Your new experience awaits. Try the new design now and help us make it even better

ORIGINAL RESEARCH article

Front. Pharmacol.

Sec. Drug Metabolism and Transport

Volume 16 - 2025 | doi: 10.3389/fphar.2025.1559303

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

Provisionally accepted
Hebatollah EitahHebatollah Eitah1*Rabab SayedRabab Sayed2,3yousreya makladyousreya maklad1amina Gamal el Dinamina Gamal el Din1khaled mahmoudkhaled mahmoud1Ayman ElsaharAyman Elsahar3Amani AlhejelyAmani Alhejely4Amal AbdulbaqiAmal Abdulbaqi4Hanan NaeimHanan Naeim1
  • 1National Research Centre (Egypt), Cairo, Egypt
  • 2Faculty of Pharmacy, Cairo University, Giza, Cairo, Egypt
  • 3School of Pharmacy, New Giza University, Giza, Beni Suef, Egypt
  • 4Jazan University, Jizan, Saudi Arabia

The final, formatted version of the article will be published soon.

Select one of your emails

You have multiple emails registered with Frontiers:

Notify me on publication

Please enter your email address:

If you already have an account, please login

You don't have a Frontiers account ? You can register here

Dipeptidyl 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).The 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 one week after DEN injection till the end of the experiment.Sitagliptin 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.These findings shed the light on the role of DPP-inhibitors in the future of cancer therapy and management.

Keywords: CYP2E1, CYP3A4, Diethylnitrosamine, DPP-4, hepatic preneoplasia, sitagliptin

Received: 14 Jan 2025; Accepted: 27 Jun 2025.

Copyright: © 2025 Eitah, Sayed, maklad, Gamal el Din, mahmoud, Elsahar, Alhejely, Abdulbaqi and Naeim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Hebatollah Eitah, National Research Centre (Egypt), Cairo, Egypt

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material