Differential gene regulation by SR12813 and rifampicin: Insights into PXR and PPARγ activation and metabolic pathway modulation in LS180 colon cancer cells.

SR12813 is an experimental cholesterol-lowering drug that reduces intracellular cholesterol through accelerated proteasomal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and is also recognized as a prototypical activator of the pregnane X receptor (PXR, NR1I2). Rifampicin, a clinically used antibiotic, likewise functions as a human PXR agonist. Although PXR-mediated induction of drug metabolism genes has been extensively characterized in hepatocytes and humanized mouse liver, comparatively little is known about the transcriptional effects of these ligands in intestinal and colon cancer cells. Here, we used RNA-sequencing in LS180 colon adenocarcinoma cells to compare transcriptional responses elicited by SR12813 and rifampicin. Both compounds induced canonical PXR targets, including CYP3A4, UGT1A1, and MDR1 (P-glycoprotein), whereas SR12813 preferentially upregulated genes associated with ketone body metabolism, lipid storage, and glycolysis. Complementary nuclear receptor reporter assays demonstrated that, in addition to robust PXR activation, SR12813 also functions as a partial agonist of peroxisome proliferator-activated receptor gamma, a receptor with critical roles in lipid metabolism and colon cancer biology. These findings demonstrate that SR12813 elicits overlapping, yet distinct transcriptional profiles relative to rifampicin, extending beyond xenobiotic metabolism to include metabolic pathways relevant to tumor progression. Collectively, our results highlight SR12813 as a dual-acting modulator of PXR and peroxisome proliferator-activated receptor gamma, and underscore its utility as a pharmacological tool for investigating nuclear receptor crosstalk in intestinal models. SIGNIFICANCE STATEMENT: SR12813 activates both pregnane X receptor and peroxisome proliferator-activated receptor gamma, demonstrating dual nuclear receptor modulation in colon cancer cells. By linking xenobiotic metabolism with lipid and mitochondrial pathways, this work uncovers previously unreported receptor crosstalk and provides a mechanistic framework for how diverse ligands can differentially shape transcriptional programs relevant to drug metabolism and tumor biology.