Valdecoxib Ameliorates Apoptosis and Ferroptosis in Tenocytes via the SIRT6/NRF2-Mediated Suppression of Oxidative Stress

Background and Aims. Valdecoxib (VAL), a nonsteroidal anti-inflammatory drug (NSAID), is widely used in the treatment of osteoarthritis and rheumatoid arthritis. In addition to its anti-inflammatory properties, VAL has been shown to improve skeletal muscle insulin resistance and attenuate hepatic steatosis in obese individuals. However, its potential effects on oxidative stress injury in tenocytes remain unclear. This study aims to explore novel functions of VAL by investigating its impact on cell death in oxidative stress-exposed tenocytes and elucidating the underlying molecular mechanisms, with a focus on its therapeutic potential for the treatment of tendinopathy. Methods. Apoptosis was assessed using cell viability assays, caspase-3 activity measurements, and TUNEL staining. Hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA) levels in tenocytes were quantified using appropriate assay kits, while reactive oxygen species (ROS) were detected by DCFDA staining. Tenocyte migration was evaluated using a scratch assay, and protein expression levels were analyzed by Western blotting. Results and Conclusion. In the present study, we found that VAL treatment suppressed apoptosis and ferroptosis and normalized the expression of extracellular matrix (ECM) degradation markers, and enhanced cell migration in H2 O2 -treated tenocytes. VAL treatment increased the expression of SIRT6 and NRF2 and the activities of antioxidant enzymes. SIRT6-targeted siRNA abrogated the effects of VAL on tenocytes treated with H2 O2 . It also reduced VAL-induced NRF2 expression and antioxidant enzyme activities. These results suggest that VAL ameliorates oxidative stress induced tenocyte dysfunction through SIRT6/NRF2-mediated signaling. Therefore, this study highlights a potential therapeutic strategy for the treatment of overuse-induced tendinopathy. (c) 2025 reserved, including those for text and data mining, AI training, and similar technologies.

Dergi

ARCHIVES OF MEDICAL RESEARCH

Yıl

2025

Cilt

56

Sayı

6

ISSN

0188-4409

eISSN

1873-5487

DOI

10.1016/j.arcmed.2025.103231

WoS UID

WOS:001493866100001