Osteoarthritis (OA) is a degenerative joint disease with limited treatment options, characterized by oxidative stress and disrupted cartilage homeostasis (Ansari et al., 2020). This thesis investigates the role of Calcium Calmodulin Kinase II (CaMKII) in adult human articular chondrocytes (AHACs) under oxidative stress, focusing on its regulatory functions in redox balance, mitochondrial dynamics, and responses to nutraceutical interventions. An experimental model to induce oxidative stress was established using 200 µM H₂O₂, providing a consistent framework to study reactive oxygen species (ROS)-mediated processes while maintaining cell viability. In contrast to other cell types where CaMKII is activated by oxidation, AHACs demonstrated phosphorylation-dependent activation under oxidative stress, highlighting cell-type-specific regulatory mechanisms. Inhibition of CaMKII resulted in increased ROS levels, while overexpression of CaMKII promoted nuclear factor erythroid-2 related factor-2 (Nrf2)-driven antioxidant responses and supported mitochondrial health through enhanced spare respiratory capacity, ATP production, and mitophagy. These findings underscore its role as a key modulator of redox and mitochondrial homeostasis. The nutraceuticals curcumin and resveratrol were evaluated for their antioxidant effects in the context of CaMKII inhibition. While both reduced ROS, their cytoprotective efficacy was limited and strongly influenced by CaMKII activity. Curcumin exhibited dependency on functional CaMKII, whereas resveratrol showed partial CaMKII-independent effects, particularly in reducing mitochondrial ROS. 3 Overall, this work positions CaMKII as a critical regulator of chondrocyte function under oxidative stress, protecting against oxidative damage and supporting cartilage homeostasis. While nutraceuticals offer potential as adjunct therapies, their limited efficacy without functional CaMKII underscores its therapeutic importance. Future research could explore the specific redox pathways modulated by CaMKII, such as Nrf2 signalling and examine its interactions with nutraceutical mediated signalling pathways.