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Peer-reviewedCC BY 4.0Frontiers in Microbiology

Berberine-fluconazole synergy against drug-resistant Candida albicans: association with disruption of the Ire1-mediated UPR pathway

  • Daifan Yue1,2
  • Dongming Zheng1,3
  • Zhen Song1
  • Dongmei Li1
  • Yan Li1
  1. 1College of Medical Technology, Chengdu University of Traditional Chinese Medicine
  2. 2Department of Laboratory Medicine, Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Sichuan Clinical Research Center for Laboratory Medicine
  3. 3Department of Nuclear Medicine, Ya’an People’s Hospital
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Abstract

Objectives: Candida albicans -associated invasive candidiasis exhibits high mortality. Azole resistance and biofilm-mediated persistent infections greatly weaken clinical antifungal efficacy, necessitating new therapeutic approaches. This study investigated the synergistic antifungal and antibiofilm activities of berberine (BBR) combined with fluconazole (FCZ) against drug-resistant C. albicans , and explored potential pathways correlated with this synergistic phenotype.

Methods: Synergistic antifungal effects were verified via fractional inhibitory concentration index and time-kill curve assays. Crystal violet staining and Spider plate culture evaluated biofilm formation and fungal morphology. Transcriptome sequencing was performed to screen potential regulatory pathways and drug targets. Endoplasmic reticulum (ER) homeostasis was assessed by examining ultrastructural changes, misfolded protein accumulation, stress sensitivity and secreted protease activity. HAC1 splicing and unfolded protein response (UPR)-related gene expression were analyzed to characterize UPR signaling alterations. Autophagy activation was evaluated via ultrastructural observation, vacuole staining, pharmacological inhibition, and detection of autophagy-related gene transcription and Atg1 protein abundance.

Results: BBR combined with FCZ exerted synergistic antifungal effects against drug-resistant C. albicans and inhibited biofilm formation. Combined treatment disrupted ER homeostasis and attenuated the Ire1-mediated UPR signaling response in C. albicans . It induced autophagy-associated alterations, accompanied by vacuolar structural impairment, up-regulated transcription of autophagy-related genes, and increased Atg1 protein abundance.

Conclusion: The synergistic effect of BBR combined with FCZ is associated with ER stress pathway dysregulation and autophagy activation in C. albicans . This study provides a potential therapeutic strategy for azole-resistant candidiasis, while further investigations are required to elucidate the precise underlying molecular mechanisms.

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Cite

BibTeXRIS
BibTeX
@article{yue2026berberinefluconazole,
  title = {{Berberine-fluconazole synergy against drug-resistant Candida albicans: association with disruption of the Ire1-mediated UPR pathway}},
  author = {Daifan Yue and Dongming Zheng and Zhen Song and Dongmei Li and Yan Li},
  journal = {Frontiers in Microbiology},
  year = {2026},
  month = oct,
  doi = {10.3389/fmicb.2026.1965937},
  url = {https://www.frontiersin.org/articles/10.3389/fmicb.2026.1965937/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Berberine-fluconazole synergy against drug-resistant Candida albicans: association with disruption of the Ire1-mediated UPR pathway
AU  - Daifan Yue
AU  - Dongming Zheng
AU  - Zhen Song
AU  - Dongmei Li
AU  - Yan Li
PY  - 2026
DA  - 2026/10/09
JO  - Frontiers in Microbiology
DO  - 10.3389/fmicb.2026.1965937
UR  - https://www.frontiersin.org/articles/10.3389/fmicb.2026.1965937/full
AB  - Objectives: Candida albicans -associated invasive candidiasis exhibits high mortality. Azole resistance and biofilm-mediated persistent infections greatly weaken clinical antifungal efficacy, necessitating new therapeutic approaches. This study investigated the synergistic antifungal and antibiofilm activities of berberine (BBR) combined with fluconazole (FCZ) against drug-resistant C. albicans , and explored potential pathways correlated with this synergistic phenotype.  Methods: Synergistic antifungal effects were verified via fractional inhibitory concentration index and time-kill curve assays. Crystal violet staining and Spider plate culture evaluated biofilm formation and fungal morphology. Transcriptome sequencing was performed to screen potential regulatory pathways and drug targets. Endoplasmic reticulum (ER) homeostasis was assessed by examining ultrastructural changes, misfolded protein accumulation, stress sensitivity and secreted protease activity. HAC1 splicing and unfolded protein response (UPR)-related gene expression were analyzed to characterize UPR signaling alterations. Autophagy activation was evaluated via ultrastructural observation, vacuole staining, pharmacological inhibition, and detection of autophagy-related gene transcription and Atg1 protein abundance.  Results: BBR combined with FCZ exerted synergistic antifungal effects against drug-resistant C. albicans and inhibited biofilm formation. Combined treatment disrupted ER homeostasis and attenuated the Ire1-mediated UPR signaling response in C. albicans . It induced autophagy-associated alterations, accompanied by vacuolar structural impairment, up-regulated transcription of autophagy-related genes, and increased Atg1 protein abundance.  Conclusion: The synergistic effect of BBR combined with FCZ is associated with ER stress pathway dysregulation and autophagy activation in C. albicans . This study provides a potential therapeutic strategy for azole-resistant candidiasis, while further investigations are required to elucidate the precise underlying molecular mechanisms.
SN  - 1664-302X
ER  -