Timing is Everything: The Fungal Circadian Clock as a Master Regulator of Stress Response and Pathogenesis

Fungi, from saprophytes to pathogens, face predictable daily fluctuations in light, temperature, humidity, and nutrient availability. To cope, they have evolved an internal circadian clock that confers a major adaptive advantage. This review argues that the fungal clock is not a passive timekeeper but a proactive regulatory hub orchestrating stress responses, metabolism, and pathogenesis. We summarize current knowledge of the core oscillator—centered on the FREQUENCY/WHITE COLLAR (FRQ/WCC) tran-scription-translation feedback loop in Neurospora crassa—and examine non-canonical timekeeping mechanisms in yeasts like Saccharomyces cerevisiae. We propose that the clock "gates" cellular defenses against oxidative, osmotic, and nutritional stress, ena-bling fungi to anticipate and withstand environmental insults. A central focus is the emerging concept of chrono-pathogenesis, in which the circadian regulation of viru-lence factors aligns fungal attacks with host vulnerability, as shown in Botrytis cinerea and Fusarium oxysporum. We explore the downstream pathways translating temporal signals into physiological outputs, including rhythmic gene expression, protein modi-fications, and chromatin remodeling. Finally, we highlight critical knowledge gaps and propose future research directions, including the development of "chrono-fungicides"—novel therapeutics that disrupt fungal clocks—as a promising strategy for managing fungal infections in agriculture and medicine.