Vitexin targets USP49-GRPR deubiquitination axis in medullary thyroid carcinoma therapy.

Medullary thyroid carcinoma (MTC) is a rare, aggressive neuroendocrine malignancy with limited therapeutic options, often exhibiting resistance to targeted therapies. This study demonstrates that the natural flavonoid vitexin suppresses MTC progression by disrupting the deubiquitination axis involving USP49 and the gastrin-releasing peptide receptor (GRPR). GRPR, known to drive tumor growth in neuroendocrine cancers, promotes cell survival via the PI3K/AKT signaling pathway. We identified USP49 as a key regulator of GRPR protein stability in MTC, a previously unrecognized interaction where USP49 counteracts GRPR ubiquitination. Vitexin inhibits USP49, destabilizing GRPR. Consequently, vitexin treatment significantly reduced MTC cell proliferation, enhanced apoptosis, and impaired migration and invasion in vitro. Furthermore, vitexin markedly inhibited tumor growth in nude mouse xenograft models, correlating with decreased Ki67 expression and increased apoptotic markers (Tunel). Mechanistically, USP49 stabilizes GRPR by preventing its ubiquitin-mediated degradation; inhibiting USP49 with vitexin resensitizes tumors to apoptosis by destabilizing GRPR. These findings highlight the therapeutic potential of targeting post-translational modification pathways, specifically deubiquitination, in MTC. Vitexin represents a promising candidate agent for overcoming therapeutic resistance by disrupting GRPR-driven survival mechanisms. This work underscores the critical role of deubiquitination in MTC progression and offers a rationale for utilizing natural compounds to modulate GPCR stability in aggressive cancers.