Fig. 4.

Ferroptosis triggers osteoarthritis. Cartilage loss in osteoarthritis is primarily due to an imbalance between the anabolic activity of chondrocytes (including the secretion of extracellular matrix elements, such as type II collagen and proteoglycans, which is reduced in osteoarthritis) and catabolic activity (activity of extracellular matrix-catabolic enzymes, such as matrix metalloproteinases and collagenases, which is upregulated in osteoarthritis). Subchondral bone remodeling is another key characteristic of osteoarthritis. The release of various mediators and the increase in bone resorption are driven by the activation of osteoclasts in subchondral bone, while some pro-catabolic mediators are also released by osteocytes or osteoblasts. Macrophages and fibroblasts in the synovium can secrete mediators (e.g., proinflammatory cytokines) that diffuse into articular cartilage and lead to cartilage damage. Iron overload in chondrocytes causes increased intracellular ROS levels and downregulation of GPX4, which further increases the sensitivity of chondrocytes to oxidative stress; promotes the release of inflammatory factors, such as IL-1β, and matrix metalloproteinases, such as MMP13; aggravates extracellular matrix degradation; and accelerates the progression of osteoarthritis. Created with BioRender.com