Osteoarthritis (OA) is the most prevalent degenerative joint disorder and an important cause of limiting adult activity [1]. Its incidence has risen dramatically due to high rates of joint trauma, population aging, muscle weakness, and soaring rates of obesity [2], imposing a grievous burden of society costs and health care [3]. Low-grade chondrocyte inflammation plays a pivotal role in OA progression [4]. The treatment of OA can only relieve the pain symptoms but fail to reverse cartilage damage [5]. For patients with severe OA, the sole option to improve quality of life is joint replacement [6]. Hence, discovering novel therapeutic strategies to modify OA progression remains critically important.

Inflammation is a key driver of OA initiation and development [1]. Pyroptosis, a programmed cell death, has been implicated in various inflammatory diseases, including diabetes [7], pulmonary fibrosis [8], Parkinson's disease [9], and OA [10]. NLRP3 inflammasome plays a central role in this process by activating Caspase 1, which cleaves GSDMD and triggers the release of IL-1β and IL-18 [11]. Importantly, inhibiting NLRP3 inflammasome-mediated chondrocyte pyroptosis helps preserve extracellular matrix (ECM) homeostasis and reduces inflammation in chondrocytes, thereby attenuating the progression of OA [12]. Thus, targeting chondrocyte pyroptosis is at the core of strategy for OA prevention.

Formyl peptide receptor 3 (FPR3), a G protein-coupled receptor, plays diverse roles in inflammation [13], angiogenesis [14], and carcinogenesis [15]. As previously revealed, FPR3 regulates glycolytic reprogramming and stemness via calcium-NFATc1 pathway in gastric cancer [16]. In allergic immune responses, it mediates Th2 polarization [17]. In Helicobacter pylori infection, it promotes eosinophil migration to gastric mucosa [18]. However, the impact of Fpr3 on OA pathogenesis remains unexplored.

This study utilized mice and cell experiments to investigate the effects of Fpr3 on OA development. The Fpr3 accelerated OA progression by promoting ECM degradation and activating chondrocyte pyroptosis.