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This research highlights the importance of the circular RNA (circRNA) circPCSK6 and its peptide derivative circPCSK6\u2010167aa in ICC. CircPCSK6 is significantly downregulated in both ICC patients and mouse primary ICC models, and its lower expression is linked to adverse prognosis, highlighting its pivotal role in ICC pathogenesis. Functionally, this study elucidates the regulatory effect of circPCSK6\u2010167aa on I\u03baB\u03b1 ubiquitination within the NF\u2010\u03baB pathway, which is mediated by its competitive binding to the E3 ligase RBBP6. This complex interaction leads to reduced activation of the NF\u2010\u03baB pathway, thereby curbing tumor cell proliferation, migration, invasion, stemness, and hepatic\u2010lung metastasis in vivo. This groundbreaking discovery expands the understanding of circRNA\u2010driven tumorigenesis through atypical signaling pathways. Additionally, this investigation identified EIF4A3 as a detrimental regulator of circPCSK6, exacerbating ICC malignancy. Importantly, by leveraging patient\u2010derived xenograft (PDX), organoids, and organoid\u2010derived PDX models, higher levels of circPCSK6\u2010167aa enhance sensitivity to gemcitabine, indicating its potential to improve the effectiveness of chemotherapy. These insights emphasize the therapeutic promise of targeting circPCSK6\u2010167aa, offering vital biological insights and clinical directions for developing cutting\u2010edge therapeutic approaches, thus revealing innovative strategies and targets for future treatments.<\/jats:p>","DOI":"10.1002\/advs.202409173","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T12:49:26Z","timestamp":1737463766000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Novel 167\u2010Amino Acid Protein Encoded by CircPCSK6 Inhibits Intrahepatic Cholangiocarcinoma Progression via IKB\u03b1 Ubiquitination"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6439-1851","authenticated-orcid":false,"given":"Canghai","family":"Guan","sequence":"first","affiliation":[{"name":"General Surgery Department The 2nd Affiliated Hospital of Harbin Medical University  148 Baojian 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