WTAP-Mediated m⁶A Modification Targets the LRP1-Lipid Metabolism Axis to Regulate Joint Cartilage Regeneration

Osteoarthritis (OA) arises from impaired epigenetic coordination of inflammatory and metabolic cues, leading to compromised cartilage homeostasis. Such coordination is partly governed by ribonucleic acid (RNA) epigenetic mechanisms, however, the role of the predominant RNA modification N⁶-methyladenosine (m⁶A) in this process remains unclear. Herein, we identify an epigenetic-metabolic pathway in which Wilms' Tumor 1-Associating Protein (WTAP)-mediated m⁶A modification stabilizes low-density lipoprotein receptor-related protein 1 (LRP1) and redirects lipid metabolism toward chondrogenesis. Loss-of-function assays demonstrate that WTAP is required for the chondrogenic differentiation of BMSCs, as its depletion suppresses the expression of multiple cartilage-associated genes. Mechanistically, WTAP enhances m⁶A methylation and stabilizes Lrp1 transcripts, a key regulator of cholesterol metabolism and matrix synthesis, thereby driving lipid metabolic reprogramming toward chondrogenesis. Structure-based screening identified silibinin and estradiol benzoate as LRP1-specific agonists that activate the WTAP-LRP1 pathway to promote cartilage repair in vivo. Collectively, our findings establish m⁶A-dependent metabolic reprogramming as a pivotal epigenetic mechanism of cartilage regeneration with therapeutic potential for promoting chondrogenesis.