DCLK1-dependent NF-κB activation mediates p-STAT3-induced osteoarthritis progression

Osteoarthritis (OA) is a widespread degenerative joint disorder marked by irreversible cartilage destruction. While signal transducer and activator of transcription 3 (STAT3) is recognised as a pivotal regulator in its pathogenesis, the downstream regulatory cascades of phosphorylated STAT3 (p-STAT3) in chondrocyte extracellular matrix (ECM) metabolism remain elusive. Our study sought to identify p-STAT3-mediated novel pathways driving OA.

P-STAT3 expression was detected in human/mouse OA cartilage. Chondrocyte-specific STAT3 knockout mice (Stat3^fl/fl; Col2a1^CreERT2) were first constructed and used to evaluate OA (spontaneous/surgically induced). RNA sequencing combined with cleavage under targets and tagmentation sequencing (CUT&Tag-seq) identified p-STAT3 downstream targets, followed by molecular interaction and pathway validation assays.

P-STAT3 was significantly upregulated in OA cartilage. STAT3 knockout ameliorated OA progression. Mechanistically, p-STAT3 directly bound the doublecortin-like kinase 1 (DCLK1) promoter to activate its transcription. DCLK1 interacted with IKKβ, promoting IKKβ phosphorylation and NF-κB activation, ultimately upregulating MMP13 and downregulating COL2A1.

This study identifies a novel p-STAT3/DCLK1/IKKβ/NF-κB axis that regulates cartilage matrix metabolism and OA progression, suggesting new therapeutic targets for OA intervention.

Doublecortin-like kinase 1 (DCLK1) is identified as a novel phosphorylated signal transducer and activator of transcription 3 (p-STAT3) transcriptional target. A novel p-STAT3/DCLK1/IKKβ/NF-κB axis regulates chondrocyte extracellular matrix (ECM) metabolism and drives osteoarthritis progression. Genetic and pharmacological translational evidence validates the p-STAT3/DCLK1 axis as a prospective therapeutic target against osteoarthritis.