Integrated Omics Reveal the Core Regulatory Network Driving High-Level DHA Production in Aurantiochytrium sp. YHPM1

The high production cost of docosahexaenoic acid (DHA) remains the main bottleneck hindering its wide application in the fields of nutrition and biomedicine, highlighting the urgent need to develop low-cost and high-level DHA biosynthetic strains. However, improving DHA productivity requires a deeper understanding of the metabolic and regulatory mechanisms that drive enhanced DHA biosynthesis in high-producing strains. This study, through the integration of transcriptomic and metabolomic analyses, revealed the molecular mechanism of the high DHA phenotype of Aurantiochytrium sp. YHPM1 strain induced by plasma mutagenesis. Compared with the wild-type SW1 strain, the YHPM1 showed higher biomass, lipid accumulation, and DHA production, reaching 8.97 g/L DHA (43.15% of total lipids) at 108 h. Metabolite profiling further revealed a marked accumulation of DHA-rich triglycerides, confirming that carbon flux is preferentially redirected to storage lipid synthesis rather than membrane lipid maintenance. Moreover, RNA-seq revealed transcriptional reprogramming in YHPM1 that promotes DHA accumulation under nitrogen limitation. The YHPM1 strain exhibited a synergistic upregulation of precursor supplying genes (such as aldo and dlat ), thereby enhancing the flux of glycerol-3-phosphate and acetyl-CoA toward the lipid biosynthetic pathway. Meanwhile, the downregulation of fox2 , acadm , and mmsA suppressed β-oxidation and competing amino acid metabolic pathways, thereby minimizing carbon loss to the greatest extent. These results indicated that YHPM1 achieved high-efficiency, industrially valuable DHA production through mutagen-driven metabolic remodeling. The mechanistic insights uncovered in this study provide a solid theoretical foundation for engineering next-generation Aurantiochytrium strains capable of enabling large-scale and economically efficient DHA biomanufacturing