FBXL3 is a substrate recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex that plays a critical role in circadian rhythm regulation 1. The complex primarily functions in the nucleus to mediate ubiquitination and proteasomal degradation of cryptochrome proteins CRY1 and CRY2, which are essential negative regulators of the circadian clock 2. Loss of FBXL3 function leads to CRY protein stabilization, causing global transcriptional repression of circadian genes and lengthened circadian periods 2. Beyond circadian control, FBXL3 and CRY2 cooperatively target the oncogenic transcription factor c-MYC for degradation at phosphorylated T58 residues 3, linking circadian regulation to cell proliferation control. Additionally, CRY proteins function as cofactors for FBXL3 in degrading other substrates including cell cycle regulator TLK2 4. Clinically, biallelic loss-of-function FBXL3 variants cause syndromic autosomal recessive intellectual disability characterized by developmental delay, short stature, and mild facial dysmorphism 5. FBXL3 also displays tumor suppressive functions in non-small cell lung cancer, where its expression is downregulated by miRNA-4735-3p 6.