Multi-Omics Analysis Reveals 1-Propanol-Induced Pentadecanoic Acid Biosynthesis in Yarrowia lipolytica

Pentadecanoic acid (C15:0) is an odd-chain fatty acid (OCFA) with significant health benefits, mainly produced by microbial fermentation. To improve C15:0 production, this study compared the effects of different alcohols on C15:0 production in Yarrowia lipolytica CICC1778, identified 1-propanol as the most effective precursor, assessed its optimal concentration, and employed transcriptomic and metabolomic analyses to elucidate the regulatory mechanisms. The results showed that supplementation with 0.5% 1-propanol resulted in a total lipid production of 1.54 g/L in Y. lipolytica CICC1778, showing no differences compared with the negative control (NC) group, while C15:0 production increased to 76.68 mg/L, representing a 794.7% increase compared with the NC group. Integrated omics analysis showed that propionylcarnitine was positively correlated with ADH2, ADH1, ACADSB, ALDH6A1, and CAT2; O-methylmalonylcarnitine was positively correlated with IVD, MCCC2, ACADSB, and ALDH6A1; and (R)-leucic acid and 2-hydroxy-3-methylbutyric acid were positively correlated with IVD, BAT2, MCCC2, and ACADSB and ALDH6A1 and BAT2, respectively. All of these DEGs and DEMs were upregulated in the alcohol-treated (ALC; supplementation with 0.5% 1-propanol) group. Taken together, supplementation with 0.5% 1-propanol was an effective strategy for enhancing C15:0 production in Y. lipolytica CICC1778; 1-propanol underwent dehydrogenation-oxidation and promoted branched-chain amino acid degradation to expand the propionyl-CoA pool, thereby facilitating C15:0 synthesis.