{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T01:01:23Z","timestamp":1790557283557,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea (NRF) grant funded by the Korea government","doi-asserted-by":"publisher","award":["NRF-2021R1A2C2014145"],"award-info":[{"award-number":["NRF-2021R1A2C2014145"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korea government","award":["RS-2022-00155857"],"award-info":[{"award-number":["RS-2022-00155857"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ferroptosis has emerged as a promising therapeutic vulnerability of diverse malignancies, yet the regulatory circuits adopted by each in cholangiocarcinoma (CCA) subtypes remain incompletely understood. We integrated the genome-wide CRISPR\u2013Cas9 loss-of-function screens and transcriptomic profiles of the Cancer Dependency Map and then systematically assessed the essentiality of ferroptosis suppressor genes (FSGs) in the intrahepatic (iCCA) and extrahepatic (eCCA) subtypes. Nineteen and 16 essential FSGs were identified in iCCA and eCCA, respectively, among which GPX4 exhibited a significantly higher dependency in iCCA. Pharmacological inhibition of GPX4 with RSL3 markedly reduced cell viability and induced lipid peroxidation in iCCA cell lines, whereas eCCA cell lines displayed pronounced resistance associated with elevated GPX4 expression. A transcriptomic comparison revealed enrichment of WNT signaling in eCCA. Co-treatment with the tankyrase inhibitor XAV-939 and RSL3 enhanced growth inhibition of eCCA cells, indicating that WNT signaling contributed to ferroptosis resistance. These findings indicate that iCCA exhibits a preferential dependency on GPX4, whereas WNT\u2013\u03b2-catenin signaling mediates resistance in eCCA. Collectively, the results clarify the molecular basis of subtype-specific ferroptosis vulnerability and offer a rationale for combinatorial therapeutic strategies that integrate GPX4 and WNT pathway inhibition when treating refractory eCCA.<\/jats:p>","DOI":"10.3390\/ijms262411990","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T15:27:20Z","timestamp":1765553240000},"page":"11990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of Differential GPX4 Essentiality Between Intrahepatic and Extrahepatic Cholangiocarcinoma via Leveraging of a Large-Scale Functional Genomic Screen"],"prefix":"10.3390","volume":"26","author":[{"given":"Ye Rim","family":"Lee","sequence":"first","affiliation":[{"name":"AI-Biology & Pharmaceutical Science, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1003-9256","authenticated-orcid":false,"given":"Chaeyoung","family":"Seo","sequence":"additional","affiliation":[{"name":"AI-Biology & Pharmaceutical Science, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6658-071X","authenticated-orcid":false,"given":"Md","family":"Abdullah","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Hyun","family":"Baek","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0625-7774","authenticated-orcid":false,"given":"Seung Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"AI-Biology & Pharmaceutical Science, Chungnam National University, Daejeon 34134, Republic of Korea"},{"name":"College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1016\/j.cell.2022.06.003","article-title":"Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications","volume":"185","author":"Stockwell","year":"2022","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/s41420-024-01863-1","article-title":"Ferroptosis: A new hunter of hepatocellular carcinoma","volume":"10","author":"Jiang","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41420-025-02308-z","article-title":"Targeting ferroptosis: A promising approach for treating lung carcinoma","volume":"11","author":"Wu","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1016\/j.cell.2023.05.003","article-title":"Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones","volume":"186","author":"Liang","year":"2023","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.chembiol.2021.01.006","article-title":"MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells","volume":"28","author":"Kuang","year":"2021","journal-title":"Cell Chem. 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