AUTHOR=Eitah Hebatollah E. , Sayed Rabab H. , Maklad Yousreya A. , Gamal el Din Amina A. , Mahmoud Khaled , El-Sahar Ayman E. , Alhejely Amani , Abdulbaqi Amal A. , Naeim Attia Hanan 

TITLE=Dipeptidyl peptidase-4 enzyme inhibition and its impacts on hepatic preneoplasia: a new avenue for liver cancer management

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1559303

DOI=10.3389/fphar.2025.1559303

ISSN=1663-9812

ABSTRACT=AimsDipeptidyl peptidase-4 enzyme (DPP-4) was reported to be associated with immune stimulation, resistance to anti-neoplastic agents and lipid accumulation. Dysregulated DPP-4 expression was reported in various malignant tumors such as hepatocellular carcinoma. Hence, the influence of sitagliptin, an inhibitor of DPP-4 enzyme, was performed in vitro (HepG2 cells) and in vivo (mouse model of hepatic preneoplasia).Main methodsThe effect of sitagliptin was investigated in vitro via MTT assay. The in vivo model of hepatic preneoplasia was conducted by weekly intraperitoneal injection of 75 mg/kg of diethylnitrosamine (DEN) for five successive weeks. Mice were treated daily with sitagliptin (50 mg/kg, p.o.) starting 1 week after DEN injection till the end of the experiment.Key findingsSitagliptin exerted a significant cytotoxic effect on HepG2 cells, which was dependent on elevating mRNA expression of p53 and BAX/BCL2. Sitagliptin also improved serum liver enzymes and attenuated histopathological alterations in mice. These changes were accompanied by reducing liver GGT, DPP-4, CYP2E1, GGT-P, NF-κB and PCNA along with increasing CYP3A4. Furthermore, sitagliptin attenuated DEN-induced liver DNA damage and inflammation.SignificanceThese findings shed the light on the role of DPP-inhibitors in the future of cancer therapy and management.