Atorvastatin regulates hepatic transcriptome PXR dependently but distinct from pregnenolone 16α-carbonitrile and does not induce PXR-mediated liver steatosis.

Activation of the pregnane X receptor (PXR) by various drugs promotes liver steatosis. Yet, atorvastatin, a widely prescribed statin and a PXR ligand, is considered hepatically safe, even in patients with metabolic dysfunction-associated steatotic liver disease. To reveal mechanistic differences between atorvastatin and steatosis-promoting PXR ligands we investigated whether atorvastatin elicits distinct transcriptional and epigenomic responses, and whether these underlie its favorable hepatic safety. Mice were treated orally for four days with atorvastatin, pregnenolone 16α-carbonitrile (PCN; prototypical PXR agonist), or pravastatin (a non-PXR-activating statin). Liver transcriptomics, chromatin accessibility profiling (ATAC-seq), and pathway analyses were performed. Long-term hepatic effects were assessed in high-fat diet (HFD)-fed mice after 28-day compound treatment. Atorvastatin regulated hepatic gene expression almost exclusively via PXR, yet its transcriptional signature was distinct from PCN, and atorvastatin did not induce a classical PXR-target Cyp3a11. Both ligands altered chromatin accessibility in overlapping but non-identical patterns. Atorvastatin primarily activated cholesterol biosynthesis genes, whereas PCN enriched steatosis and growth-related pathways. Atorvastatin activated both SREBP1 and SREBP2 proteins while PCN activated only SREBP1. 28-day treatment with PCN in HFD-fed mice aggravated liver steatosis while atorvastatin did not. Conversely, atorvastatin reduced hepatic Pxr expression and downregulated its classical target genes and had no longer effect on cholesterol synthesis genes. In conclusion, atorvastatin acts as a selective PXR activator, inducing a distinct hepatic transcriptional programme that avoids steatotic outcomes. These findings highlight the ligand-specific nature of PXR signaling and the hepatic safety of atorvastatin in metabolic disease contexts.