Polyunsaturated fatty acids (PUFAs) play critical roles in human growth and development, visual and neurological function, and cardiovascular health, and are widely used in the food, pharmaceutical, and other industries. Traditional PUFA sources are primarily derived from deep-sea fish, which are constrained by fishery resources and environmental pollution, highlighting the urgent need for sustainable production methods. The anaerobic polyketide synthase pathway mediated by PUFA synthase in marine microorganisms efficiently synthesizes docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and other important PUFAs. PUFA synthase has become the core enzyme for sustainable industrial PUFA production. This review systematically summarizes recent advances in the structural and functional mechanisms of PUFA synthase, with an emphasis on key domains including acyl carrier protein, ketosynthase, acyltransferase, dehydratase, and enoyl reductase. The latest progress on the roles of these domains in chain-length determination and double-bond introduction is summarized. On this basis, we review metabolic engineering strategies for PUFA-producing microorganisms, especially thraustochytrids, based on PUFA synthase, including genetic tool development, heterologous expression, coordinated engineering with the fatty acid synthase pathway, and optimization of upstream and downstream metabolic pathways. Finally, based on current progress and bottlenecks in mechanistic understanding, engineering strategies, and strain development, we offer perspectives on future research directions, aiming to provide a reference for the rational design of PUFA synthase and the construction of microbial cell factories.
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