FBXL6 is an E3 ubiquitin ligase component of the SCF complex that functions as a substrate-recognition protein mediating polyubiquitination and proteasomal degradation of diverse cellular targets. In cancer contexts, FBXL6 is aberrantly upregulated and drives tumorigenesis through multiple mechanisms: it promotes K63-linked polyubiquitination of KRAS and KRASG12D at lysine 128, activating MEK/ERK/mTOR signaling in hepatocellular carcinoma (HCC) 1; mediates K63-linked polyubiquitination of ATAD3A to promote metabolic reprogramming in triple-negative breast cancer 2; targets transketolase (TKT) to activate immune evasion pathways in HCC metastasis 3; degrades phosphorylated p53 to suppress tumor suppression in colorectal cancer 4; and ubiquitinates CDKN1C/p57Kip2 to drive lung adenocarcinoma progression 5. Beyond cancer, FBXL6 regulates quality control of newly synthesized mitochondrial ribosomal proteins, with FBXL6 knockout cells showing mitochondrial protein aggregation and impaired mitochondrial metabolism 6. FBXL6 overexpression also promotes keloid fibroblast proliferation via c-MYC induction 7. Elevated FBXL6 expression correlates with poor prognosis across multiple cancer types including ovarian cancer 8, positioning it as a promising therapeutic target for cancer treatment.