FBXW2 (F-box and WD repeat domain containing 2) functions as a substrate recognition component of SCF-type E3 ubiquitin ligase complexes, directing multiple oncogenic proteins for proteasomal degradation 1. The protein acts as a broad-spectrum tumor suppressor across multiple cancer types by targeting distinct substrates: NF-κB p65 in breast cancer 1, EGFR in prostate cancer 2, β-catenin in lung and gastric cancers 34, Moesin in breast cancer 5, WASL in gastric cancer 6, and MSX2 in breast cancer 7. Mechanistically, FBXW2 binds to substrates through specific degron motifs and catalyzes their ubiquitination in cooperation with E2 enzyme UBE2D2 8, leading to their degradation and suppression of oncogenic signaling pathways including Wnt/β-catenin, NF-κB, and EGF-EGFR pathways. Clinically, FBXW2 downregulation is significantly associated with poor prognosis in breast, lung, prostate, and gastric cancers 136. FBXW2 overexpression inhibits tumor growth, metastasis, cancer stemness, and chemotherapy resistance in multiple cancer models 126, making it a promising therapeutic target for cancer treatment.