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Glycogen synthase kinase 3 (GSK-3) is a conserved serine\/threonine kinase involved in multiple cellular processes; however, its functional role in\n                      <jats:italic toggle=\"yes\">Leishmania<\/jats:italic>\n                      remains poorly defined. Here, we investigated the role of the short isoform of GSK-3 (GSK-3s) in\n                      <jats:italic toggle=\"yes\">L. infantum<\/jats:italic>\n                      using a CRISPR\/Cas9-based genetic approach. Attempts to generate chromosomal GSK-3s null mutants were unsuccessful, suggesting that GSK-3s is essential for parasite viability. Chromosomal gene deletion was achieved only after episomal complementation with\n                      <jats:italic toggle=\"yes\">L. braziliensis<\/jats:italic>\n                      GSK-3s, generating a GSK3s-deficient knockdown\n                      <jats:italic toggle=\"yes\">L. infantum<\/jats:italic>\n                      line (\n                      <jats:italic toggle=\"yes\">Li\u0394chrGSK3::LbGSK3<\/jats:italic>\n                      ). Quantitative PCR revealed a 3.8-fold and 9.6-fold reduction in GSK-3s transcript levels in this\n                      <jats:italic toggle=\"yes\">L. infantum<\/jats:italic>\n                      line compared with\n                      <jats:italic toggle=\"yes\">Li::Cas9<\/jats:italic>\n                      and GSK3-overexpressing (\n                      <jats:italic toggle=\"yes\">Li::LbGSK3<\/jats:italic>\n                      ) parasites, respectively. Reduced GSK-3s expression in this parasite line resulted in severe growth impairment, morphological alterations, and cell-cycle dysregulation. GSK-3s knockdown promastigotes exhibited a 5.3-fold increase in resistance to trivalent antimony and a 1.77-fold increase in resistance to miltefosine, as well as a striking 111-fold increase in resistance to the GSK-3 inhibitor 6-bromo-5-methylindirubin-3\u2032-oxime (6-BIO), supporting the specificity of this compound toward parasite GSK-3s. In addition, GSK-3s-deficient parasites displayed a 7.5-fold increase in tolerance to hydrogen peroxide-induced oxidative stress, accompanied by differential modulation of antioxidant defense gene transcripts. In infection models, GSK-3s knockdown parasites displayed reduced early infectivity in THP-1-derived macrophages and significantly lower splenic parasite burdens, with reductions of 1.5-fold in BALB\/c mice and 2.5-fold in IFN-\n                      <jats:italic toggle=\"yes\">\u03b3<\/jats:italic>\n                      <jats:sup>\u207b\/\u207b<\/jats:sup>\n                      C57BL\/6 mice. Collectively, these findings suggest that GSK-3s may play an important role in regulating\n                      <jats:italic toggle=\"yes\">L. infantum<\/jats:italic>\n                      growth, stress adaptation, drug response, and infectivity, indicating its potential as a target for anti-leishmanial drug development.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00247-26","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:56:26Z","timestamp":1783349786000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Essential role of glycogen synthase kinase 3 in regulating growth, drug response, and infectivity in\n                    <i>Leishmania infantum<\/i>"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0828-790X","authenticated-orcid":true,"given":"Mariza Gabriela Faleiro de Moura Lodi","family":"Cruz","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Viana Moreira","family":"Silva","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0237-0183","authenticated-orcid":true,"given":"Giovanna Cec\u00edlia de Paula e","family":"S\u00e1","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8668-5634","authenticated-orcid":true,"given":"Juliana Martins","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4215-1829","authenticated-orcid":true,"given":"Giovanna Ferreira da","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1184-778X","authenticated-orcid":true,"given":"Davi Alvarenga","family":"Lima","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8694-0754","authenticated-orcid":true,"given":"Karine Ferreira","family":"Lopes","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9791-6554","authenticated-orcid":true,"given":"Ana Maria Murta","family":"Santi","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Carlos Chagas","place":["Curitiba, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8523-2155","authenticated-orcid":true,"given":"Silvane Maria Fonseca","family":"Murta","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz, Instituto Ren\u00e9 Rachou","place":["Belo Horizonte, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67629-5"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31204-2"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2014.07.016"},{"key":"e_1_3_4_5_2","unstructured":"World Health Organization. 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