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Understanding of host-parasite interactions during liver stage development is compromised by the rapid loss of functionality and Pf permissiveness of cultured primary human hepatocytes (PHHs). Here, we substantially delay the loss of Pf permissiveness by using a medium containing serum-replacement and signal transduction inhibitors. We analyzed and integrated transcriptomic profiles of cultured PHHs with the phenotypic presentation of developing Pf liver stages, revealing a number of host signaling pathways that contributed to dedifferentiation of hepatocytes and influenced Pf liver stage development. In particular, inhibition of the Wnt pathway showed a significant positive impact on size and maturity of Pf liver stage schizonts, while retaining the metabolic activity and epithelial nature of PHHs. Therefore, our study provides insights into hepatocyte characteristics that are important for Pf permissiveness and an improved\n                    <jats:italic>in vitro<\/jats:italic>\n                    liver stage model. This should facilitate identification and development of novel therapeutic strategies for Pf liver stages.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013800","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T18:33:18Z","timestamp":1766428398000},"page":"e1013800","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of Wnt signaling in primary human hepatocytes promotes Plasmodium falciparum liver stage development"],"prefix":"10.1371","volume":"21","author":[{"given":"Abhishek","family":"Kanyal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geert-Jan","family":"van Gemert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoyu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"van der Starre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes H.W.","family":"de Wilt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teun","family":"Bousema","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W.","family":"Sauerwein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rich\u00e1rd","family":"B\u00e1rtfai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7279-6058","authenticated-orcid":true,"given":"Annie S. 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