EVs-MSC alleviate RA progression via USP21-dependent BRD2 stabilization to regulate autophagy in FLS

Rheumatoid arthritis (RA) is characterized by aggressive synovial hyperplasia and joint destruction, driven largely by apoptosis-resistant fibroblast-like synoviocytes (RA FLS). While mesenchymal stem cell-derived extracellular vesicles (EVs-MSC) show therapeutic potential, their natural limitations-such as low targeting specificity and insufficient bioactive cargo-hinder clinical efficacy. This study identifies USP21 as a critical regulator of autophagy homeostasis in RA FLS and develops USP21-enriched EVs-MSC (EVs-MSC) to enhance therapeutic outcomes. Multi-omics screening revealed that USP21, a deubiquitinating enzyme, is significantly downregulated in TNFα-stimulated RA FLS. USP21 directly binds and stabilizes BRD2 by cleaving K48-linked ubiquitin chain, preventing its proteasomal degradation. Loss of USP21 disrupts autophagy balance, increasing LC3-II/Beclin1 while reducing p62, whereas EVs-MSC restore homeostasis. In a collagen-induced arthritis (CIA) model, EVs-MSC mitigated synovial hyperplasia, oxidative stress, and joint damage, whereas USP21-deficient EVs-MSC failed to confer protection. These findings establish USP21 as a molecular switch regulating autophagy in RA FLS and demonstrate that EVs-MSC offer a promising therapeutic strategy for RA, providing a theoretical basis for subsequent clinical validation.