1 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
2 Department of Biology, Concordia University, Montreal, QC, Canada.
3 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Pathogen-Host Interaction, Ministry of Education, School of Medicine, Tongji University, Shanghai, China. Electronic address: jiangyy@tongji.edu.cn.
4 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Key Laboratory of Pathogen-Host Interaction, Ministry of Education, School of Medicine, Tongji University, Shanghai, China. Electronic address: luhui2019@tongji.edu.cn.

Human body temperature has been shown to limit the antifungal efficacy of azoles; however, the precise mechanisms underlying this limitation remain insufficiently understood. In this study, we observed that short-term exposure (24 h) to human body temperature (37 °C), in contrast to 30 °C, significantly enhances the tolerance of Candida albicans to azoles without inducing resistance. Our findings suggest that this increased tolerance is due to a reduction in the degradation of C. albicans Erg11 at 37 °C compared to 30 °C, thereby promoting azole tolerance. This phenomenon occurs because Erg11 degradation is mediated by autophagy, which is inhibited in C. albicans at 37 °C. The suppression of autophagy at this temperature may be associated with elevated mitochondrial production of reactive oxygen species, leading to mitochondrial dysfunction. In response to heat stress-induced mitochondrial dysfunction, autophagy-related proteins such as Atg8 accumulate around the mitochondria, while their levels in the endoplasmic reticulum decrease, consequently inhibiting autophagy in C. albicans. These findings suggest that promoting the degradation of Erg11 in C. albicans may serve as a viable strategy to augment the fungicidal efficacy of azoles in the human host.