{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T08:06:11Z","timestamp":1781078771709,"version":"3.54.1"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":160,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>Pancreatic cancer (PC) is highly lethal and lacks causal biomarkers that can inform mechanism\u2010based therapies. Ferroptosis is an iron\u2010dependent form of regulated cell death implicated in PC, but upstream determinants of ferroptosis in PC remain unclear. We integrated large\u2010scale proteomic quantitative trait locus (pQTL) resources with Mendelian randomization (MR) and cell\u2010based experiments to identify causal regulators of ferroptosis relevant to PC. Using two\u2010sample MR with plasma pQTL data from the deCODE cohort and the UK Biobank Pharma Proteomics Project and PC genome\u2010wide association summary statistics from FinnGen, we screened 159 FerrDb\u2010defined ferroptosis\u2010related proteins and identified three ferroptosis\u2010related proteins (CTSB, IDO1, and MDM4) with significant causal effects on PC risk. A proteome\u2010wide scan further uncovered 13 proteins associated with PC. Two\u2010step mediation MR supported a causal pathway from CLEC4G through the ferroptosis regulator CTSB to PC risk. In vitro, CLEC4G knockdown increased CTSB expression and ferroptosis activity, which suppressed PC cell proliferation, colony formation, migration, and invasion. Together, our genetic and experimental evidence indicates that CLEC4G promotes PC progression by limiting CTSB\u2010associated ferroptotic activity in PC cells and supports further investigation of the CLEC4G\u2013CTSB axis in PC.<\/jats:p>","DOI":"10.1155\/humu\/7359548","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T07:48:33Z","timestamp":1781077713000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CLEC4G Promotes Pancreatic Cancer Progression by Suppressing Cathepsin B\u2010Mediated Ferroptosis: Evidence From Mendelian Randomization Study and Experimental 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