CircZSWIM6 Mediates Dysregulation of ECM and Energy Homeostasis in Ageing Chondrocytes Through RPS14 Post‐translational Modification

Abstract Background Circular RNAs (CircRNAs) are important and have different roles in disease progression. Herein, we aim to elucidate the roles of a novel CircRNA (CircZSWIM6) which is upregulated in ageing chondrocytes. Methods We verified the roles of CircZSWIM6 in senescent and osteoarthritis (OA) development in vitro through CircZSWIM6 knockdown and overexpression. RNA pulldown assay and RNA binding protein immunoprecipitation were performed to identify the interaction between CircZSWIM6 and Ribosomal protein S14 (RPS14). The roles of CircZSWIM6 in ageing‐related OA were also confirmed in non‐traumatic and traumatic model respectively. Results CircZSWIM6 regulates extracellular matrix (ECM) and energy metabolism in ageing chondrocyte. Mechanistically, CircZSWIM6 competitively bound to the E3 ligase STUB1 binding site on RPS14 (K125) to inhibit proteasomal degradation of RPS14 to maintain RPS14 function. CircZSWIM6‐RPS14 axis is highly associated with AMPK signaling transduction, which keeps energy metabolism in chondrocyte. Furthermore, CircZSWIM6 AAV infection leads to senescent and OA phenotypes in a non‐traumatic model and accelerates OA progression in a traumatic model. Conclusion Our results revealed a significant role of CircZSWIM6 in age‐related OA by regulating ECM metabolism and AMPK‐associated energy metabolism. We highlight the CircZSWIM6‐RPS14‐PCK1‐AMPK axis is a potential biomarker for OA.