARK3 Kinases Are Catalytic Codependencies of YAP\/TAZ in Human Cancer","volume":"14","author":"Klingbeil","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.chom.2021.04.006","article-title":"Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis","volume":"29","author":"Imai","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41575-022-00591-0","article-title":"The immune microenvironment in gastric adenocarcinoma","volume":"19","author":"Zavros","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4734","DOI":"10.1016\/j.cell.2021.08.003","article-title":"Spatially organized multicellular immune hubs in human colorectal cancer","volume":"184","author":"Pelka","year":"2021","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.ccell.2025.02.009","article-title":"Single-cell multi-stage spatial evolutional map of esophageal carcinogenesis","volume":"43","author":"Chang","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/s41590-022-01215-0","article-title":"Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression","volume":"23","author":"Yeo","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1126\/science.aaa6204","article-title":"T cell exclusion, immune privilege, and the tumor microenvironment","volume":"348","author":"Joyce","year":"2015","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/s41577-023-00884-8","article-title":"Localization, tissue biology and T cell state\u2014Implications for cancer immunotherapy","volume":"23","author":"Schenkel","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41419-025-07385-7","article-title":"Overcoming immunotherapy resistance in gastric cancer: Insights into mechanisms and emerging strategies","volume":"16","author":"Luo","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Gao, J.H., Lau, H.C.H., Fuhler, G.M., and Yu, J. (2026). Gastric microbiota-mediated immune remodelling in gastric cancer. Gut.","DOI":"10.1136\/gutjnl-2026-338505"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1172\/JCI130015","article-title":"Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells","volume":"130","author":"Palrasu","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Baj, J., Korona-Glowniak, I., Forma, A., Maani, A., Sitarz, E., Rahnama-Hezavah, M., Radzikowska, E., and Portincasa, P. (2020). Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells, 9.","DOI":"10.3390\/cells9041055"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2316266121","DOI":"10.1073\/pnas.2316266121","article-title":"MARK2 phosphorylates KIF13A at a 14-3-3 binding site to polarize vesicular transport of transferrin receptor within dendrites","volume":"121","author":"Han","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/bs.ctdb.2016.11.001","article-title":"Regulation of Cell Polarity by PAR-1\/MARK Kinase","volume":"Volume 123","author":"Jenny","year":"2017","journal-title":"Protein Kinases in Development and Disease"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nature05765","article-title":"Helicobacter pylori CagA targets PAR1\/MARK kinase to disrupt epithelial cell polarity","volume":"447","author":"Saadat","year":"2007","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/nsmb.1705","article-title":"Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates","volume":"17","author":"Miller","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nrc3601","article-title":"A central role for vesicle trafficking in epithelial neoplasia: Intracellular highways to carcinogenesis","volume":"13","author":"Goldenring","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"jcs260943","DOI":"10.1242\/jcs.260943","article-title":"Adaptations of membrane trafficking in cancer and tumorigenesis","volume":"137","author":"Evergren","year":"2024","journal-title":"J. Cell Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1111\/j.1349-7006.2008.00950.x","article-title":"Structural and functional diversity in the PAR1b\/MARK2-binding region of Helicobacter pylori CagA","volume":"99","author":"Lu","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"196","DOI":"10.2183\/pjab.93.013","article-title":"Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer","volume":"93","author":"Hatakeyama","year":"2017","journal-title":"Proc. Jpn. Acad. Ser. B-Phys. Biol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1136\/gutjnl-2020-321372","article-title":"European Registry on Helicobacter pylori management (Hp\u2013EuReg): Patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21,533 patients","volume":"70","author":"Nyssen","year":"2021","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1053\/j.gastro.2018.07.007","article-title":"Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions","volume":"155","author":"Savoldi","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.jare.2024.10.012","article-title":"Single-cell transcriptomic profiling uncovers cellular complexity and microenvironment in gastric tumorigenesis associated with Helicobacter pylori","volume":"74","author":"Li","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/s41596-024-01045-4","article-title":"CellChat for systematic analysis of cell-cell communication from single-cell transcriptomics","volume":"20","author":"Jin","year":"2025","journal-title":"Nat. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nmeth.4150","article-title":"Single-cell mRNA quantification and differential analysis with Census","volume":"14","author":"Qiu","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/41483","article-title":"The complete genome sequence of the gastric pathogen Helicobacter pylori","volume":"388","author":"Tomb","year":"1997","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1757-4749-6-5","article-title":"Genomic characterization of a Helicobacter pylori isolate from a patient with gastric cancer in China","volume":"6","author":"You","year":"2014","journal-title":"Gut Pathog."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7835","DOI":"10.1021\/acs.jcim.5c01063","article-title":"Recent Developments in Amber Biomolecular Simulations","volume":"65","author":"Case","year":"2025","journal-title":"J. Chem. Inf. Model."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/17\/3118\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:25:51Z","timestamp":1788773151000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/17\/3118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,6]]},"references-count":39,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["molecules31173118"],"URL":"https:\/\/doi.org\/10.3390\/molecules31173118","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,6]]}}}