Ghardaqenoids A–F: Six New Diterpenoids from the South China Sea Soft Coral Heteroxenia ghardaqensis with Lipid-Lowering Activity via the Activation of the AMPK Signaling Pathway

Six new diterpenoids, including two verticillane ghardaqenoids A-B (<b>1</b>-<b>2</b>) and four dolabellane ghardaqenoids C-F (<b>3</b>-<b>6</b>), were isolated from the soft coral <i>Heteroxenia ghardaqensis</i> collected in the South China Sea. The structures of ghardaqenoids A, D, and E (<b>1</b>, <b>4</b>, <b>5</b>) were determined by X-ray diffraction. Ghardaqenoids B, C, and F (<b>2</b>, <b>3</b>, <b>6</b>) were identified on the basis of NMR data, DP4+, and ECD spectral data. In particular, compound <b>6</b> exhibited strong in vitro lipid-lowering activity in free fatty acid (FFA)-induced HepG2 cells and liver organoids. Further mechanistic studies revealed that compound <b>6</b> regulated AMPK-related proteins and genes, thereby inhibiting the accumulation of triglycerides (TG) and total cholesterol (TC). These findings suggested that pharmacological AMPK activation serves as a promising role in lipid-lowering therapeutic strategies.