Biosynthesis of Sciadonic Acid Derived from Gymnosperms with Anti‐Colitis Activity

Sciadonic acid (SCA), Δ5-unsaturated fatty acid with anti-inflammatory and lipid-regulatory properties, is predominantly derived from seeds of gymnosperms. This study established a systematic engineered Yarrowia lipolytica platform for efficient SCA production and assessing the anti-colitis efficacy of SCA as a novel therapeutic lipid. First, production of eicosadienoic acid (EDA) was biosynthesized by iterative expression of endogenous polyunsaturated fatty acid desaturase and Δ9 elongase. Different Δ5 desaturases were screened to identify high-activity enzymes capable of catalyzing EDA-CoA substrates, bypassing the rate-limiting step of phosphatidylcholine (PC)-bound substrate catalysis. Further, combined with the deletion of the β-oxidation pathway, enhancement of triglyceride assembly and malonyl-CoA supply, the resulting strain overproduced 195.5 mg/L SCA in shake flasks. Under optimized bioreactor fermentation, SCA yield reached 1.2 g/L with glucose, representing the high level of SCA production reported in Y. lipolytica. Finally, SCA significantly ameliorated dextran sulfate sodium salt (DSS) -induced colitis in mice, demonstrating dose-dependent improvements in disease activity index, colon histopathology, and pro-inflammatory cytokine suppression. Overall, this work establishes an efficient microbial production platform for SCA and provides in vivo evidence supporting the anti-colitis potential of this bioactive lipid.