PFHxS exposure causes osteoarthritis through the innate immune signaling pathway mediated by lipid peroxidation

PFHxS have been widely used and detected in the environment. The toxicological effects of PFHxS exposure on cartilage tissues and cells are not fully clear. The objective of this work was to study the toxicological effects of PFHxS on cartilage. We investigated these effects using both in-vitro and in-vivo models. In the in-vitro model, we exposed chondrocytes to environmentally relevant concentrations of PFHxS. In the in-vivo model, we assessed cartilage damage using various staining methods, including toluidine blue, alcian blue, and safranin-fast green staining. In chondrocytes, PFHxS exposure decreased cell viability and induced inflammatory and oxidative stress responses.Further experiments showed that PFHxS induced lipid peroxidation, increased Fe²⁺ levels, and significantly decreased the expression of GPX4 and xCT, indicating the induction of ferroptosis. Oxidative stress also led to large-scale production of ds-DNA and activation of the cGAS-STING signaling pathway.In the in-vivo model, PFHxS exposure caused damage to cartilage tissues, as evidenced by the tissue staining.Similarly, in vivo findings showed that PFHxS induced ferroptosis-like characteristics in cartilage tissues, including decreased GPX4 and xCT and increased iron ion levels. This study is the first to reveal that the environmental pollutant PFHxS causes extracellular matrix degradation and functional damage to chondrocytes by inducing ferroptosis and activating the cGAS-STING inflammatory pathway. These findings establish a theoretical basis for a potential association between PFHxS environmental exposure and cartilage-degenerative diseases.