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Azole antifungals are the primary treatment for this pathogen; however, the prevalence of azole-resistant\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      strains is steadily increasing. Mutations in\n                      <jats:italic toggle=\"yes\">cyp51A<\/jats:italic>\n                      , which encodes an enzyme involved in ergosterol biosynthesis and the molecular target of the azoles, are well established to confer resistance in this fungal species. However, additional mechanisms governing resistance to this antifungal class remain understudied and poorly characterized, despite growing recognition of their importance in clinical resistance. In this study, we investigated the genetic basis of azole resistance in\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      isolates from clinical settings worldwide, with a particular focus on mechanisms independent of\n                      <jats:italic toggle=\"yes\">cyp51A<\/jats:italic>\n                      (non-canonical). Using a combination of genomic and functional approaches, including whole-genome sequencing and transcriptomic analysis, we identified novel genetic variants and characterized population structure, advancing our understanding of the genetic diversity and evolutionary dynamics of resistance in\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      . By expanding our understanding of the complex genetic and molecular factors underlying azole resistance in this important human fungal pathogen, this research is poised to inform the development of novel antifungal strategies and contribute to global efforts to combat fungal infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Azole antifungals are the frontline therapy for infections caused by the opportunistic mold\n                      <jats:italic toggle=\"yes\">Aspergillus fumigatus<\/jats:italic>\n                      , yet resistance to these drugs is rapidly increasing worldwide. Most studies have focused on mutations in\n                      <jats:italic toggle=\"yes\">cyp51A<\/jats:italic>\n                      , the canonical target of azoles; however, a growing proportion of resistant clinical isolates lack these mutations, indicating that alternative resistance mechanisms are emerging. Here, we integrate population genomics, transcriptomics, and functional analyses across a global collection of isolates to define the architecture of\n                      <jats:italic toggle=\"yes\">cyp51<\/jats:italic>\n                      -independent (non-canonical) azole resistance. We show that this resistance phenotype is strongly associated with a distinct population lineage and is driven by a highly polygenic network of metabolic, mitochondrial, and regulatory adaptations rather than single target site mutations. These isolates exhibit extensive transcriptional rewiring and metabolic remodeling under azole stress, suggesting distinct survival strategies beyond canonical resistance. Our findings reveal that azole resistance in\n                      <jats:italic toggle=\"yes\">A. fumigatus<\/jats:italic>\n                      can evolve through diverse evolutionary routes and emphasize the need to monitor and therapeutically target non-canonical pathways that may increasingly contribute to antifungal treatment failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01723-26","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:00:39Z","timestamp":1787144439000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Identification and characterization of non-canonical azole antifungal resistance pathways in\n                    <i>Aspergillus 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