{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:27:31Z","timestamp":1787146051353,"version":"build-2736575974"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"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:p>YWHA\/14-3-3 proteins are conserved phosphoserine\/phosphothreonine-binding adaptors that coordinate signaling-complex assembly, subcellular localization, stress responses and cell-state transitions. Although often discussed as a single adaptor family, colorectal cancer (CRC) studies suggest that individual YWHA isoforms act through distinct clients, RNA-associated layers and tumor-state contexts. In this narrative and mechanistic review, we synthesized PubMed-indexed CRC literature through 18 May 2026 and appraised CRC-relevant mechanistic modules using an explicit evidence-maturity rubric developed by the authors distinct from formal GRADE assessment. We propose an isoform\u2013client\u2013context framework for interpreting 14-3-3 biology in CRC. YWHAG has been linked to CTTN-dependent Wnt\/\u03b2-catenin activation, whereas YWHAE\/14-3-3\u03f5 protein has been associated with extracellular-vesicle secretion and EV-associated \u03b2-catenin\/Wnt outputs. Separately, the YWHAE-encoded lncRNA, hereafter referred to as\u00a0YWHAE lncRNA, has been proposed to activate KRAS\/ERK and PI3K\/AKT signaling\u00a0through a competing endogenous RNA mechanism. YWHAZ participates in epithelial\u2013mesenchymal and G2\/M transitions through\u00a0miR-1-3p- and TRIP13-associated mechanisms. YWHAB supports PIK3R2-dependent PI3K\/AKT signaling,\u00a0whereas YWHAH connects NAT10\/ac4C\u00a0regulation, CD8+ T-cell exhaustion\u00a0and\u00a0MAPK\/ERK-dependent autophagy-associated invasion. SFN illustrates\u00a0context-dependent tumor-suppressive or stress-adaptive functions. Overall,\u00a0total\u00a014-3-3\u00a0abundance is insufficient for mechanistic or translational interpretation.\u00a0Interactomics, phosphoproteomics, spatial profiling, extracellular-vesicle analysis\u00a0and patient-derived models should be used to prioritize YWHA-dependent candidate mechanisms for functional validation. These modules should currently be regarded as testable biomarker and therapeutic hypotheses, not as clinically validated CRC biomarkers or targets.<\/jats:p>","DOI":"10.3389\/fonc.2026.1906093","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T12:56:11Z","timestamp":1787144171000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Isoform-resolved 14-3-3\/YWHA networks in colorectal cancer: phospho-adaptor mechanisms, biomarker contexts and therapeutic opportunities"],"prefix":"10.3389","volume":"16","author":[{"given":"Qian","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shandong Provincial Third Hospital, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of 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