Narirutin inhibits inflammation and oxidative stress in osteoarthritis via suppressing AKT/NF-κB signaling

Narirutin is a flavanone with anti-inflammatory and antioxidant properties. The objective of this study was to evaluate its therapeutic potential against osteoarthritis. Anterior cruciate ligament transection (ACLT) rats were administered 10, 30, or 50 mg/kg narirutin by daily oral gavage. ATDC-5 cells were treated with 50, 100, or 200 μM narirutin in the presence of 10 ng/mL IL-1β. Extracellular matrix (ECM) degradation, inflammation, and oxidative stress in vitro and in vivo were assessed by hematoxylin and eosin and Safranin O-Fast Green staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, flow cytometry, western blotting, and immunofluorescence. In ACLT rats, narirutin ameliorated cartilage lesions, reduced the Osteoarthritis Research Society International score, and reduced serum levels of C-telopeptide of type II Collagen and cartilage oligomeric matrix protein. In both ACLT rats and ATDC-5 cells, narirutin downregulated A disintegrin and metalloproteinase with thrombospondin motifs 5, matrix metalloproteinase (MMP)-3, and MMP13 and upregulated Collagen II and Aggrecan. In addition, narirutin decreased the levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, Reactive Oxygen Species, and Malondialdehyde while increasing the levels of superoxide dismutase and glutathione. Network pharmacology analysis identified phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) as a signaling pathway regulated by narirutin in osteoarthritis. Narirutin binds to Akt1 to inhibit Akt and nuclear factor-κB (NF-κB) activation. Furthermore, NF-κB overexpression and SC79 treatment reversed the anti-inflammatory and antioxidant properties of narirutin in ATDC-5 cells. Narirutin exhibited cartilage-protective effects in osteoarthritis models by inhibiting ECM degradation, inflammation, and oxidative stress through suppressing Akt/NF-κB signaling.