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The ubiquitin‑proteasome system, a key protein degradation machinery in humans, mediates substrate recognition and proteolysis through ubiquitin‑tagged targeting of macromolecular proteins to the 26S proteasome. This evolutionarily conserved system orchestrates fundamental cell processes, including cell cycle progression, DNA damage repair, immune regulation, signal transduction and clearance of misfolded proteins. Its functional integrity is involved in the pathogenesis of various malignancies (breast and small cell lung cancer and colorectal adenocarcinoma) and degenerative diseases (Parkinson's disease). As a really interesting new gene‑type E3 ubiquitin ligase, ring finger protein (RNF)40 has emerged as a key regulator of both physiological homeostasis and disease progression. The present review systematically examines RNF40 structural architecture and its multifaceted roles in ubiquitination‑dependent proteostasis, epigenetic modulation and DNA repair mechanisms, as well as its tumor‑specific regulatory networks across cancer subtypes and therapeutic potential as a novel drug target.