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In\n                    <jats:italic>Candida glabrata<\/jats:italic>\n                    , however, it has rarely been reported. Here, we characterized heteroresistance in a multicenter collection of 156\n                    <jats:italic>C. glabrata<\/jats:italic>\n                    isolates, revealing a 25% prevalence with caspofungin specificity and 37\u00b0C dependent phenotypes. Transcriptomic profiling of the heteroresistant subpopulation under escalating drug pressure revealed an adaptive program centered on cell cycle and cell wall integrity, including several members of the calcineurin pathway. Mechanically, we identified that the phenotype was abolished by pharmacological inhibition or \u0394\n                    <jats:italic>cnb1<\/jats:italic>\n                    , \u0394\n                    <jats:italic>crz1<\/jats:italic>\n                    genetic deletion, confirming the regulatory role of calcineurin. Crucially, heteroresistance functioned as a reservoir for resistance, with in vitro descendant strains spanning a spectrum of MIC alterations. Mechanistically, we found the heteroresistance phenotype mostly independent of aneuploidy. To decipher the genetic basis, we applied an unbiased machine\u2010learning framework to genomic data, which not only identified the canonical\n                    <jats:italic>FKS2_F659del<\/jats:italic>\n                    mutation but also prioritized novel candidate\n                    <jats:italic>PIR2_G149_I167del<\/jats:italic>\n                    , demonstrating its power to uncover drivers of resistance from complex datasets. In summary, our study established a stepwise model of heteroresistance in\n                    <jats:italic>C. glabrata<\/jats:italic>\n                    , wherein calcineurin serves as a master regulator that promotes a resistance reservoir, revealing a potential vulnerability that could be exploited to prevent treatment failure.\n                  <\/jats:p>","DOI":"10.1002\/advs.76369","type":"journal-article","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T15:09:31Z","timestamp":1782659371000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Calcineurin\u2010Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in\n                    <i>Candida Glabrata<\/i>"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2671-8717","authenticated-orcid":false,"given":"Yanyu","family":"Su","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"},{"name":"Graduate School Chinese Academy of Medical Science and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 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Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Perlin","sequence":"additional","affiliation":[{"name":"Center For Discovery and Innovation Hackensack Meridian Health  111 Ideation Way Nutley New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Shor","sequence":"additional","affiliation":[{"name":"Center For Discovery and Innovation Hackensack Meridian Health  111 Ideation Way Nutley New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 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