Engineering of Microbial Cell Factories for Flavonoid Production: from Flavanone Platforms to Tailored Derivatives

Abstract Flavonoids are valuable plant polyphenols used in foods, nutraceuticals, cosmetics, and pharmaceuticals. However, their production is limited by the low abundance of many flavonoids in plants and the structural complexity that complicates chemical synthesis. Microbial cell factories provide a sustainable alternative, yet engineering requirements increase sharply from platform flavanones to oxidized and multiply tailored derivatives. This Review organizes recent advances according to product complexity, covering flavanones, oxidized flavones and flavonols, and methylated, glycosylated, and prenylated flavonoids. We examine the major constraints at each product level, including aromatic precursor and malonyl-CoA supply, enzyme activity and selectivity, redox and oxygen demands, and the regeneration of activated methyl, sugar, and prenyl donors. We further highlight the need to coordinate scaffold formation, oxidation, tailoring reactions, donor regeneration, and host metabolism rather than optimizing individual pathway steps independently. Finally, emerging artificial intelligence (AI)-assisted strategies for enzyme engineering, demand-responsive pathway regulation, automated design−build−test−learn (DBTL) cycles, and virtual-cell modeling are discussed. This product-complexity-oriented framework provides design principles for developing efficient, modular, and programmable microbial platforms for flavonoid biomanufacturing.