RNF111 is an E3 ubiquitin ligase that functions primarily as a regulator of TGF-β and BMP signaling pathways. It enhances transcriptional responses of SMAD2 and SMAD3 effectors by mediating ubiquitination and proteasomal degradation of SMAD inhibitors such as SMAD7, thereby amplifying signaling output. RNF111 also couples SMAD activation with their own degradation, ensuring temporal control of pathway activity. Additionally, RNF111 acts as a SUMO-targeted ubiquitin ligase, catalyzing Lys-63-linked ubiquitination of sumoylated substrates including XPC during nucleotide excision repair following UV irradiation 1. Clinically, RNF111 has emerged as relevant to female reproductive function. Monoallelic deleterious variants in RNF111 impair female fertility and induce premature ovarian insufficiency (POI), accounting for 0.78% of POI cases in one cohort, with pathogenic variants identified in patients with diminished ovarian reserve 2. Both heterozygous missense and null mutations in mouse models exhibit reduced litter sizes and diminished ovarian reserve, with dysregulation of BMP signaling in ovaries. Beyond reproductive disease, circular RNA derived from RNF111 (circ-RNF111) contributes to cancer progression in ovarian cancer, gastric cancer, and salivary adenoid cystic carcinoma through microRNA sponging mechanisms 34. Selective estrogen receptor degraders utilize RNF111-mediated degradation of nuclear hormone receptors, positioning RNF111 as a therapeutic target in hormone-driven malignancies 5.