Exploring Boswellia serrata Triterpenes: A New Frontier in Leukemia Inhibitory Factor Receptor Modulation

Boswellia serrata, commonly known as Indian olibanum or Indian frankincense, is a medicinal plant recognized for its significant anti-inflammatory, analgesic, and anticancer activities. In our investigation, the activity of its n-hexane extract was evaluated on targets never explored for Boswellia, mainly involved in hepatic fibrosis and cancer development. Since this extract exhibited a significant antagonistic activity on the interaction between leukemia inhibitory factor (LIF) and its receptor (LIFR), it was subjected to an untargeted metabolomic analysis using a high-resolution mass spectrometry-based approach combined with molecular networking. An unambiguous assignment of several Boswellia triterpenoid metabolites was then achieved upon isolation and NMR spectroscopic investigation to accurately identify the bioactive Boswellia components responsible for the n-hexane extract activity on the LIF/LIFR system. Key active metabolites, including boswellic acids and their derivatives and a small library of semisynthetic analogues, demonstrated potential inhibitory activity toward LIF/LIFR interaction. In particular, α-boswellic acid (1) emerged as a LIFR antagonist, able to reduce the expression of col1α1 and α-SMA in LX-2 cells. Furthermore, computational studies highlighted the role of the carboxyl group in engaging a network of electrostatic and hydrogen bond interactions within residues of human LIFR (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.