Boswellia serrata: a rich source of triterpenes acting as antagonists of the leukemia inhibitory factor receptor

Boswellia serrata, also known as Indian frankincense, is characterized by multiple beneficial effects, mainly correlated to anti-inflammatory activity [1-3]. In this study, we investigated its possible activity on targets never explored for Boswellia, mainly involved in hepatic fibrosis and cancer development [4]. The n-hexane extract exhibited a significant antagonistic activity on the interaction between Leukemia Inhibitory Factor (LIF) and its receptor (LIFR). A metabolomic-guided phytochemical investigation, based on a LC-HRMS/MS and Molecular Networking combined approach, was carried out on this extract. The following isolation and NMR analysis led to an unambiguous assignment of several Boswellia triterpenoid metabolites, including two new compounds, and a pharmacological evaluation to identify the bioactive Boswellia components responsible for the n-hexane extract activity on LIF/LIFR system. Key active metabolites, including boswellic acids and their derivatives and a small library of semisynthetic analogues, demonstrated potential inhibitory activity towards LIF/LIFR interaction. Among them, α-boswellic acid emerged as the best candidate LIFR antagonist, able to reduce the expression of col1α1 and α-SMA in LX-2 cells. Computational studies allowed to better understand the binding mode in the receptor, highlighting the role of the carboxyl group in engaging a network of electrostatic and hydrogen bond interactions within residues of hLIFR binding site. This finding suggests the potential use of Boswellia in hepatic fibrosis and sheds light on a relatively novel target for liver fibrosis therapy [5].