The study shows that the human antimicrobial peptide LL‑37 attacks the fungus Candida albicans by stressing its cell wall and causing internal stress in the fungus’s protein‑making factories, and that a fungal gene called SFP1 makes the fungus more sensitive to this attack. Deleting SFP1 makes the fungus less vulnerable and changes how it handles stress.

<i>Candida albicans</i> is a commensal fungus of humans but can cause infections, particularly in immunocompromised individuals, ranging from superficial to life-threatening systemic infections. The cell wall is the outermost layer of <i>C. albicans</i> that interacts with the host environment. Moreover, antimicrobial peptides (AMPs) are important components in innate immunity and play crucial roles in host defense. Our previous studies showed that the human AMP LL-37 binds to the cell wall of <i>C. albicans</i>, alters the cell wall integrity (CWI) and affects cell adhesion of this pathogen. In this study, we aimed to further investigate the molecular mechanisms underlying the <i>C. albicans</i> response to LL-37. We found that LL-37 causes cell wall stress, activates unfolded protein response (UPR) signaling related to the endoplasmic reticulum (ER), induces ER-derived reactive oxygen species and affects protein secretion. Interestingly, the deletion of the <i>SFP1</i> gene encoding a transcription factor reduced <i>C. albicans</i> susceptibility to LL-37, which is cell wall-associated. Moreover, in the presence of LL-37, deletion of <i>SFP1</i> attenuated the UPR pathway, upregulated oxidative stress responsive (OSR) genes and affected bovine serum albumin (BSA) degradation by secreted proteases. Therefore, these findings suggested that Sfp1 positively regulates cell wall integrity and ER homeostasis upon treatment with LL-37 and shed light on pathogen-host interactions.