Protoilludane-derived sesquiterpenoids from edible mushroom Phellinus tremulae: Anti-inflammatory evaluation in vitro and in vivo

Phellinus tremulae is a valued mushroom with dual medicinal and edible properties. A chemical investigation on P. tremulae led to the isolation and structural elucidation of eight previously undescribed sesquiterpenoids, named phellitremulins A-H (1, 2, and 5-10), along with six known analogues. Compound 5 features a unique dimeric scaffold linked by two fomannosane units, while 6 should be a key intermediate in the biosynthetic pathway leading to protoilludane sesquiterpenoids. Compounds 1-5 notably inhibited NO production in LPS-stimulated RAW264.7 cells, with IC₅₀ ranging from 1.1 to 6.6 μM. Particularly, compounds 1 and 5 markedly reduced the secretion of the pro-inflammatory cytokines TNF-α and IL-6, and significantly downregulated the protein expression level of iNOS and COX-2 in activated macrophages. Furthermore, 1 and 5 could effectively ameliorate acute inflammation in λ-carrageenan-induced mouse paw edema model. This study reveals that P. tremulae is rich in protoilludane-derived sesquiterpenoids and holds potential for anti-inflammatory applications.