Osteoarthritis (OA) is a prevalent degenerative joint disorder featured by articular cartilage deterioration, synovitis, subchondral bone remodeling and osteophyte formation [1]. With the global population aging, the prevalence of OA is rising steadily, affecting approximately 600 million people worldwide and imposing a substantial economic burden on healthcare systems [2]. Current treatment strategies for OA primarily focus on symptom relief rather than targeting the underlying disease mechanisms [3]. Therefore, elucidating the pathological processes driving OA progression and developing effective disease-modifying interventions are of critical importance.

Growing evidence has demonstrated that dysregulation of iron metabolism in chondrocytes is closely associated with the OA progression [4]. Specifically, iron overload disrupts redox homeostasis and induces oxidative stress, leading to lipid peroxidation of cellular membranes and ultimately triggering ferroptosis in chondrocytes [5]. Consequently, ferroptosis has emerged as a promising therapeutic target for chondroprotection in OA. For instance, overexpression of growth factor independence 1 (Gfi1) has been shown to inhibit chondrocyte ferroptosis and attenuate OA development [6]. The p53/SLC7A11 signaling axis represents a key regulatory pathway of ferroptosis under pathological conditions [7]. When iron is overload, activated transcription of TP53 represses SLC7A11expression, resulting in reduced cystine uptake and depletion of intracellular glutathione [8]. This cascade directly impairs GPX4 activity, leading to sustained accumulation of lipid peroxides and subsequent induction of ferroptosis [9]. Therefore, targeting P53-mediated ferroptosis in chondrocytes may represent a viable therapeutic strategy to mitigate OA progression.

Natural products serve as a vital source for drug discovery, and among them, flavonoids represent a major class that has garnered considerable attention for their therapeutic potential in chronic inflammatory diseases due to their anti-inflammatory and antioxidant properties [10]. Recent studies have demonstrated the potential of the flavonoid icaritin in promoting bone regeneration and facilitating fracture repair [11,12], highlighting the therapeutic promise of traditional Chinese medicine (TCM) in managing orthopedic disorders. Isoquercitrin (ISO), a natural flavonoid extracted from various edible and medicinal plants, exhibits a broad spectrum of biological activities, including anti-inflammatory, antioxidant, and anti-apoptotic effects [13]. Notably, ISO has been shown to inhibit apoptosis in high glucose-induced endothelial cells by promoting proteasomal degradation of the P53 protein [14]. Furthermore, ISO ameliorates diabetic retinopathy by suppressing P53-mediated ferroptosis [15]. However, the regulatory role of ISO in chondrocyte ferroptosis during OA and the underlying molecular mechanisms remain to be fully elucidated.

In this study, we investigate whether ISO alleviates tert‑butyl hydroperoxide (TBHP)-induced chondrocyte ferroptosis by targeting P53. Furthermore, the protective effects of ISO are evaluated in a rat model of OA induced by anterior cruciate ligament transection (ACLT). Our findings may provide a potential food-derived therapeutic agent for the clinical management of OA.