The Emerging Role of UCHL1 in Neurological and Musculoskeletal Diseases

Abstract

Ubiquitin C‐terminal hydrolase L1 (UCHL1) is a highly conserved deubiquitinating enzyme that has transitioned from being viewed as a “brain‐specific” protein to a global regulator of cellular proteostasis and signal transduction. As a key component of the ubiquitin‐proteasome system (UPS), UCHL1 maintains the intracellular free ubiquitin pool through its C‐terminal hydrolase activity, while also exhibiting atypical ligase‐like functions and acting as a molecular scaffold for signaling complexes. Beyond its classical role in neurons, increasing evidence suggests that UCHL1 participates in diverse pathological conditions including neurodegeneration, cancer, cardiovascular and metabolic diseases, as well as musculoskeletal disorders. Through regulation of protein turnover, oxidative stress, inflammatory signaling, and cell survival, UCHL1 emerges as a context‐dependent regulator with dual protective and pathogenic roles. This review explores the sophisticated multi‐level regulation of UCHL1, ranging from transcriptional control to epigenetic silencing and posttranslational modifications, summarizes the recent research progress of UCHL1 in various systems, and elaborates on its mechanism of action in various conditions, including neurological and musculoskeletal disorders.