FBXO48 is an orphan F-box ubiquitin E3 ligase component that functions as a critical negative regulator of AMPK signaling. As a component of the SCF ubiquitin ligase complex, FBXO48 targets phosphorylated AMPK-α (pAMPK-α) for polyubiquitylation and proteasomal degradation, thereby suppressing AMPK-dependent metabolic pathways 1. This mechanism distinguishes FBXO48 from typical AMPK activators that enhance kinase activation; instead, FBXO48 inhibition preserves activated AMPK by preventing its degradation 1. Functionally, FBXO48 inhibition promotes mitochondrial fission, facilitates autophagy, and improves hepatic insulin sensitivity in obesity models, suggesting therapeutic potential for metabolic disease 1. FBXO48 is a paralogue of FBXO7, which is mutated in Parkinson disease type 15 (PARK15) 2. Although FBXO48 localizes to the PARK3 disease locus (2p13.3), genetic screening of Chinese Han Parkinson disease patients identified no pathogenic FBXO48 mutations, suggesting limited direct involvement in Parkinson disease etiology 2. Recent medicinal chemistry efforts have identified FBXO48 inhibitors with superior AMPK-stabilizing properties compared to metformin, showing promise for treating obesity and type 2 diabetes through GDF15 upregulation 3.