Both TRULI and DAPA may serve as anti-OA drugs by modulating ZBTB20 to restore ECM homeostasis

Due to the existing challenges in modulating the activity of transcription factors directly, comprehending the upstream regulatory mechanism can offer perspectives for tackling these obstacles. Our observations that in early-stage OA chondrocytes ZBTB20 translocates into nucleus in a LATS1-dependent manner, triggers NF-κB signaling and enhances ECM degradation, leads us to consider different approaches to restore ECM balance: either by inhibiting LATS1 to impede ZBTB20 activity or by directly reducing ZBTB20 expression. The small molecular compound TRULI can block the nucleus accumulation of ZBTB20 via inhibiting LATS1 phosphorylation, and DAPA was identified as a proposing drug targeting Zbtb20.Our results demonstrated that pharmacologic blockade of LATS1 by TRULI, as well as inhibition of Zbtb20 expression by DAPA, restored the ECM homeostasis in chondrocytes and minimized matrix degradation in human articular cartilage explants.