Cinnamaldehyde suppresses Candida albicans hyphal growth and augments macrophage immunity via the MAPK-NF-κB signaling axis.

Abstract

The yeast-to-hypha transition is a key virulence determinant of Candida albicans, yet effective agents that concurrently target fungal morphogenesis and host immunity remain scarce. This study aimed to investigate the inhibitory effect of cinnamaldehyde (CIN) on hyphal formation in C. albicans and its underlying immunomodulatory mechanisms. Through XTT metabolic activity assays, cellular fluorescence staining, scanning electron microscopy (SEM), and transcriptomic sequencing, we demonstrated that CIN significantly suppresses hyphal metabolic activity, disrupts hyphal morphology, and downregulates hypha-associated genes (including TEC1, HYR1, and ECE1). At the host immunity level, cellular fluorescence staining and flow cytometry confirmed that CIN enhances macrophage -mediated fungal uptake and clearance, reduces fungal escape, and inhibits pro-inflammatory cytokines TNF-α and IL-1β. Integrated transcriptomic and GEO database analysis revealed that CIN modulates the macrophage immune response to C. albicans via the MAPK-NF-κB signaling axis, as evidenced by downregulation of p-p38, p-ERK, and p-NF-κB, and this modulation is associated with Dectin-1 and TLR-mediated pathways. Furthermore, in a murine model of colitis complicated by C. albicans infection, CIN administration alleviated disease severity, reduced intestinal fungal burden, and suppressed systemic inflammation. These findings elucidate the dual role of CIN in suppressing hyphal growth and enhancing macrophage-mediated immune responses, providing new insights for the development of natural antifungal agents.