S-HPABA, a marine fungal-derived bioactive compound, exhibits potent lipid-lowering efficacy and safety in modulating lipid dysregulation revealed by integrative lipidomics and molecular biology approaches.

INTRODUCTION: Hyperlipidemia is a widespread metabolic disorder that places a heavy burden on normal body functions. Given the drawbacks of current lipid-lowering drugs, there is considerable interest in developing alternative nutraceuticals from natural sources. S-2-(2-hydroxypropanamido) benzoic acid (S-HPABA) is a novel compound obtained for the first time from a marine fungus, which has demonstrated strong lipid-lowering effects in vitro and in vivo with an excellent safety profile.

METHODS: To investigate S-HPABA's mechanism of action, an integrated strategy of lipidomics and bioinformatics was adopted to screen candidate targets. The selected targets were then validated through RT-qPCR and western blotting.

RESULTS: The results indicated that 57 differential metabolites and 11 metabolic pathways were significantly regulated by S-HPABA. Based on the combined analyses, five targets were initially selected. Validation experiments showed that FASN, PLA2G2A and TYMP play crucial roles in the lipid-lowering process, with FASN being the most prominent.

DISCUSSION: Mechanistically, S-HPABA-induced reduction of lipid accumulation was associated with decreased FASN expression and PI3K/AKT/mTOR pathway inhibition. In summary, S-HPABA is a safe and potent lipid-lowering bioactive compound with promise as a functional food ingredient for metabolic health.