{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:21:05Z","timestamp":1788315665968,"version":"build-2803163510"},"reference-count":79,"publisher":"National Academy of Sciences","issue":"33","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI178693"],"award-info":[{"award-number":["R21AI178693"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:p>\n                    <jats:italic toggle=\"yes\">Candida albicans<\/jats:italic>\n                    is the most common invasive human fungal pathogen. We show that\n                    <jats:italic toggle=\"yes\">C. albicans<\/jats:italic>\n                    thioredoxin reductase, Trr1, is an attractive antifungal target: it is essential at human body temperature, and fungal and human thioredoxin reductases are structurally divergent, predicting high selectivity of fungal-targeted inhibitors.\n                    <jats:italic toggle=\"yes\">TRR1<\/jats:italic>\n                    depletion directly impairs oxidative damage repair, but also triggers cascading disruption of stress signaling and metabolic adaptation. Impaired oxidative stress endurance and consequent amphotericin hypersensitivity are anticipated effects of\n                    <jats:italic toggle=\"yes\">TRR1<\/jats:italic>\n                    depletion. We unexpectedly find it also sensitizes\n                    <jats:italic toggle=\"yes\">Candida<\/jats:italic>\n                    to cell wall stress and to a first-line echinocandin antifungal agent.\n                    <jats:italic toggle=\"yes\">TRR1<\/jats:italic>\n                    -depleted cells have decreased cell wall glucan content. Driven by demand for NADPH reducing equivalents, these cells increase glucose-6-phosphate flux into the pentose phosphate pathway (PPP) as evinced by sharply elevated activity of the PPP\u2019s first, rate-limiting enzyme. Since UDP-glucose\u2014the substrate for cell wall glucan biosynthesis\u2014is also derived from glucose-6-phosphate, we propose that metabolic pathway competition for this shared intermediate between NADPH production and cell wall glucan biosynthesis underlies the cell wall weakness of\n                    <jats:italic toggle=\"yes\">TRR1<\/jats:italic>\n                    -depleted cells. Decreased activity of a key UDP-glucose biosynthetic enzyme supports this mechanism. Trr1 loss of function further drives feed-forward damage cycles: it accelerates respiration which increases reactive oxygen species, reduces gluconeogenesis which further limits glucose-6-phosphate availability, and suppresses oxidative- and cell wall stress signaling pathways. Our findings support Trr1 inhibition as a promising approach to improved treatment of\n                    <jats:italic toggle=\"yes\">C. albicans<\/jats:italic>\n                    infections.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2615451123","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T19:09:16Z","timestamp":1786388956000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Cascading damage to\n                    <i>Candida albicans<\/i>\n                    cells through thioredoxin reductase loss"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4593-5734","authenticated-orcid":false,"given":"Wanjun","family":"Qi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00dvg7y05","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, Boston Children\u2019s Hospital\/Harvard Medical 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