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Cumulative evidence indicates that Cathepsin K (Cat K), a cysteine protease, is functionally linked to chronic stress and exerts critical regulatory roles in bone metabolism. Nevertheless, the molecular mechanisms whereby CS promotes osteoporosis in the background of mood\u2010related disturbances remain poorly defined. In the present work, we established a combined mouse model of osteoporosis and chronic stress. We evaluated anxiety\u2010 and depression\u2010like behaviors, the expression profiles of Cat K, autophagy\u2010, apoptosis\u2010, and inflammation\u2010associated proteins in bone tissue, as well as vascular senescence in experimental animals. Furthermore, we investigated the biological effects of serum collected from chronically\u2010stressed mice on MC3T3\u2010E1 osteoblast\u2010like cells. Following 8\u2010week chronic stress exposure, ovariectomized (OVX) mice developed prominent anxiety\u2010 and depression\u2010like behaviors, accompanied by deteriorated osteoporosis and aortic senescence. Meanwhile, bone tissues exhibited elevated levels of Cat K, p62, pro\u2010inflammatory mediators, and apoptosis\u2010related proteins, whereas the autophagy marker LC3B\/A was down\u2010regulated. Administration of E64d, a cysteine protease inhibitor, markedly reversed these pathological alterations. In vitro culture revealed that serum from chronically\u2010stressed mice suppressed the viability of MC3T3\u2010E1 osteoblast\u2010like cells. Pharmacological inhibition of Cat K restored autophagic activity, mitigated the overexpression of pro\u2010inflammatory and pro\u2010apoptotic mediators, and rescued MC3T3\u2010E1 cells from stress\u2010triggered injury. Collectively, our findings demonstrate that chronic stress induces anxiety\u2010 and depression\u2010like phenotypes in OVX mice and accelerates bone loss, at least partially via Cat K activation and autophagy suppression.<\/jats:p>","DOI":"10.1002\/jcb.70129","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:09:28Z","timestamp":1791284968000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Stress Exacerbates Osteoporosis in Ovariectomized Mice With Anxiety\u2010 and Depression\u2010Like Symptoms by Activating Cathepsin K and Impairing Autophagy"],"prefix":"10.1002","volume":"127","author":[{"given":"Shanqian","family":"Li","sequence":"first","affiliation":[{"name":"School of Public Health Guilin Medical University Guilin China"},{"name":"Guangxi Key Laboratory of Environmental Exposomics and Whole Life Cycle Health Guilin China"},{"name":"Key Cultivation Laboratory of Life Cycle Health Care Research Guilin China"},{"name":"Department of Clinical Nutrition Liuzhou Workers' Hospital Liuzhou Guangxi P.R. 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