Psoralen promotes SOCS5 to inhibit JAK/STAT3 to alleviate cartilage degeneration in knee osteoarthritis.

Abstract

BACKGROUND: Knee osteoarthritis (KOA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction. Bushen Qiangjin Capsule (BSQJ) is a clinically used traditional medicine for KOA, yet its active ingredients and mechanisms of action remain unclear. PURPOSE: This study aimed to identify the key active ingredient in BSQJ and investigate its therapeutic target and mechanism against KOA. MATERIALS AND METHODS: We integrated bioinformatics analysis of GEO datasets with molecular docking to pinpoint key targets. The therapeutic effects of the identified compound, psoralen, were then validated in a rat model of KOA using micro-CT, gait analysis, and histological staining. The mechanism was further investigated in LPS-induced chondrocytes and via siRNA silencing. RESULTS: Bioinformatics analysis identified 13 upregulated proteins and 12 downregulated proteins in KOA and SOCS5 as a key diagnostic target for KOA. Psoralen, a primary active ingredient in BSQJ, exhibited strong binding to SOCS5. In KOA rats, psoralen treatment significantly improved gait abnormalities, reduced subchondral bone sclerosis, and promoted cartilage repair. In vitro, psoralen reversed the imbalance in extracellular matrix (ECM) synthesis and enhanced chondrocyte proliferation. Mechanistically, psoralen exerted its effects by upregulating SOCS5, thereby downregulating JAK and phosphorylation of STAT3. CONCLUSION: Our findings demonstrate that psoralen is a key therapeutic component of BSQJ for KOA treatment. It alleviates cartilage degeneration by targeting SOCS5 and modulating the JAK-STAT3 pathway, thereby restoring chondrocyte metabolic homeostasis. This study provides a pharmacological basis for psoralen as a promising candidate drug for KOA.