Harnessing the power of abiotic inducers to enhance fungal secondary metabolite production: a review.

Fungi and yeasts are prolific producers of structurally diverse secondary metabolites with extensive applications in pharmaceutical, food, agricultural, and industrial biotechnology. Conventional strategies to enhance metabolite production have largely relied on rational metabolic and genetic engineering; however, these approaches are often constrained by incomplete pathway knowledge, metabolic burden, regulatory complexity, and biosafety concerns associated with genetically engineered microorganisms. In recent years, the application of abiotic stresses has emerged as a powerful and complementary strategy to activate silent biosynthetic gene clusters and redirect metabolic fluxes without direct genetic manipulation. This review provides a comprehensive overview of abiotic stress-based approaches for enhancing secondary metabolite production in fungi and yeasts. We systematically examine the effects of major stress categories, including osmotic, oxidative, pH, solvent-induced, radiation, and heavy metal stresses, on microbial metabolism and secondary metabolite biosynthesis. Evidence from diverse fungal and yeast models demonstrates that controlled stress exposure can significantly increase the yield and diversity of metabolites such as pigments, carotenoids, antibiotics, statins, lipids, organic acids, osmolytes, and antioxidants. Importantly, this review highlights that stress responses are highly strain- and metabolite-specific, underscoring the need for tailored stress packages optimized for individual industrial strains or target compounds. We also discuss universally stress-responsive metabolites, such as proline and trehalose, which consistently accumulate under multiple stress conditions and represent promising leverage points for metabolic improvement. Overall, abiotic stress-induced metabolic engineering offers a cost-effective, flexible, and non-GMO strategy to enhance fungal and yeast metabolite production, with significant implications for industrial biotechnology and natural product discovery.