Research progress on metabolic engineering for efficient squalene synthesis in yeast cell factories

Squalene, a naturally occurring triterpenoid, is widely utilized in the food, pharmaceutical, and vaccine adjuvant industries. Conventional production methods, which rely on extraction from shark liver oil or plant sources, are limited by ecological sustainability concerns and low extraction efficiency. Recent progress in synthetic biology and metabolic engineering has enabled the development of sustainable and efficient microbial platforms for squalene biosynthesis. This review provides a comprehensive overview of the biosynthetic pathways of squalene in yeast, summarizes key metabolic engineering strategies, and highlights recent advancements in the field, with an emphasis on multi-organelle synergistic engineering and critical distinction of evidence sources. We focus on approaches such as enhancing the mevalonate pathway, modulating competing metabolic routes, applying subcellular compartmentalization engineering, optimizing cofactor balance, and implementing product efflux strategies. Notably, integrated strategies, particularly organelle engineering in Yarrowia lipolytica and Saccharomyces cerevisiae, have increased squalene titers to high levels (up to 55.8 g/L). These advances provide a useful basis for future metabolic engineering efforts aimed at improving squalene production and facilitating the synthesis of related terpenoids.