Abstract 2369: Targeting peroxiredoxin 2 prevents hepatocellular carcinoma development in metabolic liver disease

Abstract Background: HCC is the third most common cause of cancer-related death and the leading cause of death among cirrhotic patients. While several treatments for HCC have been approved, chemopreventive strategies for HCC are lacking. Aiming to discover novel therapeutic targets, we combined genome wide transcriptomic analysis of liver tissues from patients with advanced liver disease and HCC and a cell-based system predicting liver disease progression and HCC risk. Computational analysis identified peroxiredoxin 2 (PRDX2) as a candidate driver of hepatocarcinogenesis. Methods: The role of PRDX2 in liver disease progression and HCC development was investigated by Prdx2 KO in a state-of-art CRIPSR/Cas9 mouse model for MASH-induced hepatocarcinogenesis. The mechanism of action was explored using RNA-Seq analyses of mouse liver tissues and validated by perturbation studies in human liver cell-based models. The translatability of our results was confirmed by targeting Prdx2 using GalNac siRNA in a mouse model of MASH, CDX mouse model, as well as perturbation studies in patient-derived HCC tumorspheroids. Results: In vivo perturbation studies in mouse models for MASH driven hepatocarcinogenesis showed that Prdx2 KO improves steatosis and robuslty prevents HCC development. RNA-Seq analyses of mouse liver tissues with validation in human cells showed that loss of Prdx2 function suppresses oncogenic signaling (i. e. p38/MAPK, PI3K/AKT signaling) and improves metabolic liver functions (i.e cholesterol, fatty acid and bile acid metabolism) through activation of the AMPK pathways. Finally, PRDX2 loss-of-function studies in hepatoma cell-based models, a CDX mouse model and patient tumorspheroids unraveled that targeting PRDX2 sensitizes cancer cell to oxidative stress and triggers apoptosis. Conclusion: Our findings demonstrate an important functional role of PRDX2 in hepatocarcinogenesis. Targeting PRDX2 is a previously undiscovered therapeutic opportunity for prevention of MASH-induced HCC. Citation Format: Emilie Crouchet, Eugénie Schaeffer, Frank Jühling, Hussein El Saghire, Anouk Charlot, Naoto Fujiwara, Shija Zhu, Fahmida Akter Rasha, Julien Moehlin, Marine A. Oudot, Clara Ponsolles, Romain Martin, Nicolas Brignon, Sarah C. Durand, Marie Parnot, Nourdine Hamdane, Danijela Heide, Jenny Hetzer, Mathias Heikenwälder, Emanuele Felli, Patrick Pessaux, Joffrey Zoll, Nathalie Pochet, Laurent Mailly, Yujin Hoshida, Thomas F. Baumert, Catherine Schuster. Targeting peroxiredoxin 2 prevents hepatocellular carcinoma development in metabolic liver disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2369.