YTHDF3 Stabilizes the Expression of m6A ‐Mediated LRRC17 and Induces Osteoarthritic Chondrocyte Senescence by Activating the STAT1 Signaling

Background Osteoarthritis (OA) is a common chronic, degenerative joint disease, that is the main cause of joint pain or loss of mobility in the elderly. Previous studies have found that LRRC17 and YTHDF3 are highly expressed in OA, but the molecular mechanisms by which they regulate OA progression remain unclear. This study investigated the mechanism by which LRRC17 and YTHDF3 regulate OA progression and their interaction. Methods Cartilage tissues from patients undergoing total knee arthroplasty were collected for chondrocyte isolation and culture. Quantitative reverse transcription PCR (qRT‐PCR) and western blot (WB) were utilized to examine the expression of YTHDF3 and LRRC17 in OA chondrocytes. Senescence‐associated β‐galactosidase (SA‐β‐gal) staining was conducted to detect cellular senescence. 2,7‐Dichlorodihydrofluorescein diacetate (DCFH—DA) staining was conducted to detect the reactive oxygen species (ROS) level of cartilage cells. The mitochondrial membrane potential of chondrocytes was detected by the JC‐1 kit. WB was conducted to detect the expression of senescence‐related proteins and STAT1. RNA immunoprecipitation (RIP) and immunofluorescence (IF) were used to detect the binding of LRRC17 to YTHDF3. Results LRRC17 is up‐regulated in OA chondrocytes, and knockdown of LRRC17 inhibits chondrocyte senescence. LRRC17 promotes chondrocyte senescence by activating the STAT1 signaling pathway. YTHDF3 stabilizes LRRC17 mRNA. Knockdown of YTHDF3 inhibited chondrocyte senescence, decreased ROS levels, upregulated mitochondrial membrane potential ratios, and inhibited STAT1, while overexpression of LRRC17 reversed these effects. Conclusions YTHDF3 stabilizes the expression of m6A‐mediated LRRC17 and induces OA chondrocyte senescence by activating the STAT1 signaling.