New hybrid iridoid glycoside oligomers from Scabiosa comosa with anti-cholestasis potential

Cholestatic liver disease (CLD) represents a significant clinical challenge due to the lack of effective drugs. Our preliminary data suggested that the inflorescences of Scabiosa comosa, a traditional Mongolian medicine clinically used against jaundice, were abundant in iridoids. However, the chemical features of iridoids present in S. comosa and their anti-cholestasis potential remain unclear. In the current study, total iridoid glycosides (TIG) were prepared from the n-BuOH extract of S. comosa inflorescences. Anti-cholestasis effects of TIG were confirmed with ANIT-induced liver injury mice model according to biochemical parameters analysis and histopathological observation. The serum metabolomics analysis, RT-qPCR and Western blot analysis demonstrated that TIG could reverse ANIT-induced abnormal in serum endogenous metabolites, up-regulate intestinal and hepatic FXR expression, enhance the intestinal barrier integrity, and alleviate liver inflammation in model mice. Phytochemical investigation of TIG yielded twenty-one iridoid glycoside derivatives (IGs), including five undescribed homologous or heterologous iridoid oligomers (1-3, 5, 9). Among them, compounds 1 and 2 possess the rare hybrid skeleton of iridoid glycoside with flavonoid. The structures of new IGs were determined through comprehensive spectroscopic analysis, HR-MS and crystallographic data. Seventeen compounds showed protective effects against ANIT-induced cytotoxicity in AML12 cells. The aldehyde moiety at C-7 might serve as a key pharmacophore in the IGs from TIG. The heterologous oligomers (1, 2) could also reverse RSL3-induced injury in HepG2 cells. Our work highlighted anti-cholestasis potential of iridoids from S. comosa and provided lead compounds for further drug development against CLD.