Cascading damage to Candida albicans cells through thioredoxin reductase loss.

Authors

Wanjun Qi, Udita Roy, Chunhui Cai, Maikel Acosta-Zaldívar, Jossalyn Mascio, John M Asara, José F Fierro, María T Andrés, Liang Sun, Julia R Köhler

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 33. Pages e2615451123. Aug 18, 2026. Epub Aug 10, 2026.

Abstract

Candida albicans is the most common invasive human fungal pathogen. We show that C. albicans 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. TRR1 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 TRR1 depletion. We unexpectedly find it also sensitizes Candida to cell wall stress and to a first-line echinocandin antifungal agent. TRR1-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's first, rate-limiting enzyme. Since UDP-glucose-the substrate for cell wall glucan biosynthesis-is 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 TRR1-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 C. albicans infections.

PMID:
42574622
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.