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Although extensively characterized in higher eukaryotes, the functional roles of DUSPs in\n                    <jats:italic>Leishmania<\/jats:italic>\n                    remain poorly understood. In this study, we investigated the function of an atypical dual-specificity phosphatase\/kinatase (LINF_340027100) in\n                    <jats:italic>Leishmania infantum<\/jats:italic>\n                    using CRISPR\/Cas9-mediated genome editing. Repeated attempts to generate\n                    <jats:italic>DUSP<\/jats:italic>\n                    -null mutants were unsuccessful, and episomal complementation prior to chromosomal disruption did not permit deletion of the endogenous locus, suggesting that\n                    <jats:italic>DUSP<\/jats:italic>\n                    is essential for promastigote viability. To investigate DUSP function, we generated parasite lines with altered gene expression, including a heterozygous knockout (\n                    <jats:italic>Li<\/jats:italic>\n                    DUSP\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ) and an episomal overexpressor (\n                    <jats:italic>Li<\/jats:italic>\n                    WT\u2009+\u2009pIR1_SAT-DUSP). Modulation of\n                    <jats:italic>DUSP<\/jats:italic>\n                    expression resulted in pronounced alterations in parasite morphology, cell-cycle progression, differentiation, and intracellular proliferation in macrophages. The\n                    <jats:italic>Li<\/jats:italic>\n                    DUSP\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    line exhibited a twofold reduction in transcript abundance and maintained normal growth kinetics, but displayed elongated morphology, increased flagellar length, and a reduced G0\/G1 population with concomitant S-phase accumulation. In addition,\n                    <jats:italic>Li<\/jats:italic>\n                    DUSP\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    parasites showed decreased tolerance to hydrogen peroxide, being 1.5- and 5.7-fold more sensitive in promastigote and intracellular amastigote forms, respectively. Conversely, the\n                    <jats:italic>DUSP<\/jats:italic>\n                    -overexpressing line exhibited a 2.3-fold increase in\n                    <jats:italic>DUSP<\/jats:italic>\n                    transcript levels, accompanied by modest impairment of promastigote proliferation, rounded morphology, altered cell-cycle distribution, and increased resistance to trivalent antimony, with 2.6- and 3.1-fold higher resistance observed in promastigote and intracellular amastigote forms, respectively. Both mutant lines showed reduced intracellular proliferation at 72 h post-infection. Transcript level analysis revealed altered expression of\n                    <jats:italic>MAPK1<\/jats:italic>\n                    ,\n                    <jats:italic>MAPK3<\/jats:italic>\n                    , and\n                    <jats:italic>MAPK10<\/jats:italic>\n                    in both promastigote and axenic amastigote-like forms, supporting a functional link between DUSP activity and MAPK signaling homeostasis. Together, these findings identify DUSP as a key regulator of parasite biology that integrates MAPK signaling with oxidative stress response, differentiation, and antimony susceptibility in\n                    <jats:italic>L. infantum<\/jats:italic>\n                    . This study provides the first functional characterization of this atypical DUSP\/kinatase in\n                    <jats:italic>Leishmania<\/jats:italic>\n                    and highlights its potential as a target for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0014330","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T17:27:21Z","timestamp":1779816441000},"page":"e0014330","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["The atypical dual-specificity protein phosphatase (DUSP)\/kinatase of Leishmania infantum modulates infectivity, oxidative stress response and antimonial resistance"],"prefix":"10.1371","volume":"20","author":[{"given":"Juliana Martins","family":"Ribeiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna Ferreira da","family":"Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena Airi Kimura","family":"Anbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla Ferreira","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda Cristina Silva de","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine Ferreira","family":"Lopes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariza Gabriela Faleiro de Moura Lodi","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9llida Marina","family":"Costa-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria Murta","family":"Santi","sequence":"additional","affiliation":[],"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":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"pntd.0014330.ref001","unstructured":"WHO. 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