Neuropeptide Y1 receptor antagonist alleviated osteoarthritis by restoring chondrocyte autophagy through PI3K/AKT/mTOR signaling pathway.

Background: Osteoarthritis (OA) is a debilitating joint disorder affecting millions worldwide, characterized by progressive cartilage degradation and chronic pain. Emerging evidence suggests that neuropeptide Y (NPY) and its Y1 receptors are involved in OA pathogenesis, although the underlying molecular mechanisms remain poorly understood. This study investigates the role of NPY/Y1R signaling in OA progression through PI3K/AKT/mTOR-mediated regulation of chondrocyte autophagy. Methods: Human cartilage samples were collected from ten OA patients (3 male,7 female, 63-75 years old) undergoing total knee arthroplasty and graded using the Kellgren-Lawrence system. Primary chondrocytes were isolated from neonatal C57BL/6 mice and treated with NPY (0.01-5 μM) or interleukin-1β (IL-1β, 10 ng/mL) to mimic OA-like degeneration. RNA sequencing (RNA-seq) and KEGG pathway analysis were performed to identify NPY-regulated signaling pathways. Results: NPY and Y1R expression were significantly elevated in human OA cartilage compared to normal tissue. Conclusion: This study demonstrates that NPY/Y1R signaling exacerbates OA progression through PI3K/AKT/mTOR-mediated suppression of chondrocyte autophagy. Pharmacological inhibition of Y1R emerges as a novel therapeutic strategy, effectively targeting both cartilage degeneration and pain, with potential disease-modifying effects on osteoarthritis progression. The translational potential of this article: This study highlights the NPY Y1 receptor as a promising therapeutic target for OA by demonstrating its role in modulating chondrocyte autophagy via the PI3K/AKT/mTOR pathway. The results support the development of Y1R antagonists as novel OA therapeutics. This work bridges molecular discovery to potential clinical application, offering hope for a transformative approach to OA management.