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disease (PD) is characterized by progressive dopaminergic neurodegeneration driven by oxidative stress, mitochondrial dysfunction, synaptic loss, and impaired neurotrophic signaling; however, the role of integrin \u03b15\u03b21 in neuronal vulnerability remains unclear. Here, the data show that rotenone-induced stress reduces integrin \u03b15 expression in a dose- and time-dependent manner, leading to increased ROS accumulation, glutathione imbalance, synaptic degeneration, senescence-like \u03b2-gal activity, and apoptosis, whereas integrin \u03b15 knockdown further exacerbates these deficits, supporting a protective role of \u03b15\u03b21. In contrast, treatment with the fibronectin-derived \u03b15\u03b21-activating peptide Ac-PHSRN-NH2 restores integrin signaling by engaging the FAK\u2013PI3K\u2013AKT\/ERK cascade and NRF2-mediated antioxidant responses, thereby reducing oxidative stress, suppressing cell death, and improving redox homeostasis. Moreover, PHSRN enhances NGF and BDNF levels, preserves synaptic integrity, and promotes dopaminergic neuronal activity and dopamine release. Consistently, in MPTP-lesioned mice, PHSRN preserves nigral TH-positive neurons, reduces apoptosis, restores neurotrophic support, and improves motor function. Collectively, these findings identify integrin \u03b15\u03b21 as a critical protective axis and support PHSRN as a potential disease-modifying therapeutic strategy for PD.<\/jats:p>","DOI":"10.3390\/antiox15070822","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:01:17Z","timestamp":1782813677000},"page":"822","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrin \u03b15\u03b21 Activation by PHSRN Peptide Elicits Neuroprotection and Functional Recovery in Parkinson\u2019s Disease Mice"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7084-9208","authenticated-orcid":false,"given":"Cheng-Chun","family":"Wu","sequence":"first","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"},{"name":"School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Kuang","family":"Wang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"},{"name":"Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ting","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Cheng","family":"Ho","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Chin","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Loong","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"},{"name":"Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1638-8049","authenticated-orcid":false,"given":"Yung-Kuo","family":"Lee","sequence":"additional","affiliation":[{"name":"Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung City 802231, Taiwan"},{"name":"Division of Experimental Surgery Center, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei 114201, Taiwan"},{"name":"School of Medicine, National Defense Medical University, Taipei 114201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Huei","family":"Chu","sequence":"additional","affiliation":[{"name":"Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung City 802231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Shin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung City 802231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-6132","authenticated-orcid":false,"given":"Jui-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"},{"name":"Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41582-020-0344-4","article-title":"Parkinson disease and the immune system\u2014Associations, mechanisms and therapeutics","volume":"16","author":"Tan","year":"2020","journal-title":"Nat. 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