Academic Journal
Ethyl caffeate reprograms macrophage immunometabolism via the SIRT3-FOXO3A-AKT axis to enhance host defense against Candida auris.
| Title: | Ethyl caffeate reprograms macrophage immunometabolism via the SIRT3-FOXO3A-AKT axis to enhance host defense against Candida auris. |
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| Authors: | Yang X; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Li J; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Zhong Y; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Shen Y; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Xu C; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Nie Z; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Wang H; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Cao R; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210008, China., Wang M; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Zhang J; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Ma C; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Cai T; Shanghai Diacart Biomedical Science and Technology Limited Company, Shanghai 201203, China., Jia C; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Wang R; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China., Yin H; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China. Electronic address: haoyin183@126.com., Chen J; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China. Electronic address: alexandercj@126.com., Cao Y; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China. Electronic address: ybcao@vip.sina.com. |
| Source: | International immunopharmacology [Int Immunopharmacol] 2026 Jul 01; Vol. 180, pp. 116651. Date of Electronic Publication: 2026 Apr 25. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Amsterdam ; New York : Elsevier Science, c2001- |
| MeSH Terms: | Macrophages*/immunology , Macrophages*/drug effects , Macrophages*/metabolism , Sirtuin 3*/metabolism , Sirtuin 3*/genetics , Candidiasis*/immunology , Candidiasis*/drug therapy , Candida*/immunology , Antifungal Agents*/pharmacology , Caffeic Acids*/pharmacology, Forkhead Box Protein O3/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Phagocytosis/drug effects ; Animals ; Mice ; Mice, Inbred C57BL ; Mice, Knockout |
| Abstract: | Background: Candida auris (C. auris) is an emerging multidrug-resistant fungal pathogen. Current antifungals are often insufficient, creating a need for host-directed strategies. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that regulates redox homeostasis, but its role in antifungal macrophage defense is not well defined. We examined how SIRT3 shapes macrophage responses to C. auris. We also evaluated ethyl caffeate (EC) as a host-directed modulator. Methods: We used murine macrophages with Sirt3 knockdown or overexpression. We quantified phagocytosis, intracellular fungal survival, mitochondrial ROS dynamics, and macrophage cell integrity using imaging, flow cytometry, CFU assays, and LDH release. We profiled infection-induced transcriptional programs by RNA-seq and performed pathway analyses. We tested EC both in vitro and in systemic infection models in Drosophila and mice. We assessed pathway markers by immunoblotting and immunofluorescence. We used the SIRT3 inhibitor 3-TYP to test inhibition sensitivity. Results: SIRT3 deficiency impaired macrophage antifungal function and was accompanied by redox imbalance. mtROS regulation was disrupted in a biphasic pattern, with an early spike followed by late depletion. Transcriptomics linked SIRT3-dependent programs to FOXO and PI3K-AKT signaling. In macrophages, SIRT3 status tracked with FOXO3A acetylation and AKT phosphorylation. EC showed weak direct antifungal activity in vitro but improved outcomes in systemic infection models. EC treatment increased SIRT3 abundance and was associated with reduced FOXO3A acetylation and restrained infection-associated AKT activation. These functional and signaling effects were largely sensitive to SIRT3 inhibition by 3-TYP. Conclusion: This study connects SIRT3-dependent redox control to FOXO3A-AKT signaling during C. auris infection. It also supports EC as a host-directed candidate that improves antifungal defense in vivo while limiting inflammatory injury. (Copyright © 2026 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Candida auris; Ethyl caffeate; Host-directed therapy; Macrophage; Mitochondrial redox; Sirt3 |
| Substance Nomenclature: | EC 3.5.1.- (Sirtuin 3) 0 (Forkhead Box Protein O3) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) 0 (FoxO3 protein, mouse) 0 (Sirt3 protein, mouse) 0 (Antifungal Agents) 0 (Caffeic Acids) |
| Entry Date(s): | Date Created: 20260426 Date Completed: 20260716 Latest Revision: 20260716 |
| Update Code: | 20260716 |
| DOI: | 10.1016/j.intimp.2026.116651 |
| PMID: | 42035544 |
| Database: | MEDLINE |
| ISSN: | 1878-1705 |
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| DOI: | 10.1016/j.intimp.2026.116651 |