AccScience Publishing / ITPS / Online First / DOI: 10.36922/ITPS025360046
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ORIGINAL RESEARCH ARTICLE

Treadmill exercise promotes melatonin regulation of TXNIP/NLRP3 and inhibits pyroptosis-mediated osteoarthritis progression in a DMM rat model

Ruba Altahla1,2 ,  Jamal Alshorman1 ,  Li Chaoyi1 ,  Muhammad Umar3 ,  Mohd M. Hourani4 ,  Yongping Wang1*
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1 Department of Orthopedics, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
2 Department of Rehabilitation, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
3 Research Center for Medical Artificial Intelligence, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
4 Head Health Centre, United Nations Relief and Works Agency, Zarqa, Jordan
INNOSC Theranostics and Pharmacological Sciences, 025360046 https://doi.org/10.36922/ITPS025360046
Received: 2 September 2025 | Revised: 25 September 2025 | Accepted: 10 October 2025 | Published online: 18 November 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Osteoarthritis (OA) is characterized by the activation of nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) by thioredoxin-interacting protein (TXNIP), which promotes inflammation and pyroptosis. This study investigates whether treadmill exercise (TE) enhances melatonin-mediated regulation of the TXNIP/NLRP3 pathway and attenuates OA progression by modulating pyroptosis in a destabilization of the medial meniscus (DMM) rat model. A total of 32 male Sprague–Dawley rats (6 weeks old; 220 ± 20 g) were randomly assigned to four groups: Sham, DMM, DMM + melatonin, and DMM + melatonin + TE. The intervention lasted for 8 weeks. Morphological staining, immunofluorescence (IF), microcomputed tomography with three-dimensional reconstruction, Western blot, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay were used to assess protein and gene expression. Compared with the DMM + melatonin group, the DMM + melatonin + TE group showed greater reductions in cartilage–subchondral bone damage and OA progression through modulation of the pyroptosis pathway. IF staining revealed that TXNIP protein expression was significantly reduced in the DMM + melatonin + TE group. Both the DMM + melatonin and combination treatment groups significantly regulated TXNIP/NLRP3 signaling and inhibited OA progression through pyroptosis. Furthermore, combining TE with melatonin significantly reduced the expression of pyroptotic cytokines compared with the DMM + melatonin group. This study suggests a potential therapeutic approach for managing OA by combining melatonin treatment with moderate TE.

Keywords
Osteoarthritis
Exercise
Melatonin
Thioredoxin-interacting protein
Nucleotide-binding and oligomerization domain-like receptor protein 3
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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INNOSC Theranostics and Pharmacological Sciences, Electronic ISSN: 2705-0823 Print ISSN: 2705-0734, Published by AccScience Publishing
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