Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

Objectives: To investigate effects of short-chain fatty acids (SCFAs) on expressions and functions of intestinal cytochrome P4503A (Cyp3a) and P-glycoprotein (P-gp). To develop a semi-physiologically based pharmacokinetic (semi-PBPK) model for assessing their contributions. Methods: Verapamil pharmacokinetics was investigated following oral administration to rats receiving water containing 150 mm SCFAs for 3 weeks. Cyp3a activities in intestinal and liver mircosomes were assessed by norverapamil formation. In-situ single-pass perfusion was used to evaluate intestinal transport of verapamil and P-gp function. Functions and expressions of Cyp3a and P-gp were measured in mouse primary enterocytes following 48-h exposure to SCFAs. Contributions of intestinal P-gp and Cyp3a to verapamil pharmacokinetics were assessed using a semi-PBPK model. Key findings: Short-chain fatty acids significantly increased oral plasma exposures of verapamil and norverapamil. SCFAs upregulated Cyp3a activity and expression, but downregulated P-gp function and expression in rat intestine, which were repeated in mouse primary enterocytes. PBPK simulation demonstrated contribution of intestinal Cyp3a to oral plasma verapamil exposure was minor, and the increased oral plasma verapamil exposure was mainly attributed to downregulation of intestinal P-gp. Conclusions: Short-chain fatty acids oppositely regulated functions and expressions of intestinal Cyp3a and P-gp. The downregulation of P-gp mainly contributed to the increased oral plasma verapamil exposure by SCFAs.

Objective: To investigate the correlation between fractional exhaled nitric oxide (FeNO) measurement and pediatric gastroesophageal reflux disease (GERD), explore potential non-invasive screening indicators for pediatric GERD. Methods: A retrospective cohort of 159 children with suspected GERD was enrolled from the Department of Pediatrics, Maternal and Child Health Hospital of Hubei Province between April 2017 and August 2025. Data on 24 h ph and multiple intraluminal impedance monitoring and FeNO were systematically collected and analyzed. Results: Among 159 children, 32 (20.1%) were diagnosed with GERD. In the 101 children under 5 years, 23 (22.8%) were GERD-positive. The median FeNO in the GERD-positive group was significantly higher than that in the GERD-negative group (18.00 vs. 10.00 ppb, P < 0.001). Spearman analysis revealed that FeNO was significantly correlated with the number of reflux cycles ( P = 0.012) and pH reflux cycles ( P = 0.010). ROC analysis for FeNO predicting GERD yielded an AUC of 0.751 ( P = 0.000), with an optimal cutoff of 17.5 ppb, a sensitivity of 52.2%, and a specificity of 87.2%. Multivariate logistic regression further confirmed FeNO as an independent risk factor for GERD in children under 5 years. However, in the 58 children aged ≥5 years, no significant difference in GERD-positive rate was observed between the FeNO ₅₀ -positive and FeNO ₅₀ -negative groups ( P = 1.00). Conclusions: Elevated FeNO is independently associated with GERD in children under 5 years, showing moderate diagnostic value as a potential non-invasive screening tool, but not in those aged ≥5 years.