The GET pathway modulates azole susceptibility through sterol metabolic remodeling and protein trafficking in filamentous fungi.

Disruption of the GET pathway increases azole resistance in filamentous fungi by altering sterol metabolism and protein trafficking, with Get-3 or Get-4 deletion conferring resistance without growth defects.

• Why it matters: Understanding non-traditional resistance mechanisms is vital as azole antifungal efficacy declines, and current knowledge focuses mainly on efflux and target modifications, leaving gaps in resistance pathways.
• What they did: Researchers used genetic deletions, proximity labeling, and transcriptomic analyses to investigate the GET pathway in Neurospora crassa and Aspergillus fumigatus, identifying 19 new resistance-related genes and mechanisms.
• The result: Findings reveal that GET deficiency reduces toxic sterol intermediates and disrupts trafficking of key proteins, providing a novel perspective on fungal stress adaptation and resistance, which could inform future antifungal strategies.