Abstract
Aspergillus flavus is best known for producing aflatoxins, highly potent hepatocarcinogens that pose a major threat to global food security. Yet recent advances in fungal genomics and metabolomics reveal that aflatoxin biosynthesis represents only a small fraction of the organism's secondary metabolic capacity. In this review, we synthesize current knowledge of the diverse and largely underexplored secondary metabolome of A. flavus, encompassing both well-characterized compounds, such as cyclopiazonic acid, kojic acid, and aflatrem, and numerous cryptic metabolites predicted from genome mining. Genome-wide analyses indicate that A. flavus harbors approximately 40–50 biosynthetic gene clusters (BGCs), many of which remain transcriptionally silent under standard laboratory conditions. We examine the multilayered regulatory mechanisms governing BGC expression, including global transcriptional regulators, chromatin-associated regulatory processes linked to the LaeA–VeA–VelB complex, and environmental cues such as nutrient availability and oxidative stress. Beyond cataloging metabolic diversity, we discuss the ecological and pathogenic functions of A. flavus secondary metabolites in host colonization, microbial competition, and stress adaptation. Finally, we highlight emerging biotechnological strategies, ranging from CRISPR-based cluster activation and heterologous expression to synthetic biology platforms that are unlocking access to cryptic fungal metabolites. By reframing A. flavus as a dual-use organism —both a biosafety concern and a reservoir of exploitable chemical diversity— this review outlines a biotechnology-driven roadmap for harnessing fungal secondary metabolism for pharmaceutical and agricultural innovation.