Toward Complex Polyketide Biosynthesis in Yarrowia lipolytica via Metabolic Reprogramming

Polyketides are among the most structurally diverse and therapeutically important classes of natural products, serving as antibiotics, anticancer agents, agrochemicals, and industrial pigments. Their structural complexity and limited natural availability have driven the development of microbial biosynthetic platforms as scalable and sustainable alternatives to traditional extraction or chemical synthesis. Yarrowia lipolytica, a non-conventional and metabolically versatile yeast, has emerged as a promising alternative chassis for polyketide biomanufacturing, owing to its streamlined central metabolism, high acetyl-CoA availability, and exceptional physiological robustness. Recent advances in metabolic engineering and synthetic biology have enabled extensive rewiring of Y. lipolytica metabolism to support the high-yield production of complex, high-value polyketides. This review summarizes state-of-the-art strategies, from classical metabolic rewiring to emerging approaches such as organelle engineering and subcellular compartmentalization. We further highlight representative case studies of polyketide biosynthesis in Y. lipolytica, critically assess current limitations, and explore future directions to establish this organism as a programmable, industrially viable platform for polyketide production.