Targeting WWP1 ameliorates osteoarthritis by suppressing KLF15 ubiquitination to restore mtDNA and mitochondrial function.

Osteoarthritis (OA), the most prevalent chronic joint disease and a leading cause of disability, is mechanistically linked to mitochondrial dysfunction in its pathogenesis. This study aimed to elucidate the regulatory role and therapeutic potential of the WWP1/KLF15/TFAM signaling axis in OA-associated mitochondrial impairment. We demonstrate that in OA chondrocytes, the E3 ubiquitin protein ligase 1 (WWP1) promotes ubiquitination and degradation of the transcription factor KLF15, reducing its protein stability. The krüppel-like factor 15 (KLF15) directly binds to the promoter of the mitochondrial transcription factor A (TFAM) and activates its transcription. Under OA conditions, TFAM expression is downregulated; restoring TFAM expression significantly enhances mitochondrial DNA (mtDNA) transcription and replication, upregulates mitochondrial-encoded genes, repairs mitochondrial membrane potential (ΔΨm), and reduces superoxide levels, thereby improving mitochondrial function and reversing metabolic dysregulation in chondrocytes. In conclusion, our findings reveal that WWP1 impairs mtDNA biogenesis by mediating KLF15 ubiquitination and degradation, leading to suppressed TFAM transcription. This results in reduced expression of mitochondrial-encoded genes and mitochondrial dysfunction, which collectively exacerbate OA pathogenesis. These insights identify the WWP1/KLF15/TFAM axis as a promising therapeutic target for OA.