# Targeting PDK1: A novel approach to combat hypoxia‐induced epithelial‐mesenchymal transition in chronic rhinosinusitis with nasal polyps

## TL;DR

This study shows that targeting PDK1 could help treat chronic rhinosinusitis with nasal polyps by blocking hypoxia-induced changes in nasal cells.

## Contribution

The study identifies PDK1 as a novel therapeutic target for hypoxia-induced EMT in CRSwNP.

## Key findings

- Hypoxia activates glycolysis-related enzymes PDK1 and LDHA in nasal epithelial cells.
- PDK1 overexpression or lactate stimulation triggers epithelial-mesenchymal transition (EMT).
- Inhibiting PDK1 reduces hypoxia-induced EMT in nasal epithelial cells.

## Abstract

Hypoxia is a prevalent pathological process in chronic rhinosinusitis with nasal polyps (CRSwNP), leading to a cascade of pathological events, including epithelial‐mesenchymal transition (EMT). However, the mechanisms underlying hypoxia‐induced EMT remain unclear. This study aims to elucidate the mechanisms driving EMT under hypoxic conditions in CRSwNP.

Transcriptome and proteome analyses of hypoxia‐treated human nasal epithelial cells (HNECs) were performed to identify key molecules and pathways. The expression of hypoxia‐inducible factor‐1α (HIF‐1α), pyruvate dehydrogenase kinase (PDK1), lactate dehydrogenase A (LDHA), and EMT markers was assessed in nasal tissues from CRSwNP patients. In vitro, cultured HNECs were exposed to hypoxia and lactate, or overexpressed PDK1, to evaluate changes in EMT markers.

Hypoxia activated the glycolysis‐related pathway in HNECs, with PDK1 and LDHA identified as significantly upregulated glycolysis‐related enzymes. The expression of PDK1 and LDHA was closely correlated with HIF‐1α and EMT markers in nasal tissues. Hypoxia induced an increase in PDK1 and LDHA expression, lactate production, and EMT occurrence in HNECs. PDK1 overexpression or lactate stimulation also triggered EMT, while PDK1 inhibition attenuated hypoxia‐induced EMT in HNECs.

This study is the first to reveal that hypoxia‐induced activation of PDK1 plays a critical role in regulating EMT by promoting lactate production, thereby providing a potential therapeutic target for CRSwNP.