{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T02:50:20Z","timestamp":1762483820007,"version":"build-2065373602"},"reference-count":27,"publisher":"IMR Press","issue":"10","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2021YFC2009300","2021YFC2009305"],"award-info":[{"award-number":["2021YFC2009300","2021YFC2009305"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82203670"],"award-info":[{"award-number":["82203670"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tianjin Medical University General Hospital Young Technical Backbone Program","award":["GG-202407"],"award-info":[{"award-number":["GG-202407"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Bladder outlet obstruction (BOO) frequently accompanies benign prostate hyperplasia (BPH) in aging males and often leads to bladder fibrosis, a secondary pathological change that contributes to bladder dysfunction. The role of Cathepsin S (CTSS), a cysteine protease associated with immune responses, in this process remains to be fully elucidated. Methods: Bladder tissues from BOO model mice were analyzed using microarray profiling, followed by Gene Ontology (GO) and pathway enrichment analyses. Candidate genes, including CTSS, C-X-C Motif Chemokine Ligand 17 (CXCL17), and Angiopoietin Like 7 (ANGPTL7), were identified. CTSS was selected for further investigation based on its association with fibrotic processes. The functional role of CTSS in smooth muscle cell hypertrophy and fibrosis was verified both in vivo and in vitro. A co-culture system of smooth muscle cells and monocyte\u2013macrophages was used to explore the underlying mechanism. Results: Microarray and bioinformatic analysis identified CTSS as a key candidate gene associated with immune response in BOO-induced bladder fibrosis. CTSS expression was upregulated in BOO bladders and was demonstrated to promote smooth muscle cell hypertrophy and fibrotic changes. Mechanistically, CTSS mediated proteolytic cleavage of the interleukin-6 receptor (IL-6R) on immune cells, generating soluble IL-6R (sIL-6R). This process facilitated IL-6 trans-signaling, which in turn promoted smooth muscle cell hypertrophy and exacerbated bladder fibrosis. Conclusions: These findings indicate that CTSS contributes to BOO-induced bladder dysfunction and fibrosis by activating IL-6 trans-signaling through cleavage of IL-6R. CTSS may represent a potential therapeutic target for mitigating bladder fibrosis in BPH.<\/jats:p>","DOI":"10.31083\/fbl45355","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T02:40:44Z","timestamp":1762483244000},"source":"Crossref","is-referenced-by-count":0,"title":["Cathepsin S Contributes to Bladder Fibrosis Following Bladder Outlet Obstruction via IL-6 Trans-signaling"],"prefix":"10.31083","volume":"30","author":[{"given":"Mengchen","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Urology, Tianjin Medical University General Hospital, 300052 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xilei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology, Tianjin Medical University General Hospital, 300052 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology, Tianjin Medical University General Hospital, 300052 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0550-1800","authenticated-orcid":true,"given":"Tianyu","family":"Shen","sequence":"first","affiliation":[{"name":"School of Medicine, Nankai University, 300071 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9051-2260","authenticated-orcid":true,"given":"Liang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology, Tianjin Medical University General Hospital, 300052 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"D\u2019Silva KA, Dahm P, Wong CL. 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