{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:46:37Z","timestamp":1785818797959,"version":"3.56.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gastric cancer (GC) constitutes a substantial global public health challenge, and the lack of tractable molecular targets limits therapeutic progress. Mesoderm-Specific Transcript (MEST) has been implicated in tumor-related signaling, yet its functional role and druggability in GC remain undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The analyses of GC tissue microarrays and cohorts were performed to evaluate MEST expression and its clinical significance. CRISPR\/Cas9-mediated MEST knockout was used to characterize its oncogenic functions in GC cells and xenograft models. Integrated RNA sequencing and pathway analysis was utilized to elucidate signaling pathways under the regulation of MEST. A structure-guided virtual screen combined with SPR binding and phenotypic assays were employed to discover small molecules targeting MEST. The therapeutic effects and mechanism of the lead compound were evaluated using GC cell lines, patient-derived organoids, cell-derived xenograft (CDX), and patient-derived xenograft (PDX) models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>MEST expression in GC tissues was elevated and linked to poor prognosis. Functionally, genetic ablation of MEST impaired GC cell proliferation, invasion, migration, and suppressed tumor growth in CDX models. Screening of approved-compound libraries identified cobicistat as a previously unrecognized high-affinity candidate MEST-inhibitory compound. Cobicistat suppressed tumor growth across a panel of preclinical GC models, including cell lines, organoids, CDX and PDX. Mechanistically, MEST may drive GC progression by activating the NF-\u03baB pathway, whereas cobicistat may antagonize MEST binding and blocked NF-\u03baB pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MEST functions as a key oncoprotein driving GC progression via NF-\u03baB activation. Cobicistat, a candidate MEST-inhibitory compound, exhibits favorable preclinical efficacy and safety, providing a promising candidate for targeted GC therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1901635","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:27:05Z","timestamp":1785817625000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting MEST using cobicistat as a therapeutic strategy for gastric cancer through suppressing NF-\u03baB signaling"],"prefix":"10.3389","volume":"16","author":[{"given":"Hongtai","family":"Cao","sequence":"first","affiliation":[{"name":"Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huili","family":"Ye","sequence":"additional","affiliation":[{"name":"Cuiying Biomedical 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