{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:48:59Z","timestamp":1792406939792,"version":"4.4.0"},"reference-count":30,"publisher":"Bioscientifica","issue":"10","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Papillary thyroid carcinoma (PTC) usually has a good prognosis, but lacks effective molecular biomarkers and therapeutic targets. However, a subset of patients develops lymph node metastasis, radioiodine resistance, and recurrence. Cathepsin S (CTSS), a lysosomal cysteine protease, has been implicated in several malignancies, yet its role and regulation in PTC remain unclear. We integrated GEO and TCGA-THCA datasets with eQTL-based genetic instrument analyses to screen PTC-related genes and evaluate their association with clinicopathological features and DFS. CTSS expression was examined in clinical tissues and cell lines by immunohistochemistry, RT-qPCR, and western blotting. Gain- and loss-of-function models were used to assess the effects of CTSS on PTC cell proliferation, colony formation, migration, apoptosis, and nude-mouse tumor growth. RNA-seq and TCGA pathway-score correlation analysis were used to explore downstream pathways, and transcriptional regulation was investigated by in silico prediction, ChIP-qPCR, and dual-luciferase assays. CTSS emerged as a candidate gene associated with PTC occurrence, lymph node metastasis, and shorter DFS. CTSS was markedly upregulated in PTC tissues and cell lines. Functionally, CTSS knockdown suppressed proliferation and migration\/invasion and promoted apoptosis, whereas CTSS overexpression enhanced malignant phenotypes in the examined PTC cell models. CTSS expression was associated with activation of the PI3K\/AKT\/mTOR pathway, and CTSS inhibition attenuated pathway activation and tumor growth. TCF4 bound the CTSS promoter, increased CTSS transcription, and TCF4 knockdown reduced CTSS expression and PI3K\/AKT\/mTOR pathway activity. These findings suggest that CTSS promotes malignant phenotypes in PTC and is associated with PI3K\/AKT\/mTOR activation, while TCF4 may contribute to CTSS transcriptional regulation.<\/jats:p>","DOI":"10.1530\/erc-25-0517","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:54:43Z","timestamp":1791208483000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["TCF4-driven cathepsin S promotes papillary thyroid carcinoma via PI3K\/AKT\/mTOR"],"prefix":"10.1530","volume":"33","author":[{"given":"Xinyi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of General Surgery, The Yancheng Clinical College of Xuzhou Medical University 1 , ,","place":["Yancheng, China"]},{"name":"Department of General Surgery, The First people\u2019s Hospital of Yancheng 2 , ,","place":["Yancheng, China"]},{"name":"Yancheng Key Laboratory of Molecular Epigenetics, Yancheng Medical Research Center of Nanjing University Medical School, The First People\u2019s Hospital of Yancheng 3 , , ,","place":["Yancheng, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Medicine, Tongji University 4 , ,","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Yancheng Clinical College of Xuzhou Medical University 1 , ,","place":["Yancheng, China"]},{"name":"Department of General Surgery, The First people\u2019s Hospital of Yancheng 2 , ,","place":["Yancheng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhou","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Yancheng Clinical College of Xuzhou Medical University 1 , ,","place":["Yancheng, China"]},{"name":"Department of General Surgery, The First people\u2019s Hospital of Yancheng 2 , ,","place":["Yancheng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Yancheng Clinical College of Xuzhou Medical University 1 , ,","place":["Yancheng, China"]},{"name":"Department of General Surgery, The First people\u2019s Hospital of Yancheng 2 , ,","place":["Yancheng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The Yancheng Clinical College of Xuzhou Medical University 1 , ,","place":["Yancheng, China"]},{"name":"Department of General Surgery, The First people\u2019s Hospital of Yancheng 2 , ,","place":["Yancheng, 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