Engineering yeast for sustainable production of sterols, steroids, and bile acids: advances, strategies, and future directions

Sterols, steroids, and bile acids form an interconnected metabolic network that regulates membrane organization, signal transduction, and metabolic homeostasis. Among them, bile acids have emerged as key signaling metabolites controlling lipid and glucose metabolism, inflammation, and host–microbiota interactions. Although sterol and steroid engineering in Saccharomyces cerevisiae have progressed substantially, de novo bile acid biosynthesis in yeast remains unresolved. This review highlights recent progress in engineering yeast to produce sterols and steroids, focusing on the structural and regulatory bottlenecks restricting metabolic flux. Although pathway rewiring, transcriptional control, cofactor balancing, and fermentation optimization have driven efficient sterol and steroid production, full reconstruction of the primary bile acid pathway from cholesterol remains a major hurdle. Conversely, the downstream production of secondary and conjugated bile acids from the primary bile acids has proven successful. Beyond manufacturing, bile acid–producing yeast provide powerful platforms to investigate host-microbiome signaling and develop novel microbial therapeutics.