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Here, we identified alpha\u2010L\u2010fucosidase 2 (FUCA2) as a crucial driver of LUAD by preventing cellular senescence. Mechanistically, through the restriction of fucosyltransferase 3 (FUT3)\u2010mediated \u03b1\u20101,3\u2010fucosylation of ErbB3 at Asn437, FUCA2 safeguarded ErbB3\u2013ErbB2 heterodimerization to promote ErbB3 activation and sustain persistent AKT signaling. Active AKT prevented p53 protein stabilization in TP53\u2010wild\u2010type LUAD cells and inhibited p27 protein accumulation in TP53\u2010mutant LUAD cells, thereby counteracting senescence and supporting malignant growth. Notably, low\u2010dose Capivasertib, an AKT inhibitor targeting tumors with PIK3CA\/AKT1\/PTEN mutation(s), induced senescence selectively in FUCA2\u2010high LUAD irrespective of PIK3CA\/AKT1\/PTEN\/TP53 mutational status, and its combination with the nutraceutical senolytic procyanidin C1 achieved potent and low\u2010toxicity suppression of LUAD across multiple preclinical models. Together, our results uncover the FUCA2\u2013ErbB3 fucosylation\u2013AKT pathway as a central regulator of senescence and propose a FUCA2\u2010guided drug repurposing strategy for LUAD.<\/jats:p>","DOI":"10.1002\/advs.202523667","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T09:54:30Z","timestamp":1781603670000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FUCA2 Sustains AKT Signaling and Suppresses Senescence by Antagonizing FUT3\u2010Mediated ErbB3 Fucosylation in Lung Adenocarcinoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Lu","family":"Chen","sequence":"first","affiliation":[{"name":"Cancer Research Center School of Medicine Xiamen University  Xiamen China"},{"name":"National Institute for Data Science in Health and Medicine School of Medicine Xiamen University  Xiamen 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