Single-cell transcriptomic atlas reveals the underlying mechanism of indole-3-acetic acid in protecting against acute cholestatic liver injury.

Cholestasis resulting from disorders of bile secretion and excretion is a serious manifestation of hepatopathy. Indole-3-acetic acid (3-IAA), a biologically active indole derivative from the tryptophan metabolic pathway, has recently attracted considerable attention. However, the therapeutic potential of 3-IAA in acute cholestatic liver injury (ACLI) remains unclear. By integrating transcriptomics and metabolomics, our study revealed that endogenous 3-IAA was downregulated in bile duct ligation induced ACLI rats. Further in vivo animal experiments demonstrated that exogenous 3-IAA administration effectively attenuated the progression of ACLI. Through single-cell RNA sequencing, our study comprehensively mapped the single-cell atlas relating to 3-IAA alleviating ACLI. Mechanistically, 3-IAA may inhibit hepatocyte inflammatory response and promote hepatocyte regeneration by regulating GZMA+GZMK+ effector NK cell and expanding hepatic anti-inflammatory CD59+ macrophages. Taken together, our study revealed the liver protective effect and potential immune mechanism of 3-IAA in ACLI, positioning it as a promising therapeutic candidate for cholestatic liver injury.