FEM1B is a substrate-recognition component of the CRL2 (Cullin2-RING) E3 ubiquitin ligase complex that functions as a key regulator of cellular homeostasis through multiple mechanisms. Mechanistically, FEM1B recognizes C-degrons (C-terminal degradation signals) at the extreme C terminus of target proteins, with zinc ions acting as a molecular glue to facilitate substrate binding 1. The CRL2(FEM1B) complex specifically recognizes proteins ending with -Gly-Leu-Asp-Arg motifs and employs a bipartite mechanism recognizing both C-terminal proline and upstream aromatic residues 2. A critical function of FEM1B is sensing reductive stress through recognition of reduced cysteine residues in FNIP1, triggering its degradation to restore mitochondrial ROS production and maintain redox homeostasis 34. FEM1B also regulates mitochondrial dynamics by controlling PLD6 turnover through interaction with the mitochondrial import receptor TOM20 5. Additionally, FEM1B mediates degradation of multiple substrates including GLI1, SLBP, and ANKRD37, and functions in replication stress responses by facilitating CHK1 activation through Rad9 recruitment 6. Clinically, FEM1B dysfunction is associated with neurodevelopmental disorders with behavioral, ear, and skeletal abnormalities 1. Tight regulation of FEM1B activity is essential; gain-of-function mutations produce developmental syndromes similar to BEX deletion, underscoring the importance of balanced zinc-dependent reductive stress signaling for organismal homeostasis.