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Given the established link between vascular aging and musculoskeletal disorders, the vascular\u2010skeletomuscular axis represents a complex network wherein conditions interact via mechanisms including impaired blood flow, inflammation, oxidative stress, and hormonal imbalances. As pharmacological interventions targeting lysosomal cathepsins face developmental and application challenges, exploring non\u2010pharmacological alternatives becomes imperative. This review investigates the regulatory roles of the lysosomal cathepsin family, especially cathepsins B, K, and L, in musculoskeletal degenerative diseases and evaluates how exercise interventions modulate their activities. It proposes exercise as a viable non\u2010pharmacological strategy to selectively influence lysosomal cathepsin functions, thereby offering therapeutic potential in managing vascular\u2010musculoskeletal degenerative diseases. The review elucidates several key concepts: the intricate interaction between vascular aging and musculoskeletal degenerative pathologies; the pivotal roles of lysosomal cathepsins in disease progression through metabolic regulation, inflammatory modulation, macrophage polarization, and autophagy dysfunction; and the multifaceted mechanisms by which exercise influences cathepsin activity, including calcium homeostasis, cellular energy metabolism enhancement, inflammatory response reduction, autophagy stimulation, myokine secretion, and vascular function improvement. This comprehensive analysis provides novel insights into exercise as a selective modulator of lysosomal cathepsin activity, highlighting its significant potential for advancing diagnostic and clinical therapeutic approaches.<\/jats:p>","DOI":"10.1096\/fj.202501901r","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:14:32Z","timestamp":1760166872000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the Role of Exercise and the Lysosomal Cathepsin Family in the Regulation of Vascular\u2013Musculoskeletal Degenerative Diseases"],"prefix":"10.1096","volume":"39","author":[{"given":"Kangcheng","family":"Fan","sequence":"first","affiliation":[{"name":"College of Exercise and Health Shenyang Sport University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"College of Exercise 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