Macrophage‐Mediated Transport of Insoluble Indirubin Induces Hepatic Injury During Intestinal Inflammation

Abstract Many plant‐derived bioactive molecules with low solubility and permeability can cause hepatocyte injury. However, the mechanism by which they induce hepatic damage without passive diffusion into the hepatic circulatory system remains unclear. This study demonstrate that indirubin, the main component of indigo naturalis with poor aqueous solubility, predisposes mice with chronic colitis to hepatic injury. This closely mimics the hepatic damage commonly observed in ulcerative colitis patients treated with indigo naturalis. Upon administration, indirubin is detected in the plasma, Peyer's patches, and hepatic tissue, with its distribution linked to macrophage infiltration into the liver. Ablation of macrophages significantly reduces indirubin accumulation and attenuates elevated hepatic transaminases in mice with chronic colitis. Mechanistically, macrophages internalize and transport indirubin aggregates from Peyer's patches through the circulatory system to the livers. This internalization activates the NLRP3 inflammasome, leading to the formation of macrophage extracellular traps (METs), which contribute to oxidative stress‐induced liver injury. The study identifies indirubin as a potentially toxic component of indigo naturalis that provokes METs‐mediated oxidative damage. Additionally, the findings reveal a novel transport pathway for poorly soluble molecules to reach the liver via uptake by macrophages within Peyer's patches.