ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Stem Cell Research
DPP4 inhibition affects metabolism and inflammation associated pathways in hiPSC-derived steatotic HLCs
Provisionally accepted
- 1Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Düsseldorf, Germany
- 2Zayed Center for Research into Rare Diseases in Children (ZGR), University College London Elizabeth Garrett Anderson Institute for Women's Health, London, United Kingdom
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Introduction: Metabolic dysfunction-associated steatotic liver disease (MAFLD) has a high prevalence and high co-morbidity for other diseases. Due to the complexity of this multifactorial disease, therapy options are still rather limited. We employed an in vitro pluripotent stem cell-based model to decipher potential disease-associated molecular pathways and to study the mode of action of prospective drugs. Dipeptidyl peptidase 4 (DPP4) or Cluster of differentiation 26 (CD26) is involved in inflammation, infections, immune disorders, type 2 diabetes, kidney disease and cancer. Methods: We induced the steatosis phenotype in human induced pluripotent stem cell (iPSC) derived hepatocyte-like cells (HLCs) by oleic acid (OA)-feeding and confirmed regulation of clinically relevant pathways by NGS-based global transcriptomic analyses. Analysis of the secretome of steatotic HLCs revealed DPP4 as a potential key mediator of the disease. To further elucidate its role in the development of MAFLD, we inhibited DPP4 activity with Vildagliptin (VILDA) and analyzed the global transcriptome changes as well as specific gene and protein expression of steatosis-associated genes with and without DPP4 inhibition. Results: MAFLD-associated pathways such as PPAR-and TNF signaling were differentially regulated in hiPSC-derived steatotic HLCs. We found increased hepatic DPP4 activity and secretion upon OA. Gene expression of fatty acid and purine metabolism and inflammation-associated pathways were regulated upon DPP4 inhibition. Discussion: Our HLC-model confirmed association of DPP4 with metabolism and inflammation which foster the development of MAFLD. Inhibiting DPP4 with VILDA partially relieved the steatotic phenotype on a global transcriptomic level. Impact and implications: This is a provisional file, not the final typeset article Given the difficulties of identifying suitable anti-MAFLD drugs, novel model systems are urgently needed. Our in vitro HLC-model reproduced DPP4-dependent aspects of the disease and responded positively to Vildagliptin treatment. Further elucidation of the role of DPP4 in the etiology of MAFLD and other diseases is warranted.
Keywords: Diabetes5, Dipeptidylpeptidase 4 (DPP4)3, Hepatocyte-like cells2, human induced pluripotent stem cells (iPSCs)1, MAFLD/MASLD4, Vildagliptin6
Received: 15 Aug 2025; Accepted: 08 Jan 2026.
Copyright: © 2026 Lörch, Wruck, Reiss, Adjaye and Graffmann. 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: Nina Graffmann
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