Liver transcriptomics reveals dysregulated hepatic absorption, distribution, metabolism, and excretion signatures in a mouse model of erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is an inherited disorder caused by loss-of-function mutations in the ferrochelatase (FECH) gene. FECH deficiency leads to the accumulation of its substrate protoporphyrin IX (PPIX), resulting in cholestatic liver injury in patients with EPP. Because the liver is the primary organ responsible for drug metabolism and disposition, liver injury can alter these processes and compromise drug safety. However, safety-oriented precision medicine strategies for EPP remain poorly defined. Moreover, marked interindividual variability in EPP-associated liver injury has been observed, but the underlying risk factors remain unclear. To address these gaps, we performed RNA sequencing of liver tissue from an EPP mouse model carrying a Fech mutation. Compared with wild-type mice, more than 1700 genes were upregulated and more than 900 genes were downregulated in the liver of EPP mice. Pathway enrichment analysis revealed that upregulated pathways include immune activation, inflammatory responses, and extracellular matrix remodeling, whereas downregulated pathways include cholesterol biosynthesis, fatty acid β-oxidation, bile acid biosynthesis, and xenobiotic metabolism. Focusing on drug metabolism and disposition, we found broad downregulation of genes encoding phase I and phase II drug-metabolizing enzymes and drug transporters. Mechanistically, suppression of xenobiotic metabolism-related genes was associated with PPIX-induced liver injury and activation of inflammatory responses. Together, these findings demonstrate that PPIX-induced liver injury broadly disrupts hepatic signaling pathways, particularly those governing liver pathophysiology and xenobiotic metabolism. SIGNIFICANCE STATEMENT: Erythropoietic protoporphyria (EPP) can cause cholestatic liver injury with poorly defined implications for drug safety. Using an EPP mouse model, the study demonstrated that EPP-associated liver damage broadly suppresses hepatic drug-metabolizing enzymes and transporters while activating inflammatory signaling pathways. These findings can potentially be used to guide absorption, distribution, metabolism, and excretion-based precision medicine in patients with EPP to improve therapeutic safety.