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Here, we uncover a mechanism of acquired azole resistance in\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    through mutations in\n                    <jats:italic>CAP1<\/jats:italic>\n                    , encoding a conserved fungal transcription factor that mediates the oxidative stress response. We analyzed 300 clinical isolates and identified 25 distinct\n                    <jats:italic>CAP1<\/jats:italic>\n                    missense or nonsense mutations, with many occurring within the DNA-binding domain. We identified two nearly identical\n                    <jats:italic>CAP1<\/jats:italic>\n                    heterozygous nonsense mutations, one in an isolate obtained from a bloodstream infection and one in a population of cells undergoing adaptation to fluconazole\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Both\n                    <jats:italic>CAP1<\/jats:italic>\n                    nonsense mutations resulted in loss of the C-terminal nuclear export signal, leading to nuclear retention of Cap1 and subsequent activation of genes associated with the oxidative stress response and drug transport. The\n                    <jats:italic>CAP1<\/jats:italic>\n                    C-terminal truncations conferred significant fitness advantages in the presence of fluconazole, both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and in a murine model of candidiasis. Strikingly, we discovered a therapeutic vulnerability: azole concentrations above the minimal inhibitory concentration were fungicidal to mutants with the\n                    <jats:italic>CAP1<\/jats:italic>\n                    C-terminal truncation. The fungicidal effect was attributed to both elevated azole-induced reactive oxygen species and a compromised oxidative stress response in Cap1-truncated cells. Our results provide novel characterization of\n                    <jats:italic>de novo<\/jats:italic>\n                    <jats:italic>CAP1<\/jats:italic>\n                    point mutations emerging in both laboratory and clinical contexts, elucidate the mechanisms underlying Cap1-regulated stress responses, and reveal a potential therapeutic target for overcoming drug resistance in\n                    <jats:italic>C. albicans<\/jats:italic>\n                    infections.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003631","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T18:53:02Z","timestamp":1770058382000},"page":"e3003631","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Recurrent mutations in the stress regulator Cap1 reveal a trade-off between azole resistance and oxidative stress response in Candida albicans"],"prefix":"10.1371","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5323-173X","authenticated-orcid":true,"given":"Xin","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Hilk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma V.","family":"Solis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Zajac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott G.","family":"Filler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3298-2400","authenticated-orcid":true,"given":"Anna","family":"Selmecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"pbio.3003631.ref001","doi-asserted-by":"crossref","DOI":"10.1016\/j.amjmed.2011.11.001","article-title":"Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment","volume":"125","author":"MA Pfaller","year":"2012","journal-title":"Am J Med"},{"key":"pbio.3003631.ref002","doi-asserted-by":"crossref","DOI":"10.1093\/ofid\/ofy358","article-title":"Twenty years of the SENTRY antifungal surveillance program: results for Candida species from 1997-2016","volume":"6","author":"MA Pfaller","year":"2019","journal-title":"Open Forum Infect 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