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Pituitary adenylate cyclase\u2010activating polypeptide (PACAP) is a neuropeptide known for its anti\u2010inflammatory and cytoprotective effects; however, its role in chondrocyte senescence remains poorly understood. This study investigated the protective effects of PACAP38 on tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1)\u2010 induced chondrocyte senescence and the underlying mechanisms. Intracellular reactive oxygen species (ROS) levels were measured using 2\u2032,7\u2032\u2010dichlorodihydrofluorescein diacetate (DCFH\u2010DA) staining, oxidative DNA damage was assessed by 8\u2010hydroxy\u20102\u2032\u2010deoxyguanosine (8\u2010OHdG) enzyme\u2010linked immunosorbent assay (ELISA), and senescence markers were evaluated by senescence\u2010associated \u03b2\u2010galactosidase (SA\u2010\u03b2\u2010Gal) staining, telomerase activity assay, and telomere length analysis. Gene and protein expression were examined via real\u2010time polymerase chain reaction (PCR) and Western blotting. We found that PACAP type I receptor (PAC1R), the receptor for PACAP, was expressed in both murine and human chondrocytes and was downregulated by TNF\u2010\u03b1 stimulation. PACAP38 treatment significantly reduced ROS and 8\u2010OHdG levels, restored telomerase activity and telomere length, and decreased SA\u2010\u03b2\u2010Gal activity. Mechanistically, PACAP38 upregulated sirtuin 3 (SIRT3), a mitochondrial deacetylase that regulates oxidative stress and metabolism, while suppressing acetylated p53 (ac\u2010p53) and plasminogen activator inhibitor\u20101 (PAI\u20101) expression. Furthermore, PACAP38 reversed TNF\u2010\u03b1\u2010induced dephosphorylation of AMP\u2010activated protein kinase alpha (AMPK\u2010\u03b1) and its downstream target acetyl\u2010CoA carboxylase (ACC). Importantly, inhibition of AMPK by compound C abolished these protective effects, confirming the essential role of the AMPK\u2010SIRT3 signalling pathway. In conclusion, our findings demonstrate that PACAP38 mitigates TNF\u2010\u03b1\u2010induced chondrocyte senescence via activation of the AMPK\u2010SIRT3 signalling axis, suggesting a potential therapeutic strategy for OA.<\/jats:p>","DOI":"10.1111\/1440-1681.70062","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T07:04:06Z","timestamp":1754636646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>PACAP<\/scp> Inhibits <scp>TNF<\/scp>\u2010\u03b1\u2010 Induced Senescence in Primary Chondrocytes by <scp>SIRT3<\/scp>: An Implication in Osteoarthritis"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4601-5123","authenticated-orcid":false,"given":"Xuewu","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Orthopedic The First Clinical Medical College of China Three Gorges University, Yichang Central People's Hospital  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