Silymarin and Its Isolated Flavanonol Lignans Are Liver X Receptor Antagonists

Silymarin is a mixture of bioactive natural products from milk thistle (Silybum marianum) fruit extracts, which have a long history as a phytotherapeutic agent in treating various liver-related ailments. Even though important pharmacological effects of silymarin, such as the antioxidative properties, have been proven, the exact molecular mechanisms for its liver-protective action remain elusive. Here, we provide in vitro pharmacological data showing that silymarin, as a mixture and also its individual flavanonol lignans, antagonize liver X receptor (LXR). In HepG2 cells, the isolated silymarin flavanonol lignans showed LXR-mediated anti-steatotic effects that may play a crucial role in the hepatoprotective action of silymarin. Our findings underscore the potential of silymarin, both as a mixture and in the form of its isolated flavanonol lignans, as therapeutic agents for liver disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). There is an urgent need for well-designed clinical trials engaging standardized milk thistle fruit extract to explore its efficacy in MASLD.