{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T02:12:48Z","timestamp":1773972768552,"version":"3.50.1"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2020_EKEA.64"],"award-info":[{"award-number":["2020_EKEA.64"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009400","name":"Medizinische Fakult\u00e4t, Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009400","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Metabolic dysfunction-associated steatotic liver disease (MAFLD) has a high prevalence and high comorbidity for other diseases. Due to the complexity of this multifactorial disease, therapy options are still rather limited. We employed an\n                      <jats:italic>in vitro<\/jats:italic>\n                      pluripotent stem cell-based model to decipher potential disease-associated molecular pathways and 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 transcriptomic changes and specific gene and protein gene expression of steatosis-associated genes with and without DPP4 inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 feeding. Gene expression of fatty acid and purine metabolism and inflammation-associated pathways was regulated upon DPP4 inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our HLC model confirmed the association of DPP4 with metabolism and inflammation, which foster the development of MAFLD. Inhibiting DPP4 activity with VILDA partially relieved the steatotic phenotype on a global transcriptomic level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Impact and implications<\/jats:title>\n                    <jats:p>\n                      Given the difficulties of identifying suitable anti-MAFLD drugs, novel model systems are urgently needed. Our\n                      <jats:italic>in vitro<\/jats:italic>\n                      HLC-model reproduced the DPP4-dependent aspects of the disease and responded positively to VILDA treatment. Further elucidation of the role of DPP4 in the etiology of MAFLD and other diseases is warranted.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1686556","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:55:00Z","timestamp":1772088900000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["DPP4 inhibition affects metabolism and inflammation associated pathways in hiPSC-derived steatotic HLCs"],"prefix":"10.3389","volume":"14","author":[{"given":"Christiane","family":"Loerch","sequence":"first","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University","place":["D\u00fcsseldorf, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wasco","family":"Wruck","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University","place":["D\u00fcsseldorf, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Wittich","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort","place":["Hamburg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabea","family":"Hokamp","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University","place":["D\u00fcsseldorf, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Reiss","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University","place":["D\u00fcsseldorf, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ole","family":"Pless","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort","place":["Hamburg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Adjaye","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University","place":["D\u00fcsseldorf, Germany"]},{"name":"University College London, EGA Institute for Women`s Health, Zayed Center for Research into Rare Diseases in Children (ZGR)","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Graffmann","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University","place":["D\u00fcsseldorf, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1016\/j.jcmgh.2022.08.001","article-title":"Sex-dependent hepatoprotective role of IL-22 receptor signaling in non-alcoholic fatty liver disease-related fibrosis","volume":"14","author":"Abdelnabi","year":"2022","journal-title":"Cell Mol. 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