RNF103 is an E3 ubiquitin-protein ligase functioning as an endoplasmic reticulum (ER)-localized RING-finger domain protein involved in ER-associated protein degradation (ERAD) 1. It recruits ubiquitin-conjugating enzymes (E2s) through its RING-H2 finger motif to facilitate ubiquitination of target proteins, with interaction selectivity partly governed by electrostatic interactions at the RING-finger interface 2. The protein is predominantly expressed in cerebellum and hippocampus 3, regions critical for emotional regulation and memory. Clinically, RNF103 has emerged as a novel biomarker for diabetic foot ulcers (DFU), where it is significantly downregulated in healed cases and linked to extracellular interactions essential for tissue repair and cellular communication 4. Additionally, genome-wide association studies identified RNF103 as associated with triglyceride levels in linkage analyses 5. The ERAD pathway function suggests RNF103's role in protein quality control, critical for neuronal homeostasis. Emerging evidence indicates KF-1 (RNF103's functional homologue designation) expression is upregulated following antidepressant treatment and may suppress anxiety-related behaviors through degradation of anxiety-promoting proteins in the prefrontal cortex and hippocampus 67. These findings position RNF103 at the intersection of protein quality control, metabolic regulation, and neuropsychiatric function.