FBXO27 (F-box protein 27) functions as a substrate-recognition component of SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complexes, with specialized roles in glycoprotein quality control and organellar homeostasis. 1 The protein recognizes and ubiquitinates denatured glycoproteins bearing complex-type N-linked oligosaccharides, with FBXO27 being one of five FBA family members (FBXO2, FBXO6, FBXO17, FBXO27, FBXO44) displaying differential glycan substrate specificity. 2 Distinctively, FBXO27 undergoes N-myristoylation, enabling membrane localization and rapid accumulation at damaged lysosomes. 1 Upon lysosomal damage, SCFFBXO27 ubiquitinates glycoproteins including LAMP1, LAMP2, VAMP3, and VAMP7, with LAMP2 ubiquitination preferentially enhancing autophagic machinery recruitment to damaged lysosomes to trigger lysophagy. 1 This mechanism integrates FBXO27 into the endoplasmic reticulum-associated degradation (ERAD) pathway and organelle-specific autophagy processes critical for maintaining cellular homeostasis. 3 Clinically, dysregulation of FBXO27 has been implicated in cardiac pathology, with F-box protein dysregulation exacerbating heart disease. 4 Additionally, FBXO27 was identified among key genes dysregulated in recurrent pregnancy loss associated with endoplasmic reticulum stress and unfolded protein responses. 5