Urolithin A attenuates apoptosis and ferroptosis in hyperlipidemic tenocytes through PPARδ/ALDH2-mediated antioxidative signaling

Abstract

Urolithin A (URA), a product of the gut microflora from foods rich in ellagitannins found in berries and nuts, has demonstrated anti-inflammatory and antioxidative stress properties in various disease models. Ferroptosis, an iron-dependent form of cell death, is considered a pathogenic cause of tendinopathy. However, the effects of URA on hyperlipidemic tenocytes and the related molecular mechanisms for the treatment of tendinopathy have not been elucidated. The expression of various proteins in human primary tenocytes was assessed via Western blot analysis. Tenocyte reactive oxygen species (ROS) were detected via DCFDA staining. Apoptotic tenocytes were visualized via TUNEL staining. The activities of antioxidant enzymes and caspase 3 were measured via activity assays. Cell viability was examined via the MTT assay. In this study, we found that URA treatment blocked ferroptosis and apoptosis and improved oxidative stress in palmitate-treated tenocytes. Moreover, URA treatment reversed the changes in the expression of extracellular matrix (ECM) markers and impaired cell migration. siRNA targeting PPARδ or ALDH2 abrogated the effects of URA on tenocytes treated with palmitate. Additionally, treatment of tenocytes with URA increased SOD and catalase activities. These results suggest that URA ameliorates tenocyte ferroptosis and apoptosis through PPARδ/ALDH2 signaling-mediated suppression of oxidative stress. By utilizing natural bioactive compounds derived from renewable dietary sources, this study highlights a potential therapeutic avenue for treating obesity-related tendinopathy while emphasizing the importance of sustainable, health-promoting interventions.