Antifungal Activity of the Lipophilic Antioxidant Ferrostatin‐1

Abstract

Ferrostatin-1 (Fer-1) is a lipophilic antioxidant that effectively blocks ferroptosis, a distinct non-apoptotic form of cell death caused by lipid peroxidation. During many infections, both pathogens and host cells are subjected to oxidative stress, but the occurrence of ferroptosis had not been investigated. We examined ferroptosis in macrophages infected with the pathogenic yeast Histoplasma capsulatum. Unexpectedly, Fer-1 not only reduced the death of macrophages infected in vitro, but inhibited the growth of H. capsulatum and related species Paracoccidioides lutzii and Blastomyces dermatitidis at concentrations under 10 μm. Other antioxidant ferroptosis inhibitors, including liproxstatin-1, did not prevent fungal growth or reduce macrophage death. Structural analysis revealed a potential similarity of Fer-1 to inhibitors of fungal sterol synthesis, and ergosterol content of H. capsulatum decreased more than twofold after incubation with Fer-1. Strikingly, additional Fer-1 analogues with slight differences from Fer-1 had limited impact on fungal growth. In conclusion, the ferroptosis inhibitor Fer-1 has unexpected antifungal potency distinct from its antiferroptotic activity.

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

“…S6). This finding is consistent with previous reports showing that Fer-1 treatment reduces macrophage cell death during Histoplasma capsulatum infection 66 . Increased BMDM survival was associated with increased C. albicans killing (Fig.…”

Regulation of lipid peroxidation and ferroptosis in diverse species

“…Further detailed studies of ferroptosis pathway components and regulators may uncover a possible ancient origin and role of ferroptosis in archaea, bacteria, and fungi or their participation in nondeath mechanisms. These studies have to be performed carefully, as use of only a few characteristic ferroptosis inhibitors may yield misleading results, as illustrated by a study on macrophages infected with the pathogenic yeast Histoplasma capsulatum (Horwath et al 2017). It was found that a prototypical ferroptosis inhibitor, ferrostatin-1, reduced the death of macrophages, implying a possible ferroptotic mechanism.…”

Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?

“…However, we need to pay more attention to the direct inhibitory effect of the regulator on pathogens. One study pointed out that Fer-1, a commonly used ferroptosis-inhibiting agent, reduced growth of C. neoformans in the YNB media by >95% ( 116 ). Hence, when designing an experiment, we should be able to regulate ferroptosis through multiple pathways.…”

“…Similarly, another study discovered that macrophages infected with Histoplasma capsulatum , an environmentally-acquired fungal pathogen, can also lead to increased intracellular oxidation products, and eventually cell death ( 116 ). Despite the fact that the ferroptosis inhibitor Fer-1 can reduce the cell death caused by H. capsulatum infection, further experiments have validated that the mechanism decreases fungal ergosterol synthesis, instead of inhibiting ferroptosis ( 116 ). Consequently, upon exploring the relationship between ferroptotic cell death and pathogenic mechanism of pathogens, attention needs to be paid to ferroptosis inhibitors, especially Fer-1, which may have a direct inhibitory effect on pathogens.…”