# CYP3A5 unexpectedly regulates glucose metabolism through the AKT–TXNIP–GLUT1 axis in pancreatic cancer

## TL;DR

This study shows that the CYP3A5 enzyme helps pancreatic cancer cells take in more glucose, promoting their growth and movement.

## Contribution

The paper reveals a new role for CYP3A5 in regulating glucose metabolism in pancreatic cancer through the AKT–TXNIP–GLUT1 pathway.

## Key findings

- CYP3A5 knockdown reduces glucose-related metabolites in pancreatic cancer cells.
- CYP3A5 restricts TXNIP translation, increasing GLUT1 at the cell membrane.
- CYP3A5-generated reactive oxygen species inhibit the AKT–4EBP1–TXNIP pathway.

## Abstract

CYP3A5 is a cytochrome P450 (CYP) enzyme that metabolizes drugs and contributes to drug resistance in cancer. However, it remains unclear whether CYP3A5 directly influences cancer progression. In this report, we demonstrate that CYP3A5 regulates glucose metabolism in pancreatic ductal adenocarcinoma. Multi-omics analysis showed that CYP3A5 knockdown results in a decrease in various glucose-related metabolites through its effect on glucose transport. A mechanistic study revealed that CYP3A5 enriches the glucose transporter GLUT1 at the plasma membrane by restricting the translation of TXNIP, a negative regulator of GLUT1. Notably, CYP3A5-generated reactive oxygen species were proved to be responsible for attenuating the AKT–4EBP1–TXNIP signaling pathway. CYP3A5 contributes to cell migration by maintaining high glucose uptake in pancreatic cancer. Taken together, our results, for the first time, reveal a role of CYP3A5 in glucose metabolism in pancreatic ductal adenocarcinoma and identify a novel mechanism that is a potential therapeutic target.