Metabolic Engineering of Yeasts for the Production of the Triterpene Squalene: Current Status and Future Prospective

Squalene, a linear triterpene compound characterized by its distinctive isoprenoid backbone with six transisoprene units, is widely used in the medicinal, nutraceutical, and cosmetic industries. The escalating global demand for squalene, coupled with growing ethical concerns over shark-derived sources and the inherent limitations of plant extraction (low yield) and chemical synthesis (environmental burden), has propelled microbial biosynthesis as a sustainable alternative. While substantial progress has been made in elucidating the mevalonate pathway and regulatory mechanisms of squalene biosynthesis, achieving industrially viable titers through microbial platforms remains an unresolved challenge. This review systematically summarizes recent advances in squalene biosynthesis using yeast chassis, with a focus on metabolic engineering strategies implemented in Saccharomyces cerevisiae and Yarrowia lipolytica. Furthermore, we elaborated on how squalene yields a diverse array of downstream derivatives through intricate enzymatic reactions. These derivatives-including triterpenoid saponins, triterpenoid acids, and steroids-exhibit significant applications in the pharmaceutical, nutraceutical, and cosmetic sectors. By integrating systems metabolic engineering with emerging synthetic biology tools, this work provides a roadmap for advancing strain engineering toward economically feasible squalene biomanufacturing.