2. Academic Validation
  3. Targeting the NRF2 pathway with linagliptin to inhibit human hepatocellular carcinoma growth

Targeting the NRF2 pathway with linagliptin to inhibit human hepatocellular carcinoma growth

  • Free Radic Biol Med. 2025 Jun 26:238:303-315. doi: 10.1016/j.freeradbiomed.2025.06.048.
Yu-Teng Chang 1,  Chia-Che Chang 2,  Ming-Jen Chang 1,  Jeng-Jer Shieh 3,  Ming-Ju Wu 4
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 402, Taiwan.
  • 2 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 402, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 402, Taiwan.
  • 3 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 402, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 402, Taiwan; Department of Education and Research, Taichung Veterans General Hospital, Taichung, 407, Taiwan. Electronic address: shiehjj@dragon.nchu.edu.tw.
  • 4 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 402, Taiwan; Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 407, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan; Graduate Institute of Clinical Medical Sciences, School of Medicine, China Medical University, Taichung, 404, Taiwan. Electronic address: wmj530@gmail.com.
PMID: 40581165 DOI: 10.1016/j.freeradbiomed.2025.06.048
Abstract

Linagliptin, a potent Dipeptidyl Peptidase 4 (DPP4) inhibitor, demonstrates significant potential as a therapeutic agent for hepatocellular carcinoma (HCC). This study evaluated the effects of linagliptin on HCC cell lines, focusing on mechanisms involving Reactive Oxygen Species (ROS) production, nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation, and Autophagy. Linagliptin effectively suppressed cell proliferation and induced Apoptosis in HCC cell lines, particularly Hep3B cells, while sparing normal hepatic cells. It promoted ROS production and activated the NRF2 pathway and Autophagy, highlighting a dual role in tumor regulation. Combination therapy with linagliptin and the NRF2 inhibitor brusatol enhanced tumor cell death, suggesting synergistic efficacy. In vivo, linagliptin reduced tumor growth in a xenograft model, with further suppression observed when combined with brusatol. These findings underscore linagliptin's therapeutic potential and its combinatorial efficacy with NRF2 inhibitors, providing a foundation for further clinical investigation in HCC treatment.

Keywords

Brusatol; Dipeptidyl peptidase 4; Hepatocellular carcinoma; Linagliptin; Nuclear factor erythroid 2–related factor 2.

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