Oxygenated aromatic cadinane sesquiterpenoid dimers from Stahlianthus involucratus as a new class of anti-obesity agents.

Stahlianthus involucratus, a medicinal herb indigenous to Southwest China traditionally used for inflammation, remains unexplored for anti-obesity potential. Bioactivity-guided fractionation afforded an active fraction that markedly ameliorates high-fat diet (HFD)-induced obesity and related metabolic disorders. Phytochemical investigation of this active fraction afforded thirteen oxygenated aromatic cadinane-type sesquiterpenoid dimers (CSDs, 1-13), including eight new compounds. Their structures were established by extensive spectroscopic analyses, including NMR, HRESIMS, ECD and single-crystal X-ray diffraction. Notably, compounds 1-3 possess unprecedented carbon-nor skeletons featuring a rare pyran-4-one-like ring C. Anti-adipogenic screening in 3T3-L1 preadipocytes identified compound 13 as the most potent congener, further favored by its abundance as a major constituent. Oral administration of 13 in HFD-fed obese mice significantly attenuated obesity-associated phenotypes without discernible hepatorenal toxicity. Mechanistically, 13 concurrently suppresses the lipogenic CREB-C/EBPβ/δ-PPARγ cascade and potentiates the thermogenic PRDM16-PGC1α-UCP1 axis. Collectively, these results establish the aromatized CSDs as the principal active components of S. involucratus and underscore its promise as a functional food candidate for obesity intervention.