FBXO44 is a substrate-recognition component of two distinct E3 ubiquitin ligase complexes: the SCF(FBXO44) complex (containing SKP1-CUL1-FBXO44) and the CUL4B-DDB1-FBXO44 complex 12. These complexes mediate ubiquitination and proteasomal degradation of multiple protein substrates, including BRCA1 3, RGS2 2, and FOXP1 4. In cancer biology, FBXO44 plays context-dependent roles: it suppresses repetitive element transcription post-DNA replication by recruiting SUV39H1 and chr1 remodeling complexes to H3K9me3-marked nucleosomes, and inhibiting this function induces DNA replication stress and viral mimicry in cancer cells 5. Conversely, FBXO44 promotes colorectal and esophagogastric adenocarcinoma progression by degrading the tumor suppressor FOXP1 via AURKA-dependent phosphorylation, leading to upregulation of Cyclin E2 and enhanced cell proliferation 46. FBXO44 expression inversely correlates with replication stress and antiviral signaling, with elevated FBXO44 levels associated with poor cancer prognosis 5. Beyond cancer, FBXO44 dysregulation contributes to cardiac homeostasis imbalance and represents a potential therapeutic target in heart diseases 7. These findings identify FBXO44 as a critical regulator of protein stability with dual roles in cancer suppression and progression depending on cellular context.