Schisandra chinensis lignans improve insulin resistance by targeting TLR4 and activating IRS-1/PI3K/AKT and NF-κB signaling pathways

Schisandra chinensis, a traditional Chinese medicine, has been widely applied in China to treat diabetes and its complications. The aim of this study was to discover the active compounds and explain related molecular mechanism contributing to the anti-diabetic effect of Schisandra chinensis. Herein, the therapeutic effects of Schisandra chinensis extracts on type 2 diabetes mellitus (T2DM) were firstly confirmed in vivo. Subsequently, various lignans were isolated from Schisandra chinensis and tested for hypoglycemic activity in palmitic acid-induced insulin-resistant HepG2 (IR-HepG2) cells. Among these lignans, R-biar-(7S,8R)-6,7,8,9-tetrahydro-1,2,3,12,13,14-hexamethoxy-7,8-dimethyl-7-dibenzo [a, c] cyclooctenol (compound 2) and Gomisin A (compound 4) were identified significantly increased the glucose consumption in IR-HepG2 cells. Meanwhile, compounds 2 and 4 activated the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT) pathway, which regulates glucose transporter 2 (GLUT2) and glucose-6-phosphatase (G6Pase), essential for gluconeogenesis and glucose uptake. These compounds also inhibited the nuclear factor-κB (NF-κB) signaling pathway, reducing interleukin-6 (IL-6) levels. Importantly, the hypoglycemic effects of compounds 2 and 4 were diminished after Toll-like receptor 4 (TLR4) knockdown. Cellular thermal shift assays confirmed increased TLR4 protein stability upon treatment with these compounds, indicating direct binding to TLR4. Furthermore, TLR4 knockdown reversed the effects of compounds 2 and 4 on the NF-κB and IRS-1/PI3K/AKT pathways. Taken together, compounds 2 and 4 alleviate IR by targeting TLR4, thereby modulating the NF-κB and IRS-1/PI3K/AKT pathways. These findings suggest that compounds 2 and 4 could be developed as therapeutic agents for T2DM.