Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 Signaling

Osteoarthritis (OA) is a long-term degenerative condition of the joints, characterized by persistent inflammation, progressive cartilage breakdown, and impaired mitochondrial function. Recent studies have shown that hyperactivation of the mTORC1 pathway and metabolic reprogramming of chondrocytes contribute to disease progression. Nitazoxanide (NTZ), an oral antiparasitic agent approved by the Food and Drug Administration, has shown anti-inflammatory and mitochondrial protective effects in various disease situations; despite this, its application in osteoarthritis has yet to be fully investigated. Here, we assessed the therapeutic efficacy of NTZ using IL-1β-stimulated primary chondrocytes derived from patients with OA. NTZ substantially reduced the expression of proinflammatory cytokines and matrix metalloproteinases, restored mitochondrial membrane potential, and reduced mitochondrial reactive oxygen species levels. NTZ also effectively reversed IL-1β-induced glycolytic metabolic changes by inhibiting glucose uptake and GLUT1 expression. Mechanistically, NTZ inhibited the activation of the mTORC1 pathway and substantially increased AMPK phosphorylation. The siRNA-mediated AMPK knockdown negated NTZ-induced mitochondrial and metabolic improvements, suggesting that AMPK is a key upstream regulator of the protective actions of NTZ. NTZ can, therefore, effectively inhibit inflammatory metabolic reprogramming and mitochondrial dysfunction in OA chondrocytes through AMPK-dependent mTORC1 signaling inhibition, highlighting its potential as a disease-modifying therapy for OA.