Gut microbiota metabolite Urolithin B inhibits chondrocyte ferroptosis by rewriting iron homeostasis via FGFR3/NCOA4/FTH1 axis, alleviating osteoarthritis

Background

Osteoarthritis (OA) is a prevalent chronic disease characterized by articular cartilage degeneration. The lack of safe and effective therapies has made OA a leading global cause of disability, severely impacting patient quality of life. Urolithin B (UB), a bioactive metabolite derived from gut microbiota processing of ellagic acid, exhibits potent antioxidant and anti-inflammatory properties, positioning it as a promising therapeutic candidate for OA. However, the precise mechanisms by which UB inhibits OA progression remain unknown.

Purpose

This study aimed to evaluate the therapeutic potential of UB for OA and elucidate its underlying mechanisms of action.

Methods

The therapeutic effects of UB on OA were assessed using interleukin-1β (IL-1β)-induced chondrocyte models and rats subjected to anterior cruciate ligament transection (ACLT). Integrated transcriptome analysis was employed to comprehensively investigate the relevant mechanisms. Fibroblast growth factor receptor 3 (FGFR3)-specific small interfering RNA (siRNA) and overexpression plasmids were utilized in vitro to validate the role of FGFR3 as a specific downstream target of UB and its functional significance in osteoarthritis progression. Furthermore, FGFR3 gene knockdown was performed in UB-treated ACLT rats to confirm the critical role of both UB and its downstream target, FGFR3.

Results

This study reports the novel discovery that UB significantly mitigates IL-1β-induced extracellular matrix degradation and alleviates OA progression through a previously unrecognized mechanism involving iron homeostasis regulation. Mechanistically, we demonstrate that UB inhibits chondrocyte ferroptosis by upregulating FGFR3 expression, which suppresses ferritinophagy by disrupting the interaction between nuclear receptor coactivator 4 (NCOA4) and ferritin heavy chain 1 (FTH1). Our findings establish the novel protective role of the FGFR3/NCOA4/FTH1 signaling axis in chondrocytes under inflammatory conditions by restoring iron homeostasis.

Conclusions

We identified FGFR3 as a novel therapeutic target for the prevention and alleviation of OA. The validation of UB as a functional agonist of FGFR3, revealing its potential as a new therapeutic candidate and providing a new perspective for combating OA.