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 co...
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MDPI AG
2025-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/5/512 |
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| author | Ha Eun Kim Jong Yeong Lee Ga-Yeon Son Jun-Young Park Ki Bum Kim Chul-Min Choi Young Jae Moon Jin Kyeong Choi |
| author_facet | Ha Eun Kim Jong Yeong Lee Ga-Yeon Son Jun-Young Park Ki Bum Kim Chul-Min Choi Young Jae Moon Jin Kyeong Choi |
| author_sort | Ha Eun Kim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a7c24cc4ad4e462d9bafab0817b1da4f |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-a7c24cc4ad4e462d9bafab0817b1da4f2025-08-20T02:33:36ZengMDPI AGAntioxidants2076-39212025-04-0114551210.3390/antiox14050512Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 SignalingHa Eun Kim0Jong Yeong Lee1Ga-Yeon Son2Jun-Young Park3Ki Bum Kim4Chul-Min Choi5Young Jae Moon6Jin Kyeong Choi7Department of Immunology, Jeonbuk National University Medical School, Jeonju 54907, Republic of KoreaDepartment of Immunology, Jeonbuk National University Medical School, Jeonju 54907, Republic of KoreaDepartment of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USADepartment of Biochemistry, Chungbuk National University, Cheongju 28644, Republic of KoreaDepartment of Orthopedic Surgery, Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of KoreaDepartment of Healthcare, Dongguk University Duica, Seoul 04620, Republic of KoreaDepartment of Orthopedic Surgery, Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of KoreaDepartment of Immunology, Jeonbuk National University Medical School, Jeonju 54907, Republic of KoreaOsteoarthritis (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.https://www.mdpi.com/2076-3921/14/5/512nitazoxanideosteoarthritischondrocytesAMPKmTORC1mitochondrial dysfunction |
| spellingShingle | Ha Eun Kim Jong Yeong Lee Ga-Yeon Son Jun-Young Park Ki Bum Kim Chul-Min Choi Young Jae Moon Jin Kyeong Choi Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 Signaling Antioxidants nitazoxanide osteoarthritis chondrocytes AMPK mTORC1 mitochondrial dysfunction |
| title | Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 Signaling |
| title_full | Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 Signaling |
| title_fullStr | Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 Signaling |
| title_full_unstemmed | Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 Signaling |
| title_short | Nitazoxanide Modulates Mitochondrial Function and Inflammatory Metabolism in Chondrocytes from Patients with Osteoarthritis via AMPK/mTORC1 Signaling |
| title_sort | nitazoxanide modulates mitochondrial function and inflammatory metabolism in chondrocytes from patients with osteoarthritis via ampk mtorc1 signaling |
| topic | nitazoxanide osteoarthritis chondrocytes AMPK mTORC1 mitochondrial dysfunction |
| url | https://www.mdpi.com/2076-3921/14/5/512 |
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