Abstract Background: Cholangiocarcinoma (CCA) is a highly lethal epithelial cell malignancy of the hepatic biliary tract. Efficacy of current standard-of-care therapy is limited. Ferroptosis, an iron-catalyzed, caspase-independent cell death driven by phospholipid peroxidation, has emerged as a novel therapeutic target. Our goal is to develop a tumor-selective therapeutic approach targeting ferroptosis in CCA using siRNA-based nanotherapeutics. Materials 0.001 vs. siNC). In CCA-bearing mice, intravenous administration of siRNA lactosomes was well-tolerated with no liver or systemic toxicity observed and demonstrated robust tumor distribution compared to non-tumorous tissues. Efficacy studies demonstrated that siGPX4/siFSP1-lactosomes significantly reduced intratumor Gpx4 and FSP1 mRNA expression by 40-60% and induced significant upregulation of ferroptosis markers Ptgs2 and Acsl4 (p0.01 vs. siNC). Ferroptosis in siRNA-lactosome treated tumors was confirmed by immunohistochemistry for phospholipid peroxidation markers oxPAPC and 4-HNE. Additionally, proliferation marker Ki67 was significantly downregulated in siGPX4/siFSP1-lactosome treated tumors (p0.05 vs. siNC), indicating ferroptosis-mediated tumor suppression. Importantly, siGPX4/siFSP1-lactosomes reduced tumor burden and expression of CCA markers CK19/7 in treated mice, as compared to control mice. Conclusions: siRNA-based nanotherapeutics targeting CCA can effectively and safely induce ferroptosis in vitro and in vivo, representing a potential therapeutic strategy for CCA treatment. Citation Format: Peyton Classon, Danielle Marie Carlson, Jayla Millender, Irene Yan, Sumera Ilyas, Rory L. Smoot, TUSHAR PATEL, Gregory J. Gores, Davide Povero. Targeting cholangiocarcinoma with ferroptosis-inducing siRNA-based nanotherapeutics abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5664.
Classon et al. (Fri,) studied this question.