Daphnane Diterpenoids from Daphne retusa with Antiadipogenic Activity: Concurrent Suppression of Lipid Biosynthesis and Enhancement of Metabolic Pathways

Abstract

Phytochemical investigation of the rarely studied Daphne retusa employing molecular networking and bioactivity-guided strategies led to the identification of 12 daphnane diterpenoids (1-12), including seven previously undescribed compounds, daphretusins A-G (1-7). Structural elucidation was achieved through comprehensive spectroscopic analysis (HRESIMS, 1D/2D NMR), combined with experimental and calculated electronic circular dichroism (ECD), NMR calculations, and DP4+ analysis. All isolates demonstrated potent dose-dependent antiadipogenic effects, inhibiting lipid accumulation in 3T3-L1 cells with EC₅₀ values ranging from 0.07 to 4.2 μM. Mechanistic studies revealed a dual mode of action, with compound 11 serving as a representative example for its potent bioactivity and exceptional selectivity: it concurrently (1) inhibited lipid biosynthesis via downregulation of key adipogenic transcription factors (PPARγ, C/EBPα, and SREBP-1) and lipogenic enzymes (FASN, ACC, and SCD1), while (2) promoting lipid metabolism through CPT-1-mediated activation of β-oxidation.