{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T19:11:48Z","timestamp":1777403508310,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Colorectal cancer (CRC) remains one of the most lethal malignancies worldwide, with 5-fluorouracil (5-Fu) as a mainstay of treatment. However, intrinsic and acquired resistance to 5-Fu significantly limits therapeutic success. Furin, a proprotein convertase, is known to activate multiple substrates critical for tumor progression, yet its precise role in CRC remains unclear. In this study, we examined furin expression in a large cohort of CRC patient samples and performed functional analyses in CRC cell lines and xenograft models. Furin overexpression was seen in 46.9% (530\/1131) of CRC cases and was significantly correlated with TGF-\u03b2 and ERK1\/2 activation. In vitro, induced furin overexpression enhanced proliferation and clonogenicity, accompanied by upregulation of TGF-\u03b2 and ERK1\/2 phosphorylation, whereas furin silencing attenuated tumor cell growth and TGF-\u03b2\/ERK signaling. Manipulation of TGF-\u03b2 revealed a reciprocal regulatory loop, whereby TGF-\u03b2 upregulated furin expression, establishing a feed-forward circuit that augmented ERK signaling and tumor growth. Notably, 5-Fu-resistant CRC cell lines displayed elevated furin, TGF-\u03b2, and phospho-ERK1\/2, while furin knockdown restored drug sensitivity. In vivo, furin overexpression enhanced tumor growth in xenografts, whereas its depletion markedly reduced tumor burden and TGF-\u03b2\/ERK signaling activity. Collectively, these findings demonstrate that furin promotes CRC progression and chemoresistance through a positive feedback loop with TGF-\u03b2 that sustains ERK activation. Targeting furin, alone or in combination with TGF-\u03b2\/ERK inhibitors, may offer a promising therapeutic strategy for CRC.<\/jats:p>","DOI":"10.3390\/cells15010043","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T02:07:58Z","timestamp":1766714878000},"page":"43","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Furin Drives Colorectal Cancer Progression and Chemoresistance Through the TGF-\u03b2\/ERK Signaling Pathway"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3401-2736","authenticated-orcid":false,"given":"Pratheesh Kumar","family":"Poyil","sequence":"first","affiliation":[{"name":"Experimental Therapeutics, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul K.","family":"Siraj","sequence":"additional","affiliation":[{"name":"Translational Oncology Research, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep Kumar","family":"Parvathareddy","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafia","family":"Begum","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Padmanaban Annaiyappa","family":"Naidu","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saravanan","family":"Thangavel","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khadija","family":"Alobaisi","sequence":"additional","affiliation":[{"name":"Translational Oncology Research, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8091-5280","authenticated-orcid":false,"given":"Saud","family":"Azam","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fouad","family":"Al-Dayel","sequence":"additional","affiliation":[{"name":"Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-3419","authenticated-orcid":false,"given":"Khawla S.","family":"Al-Kuraya","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Innovation & Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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