# Metabolic Detoxification of Glucose and 4-Hydroxynonenal in Human Neuroblastoma Cell Models

## TL;DR

This study explores how neuroblastoma cells handle glucose and a harmful aldehyde called 4-HNE, finding that the enzyme AKR1B1 is crucial for protecting these cells from oxidative damage.

## Contribution

The study reveals the specific role of AKR1B1 in detoxifying 4-HNE in neuroblastoma cells under metabolic and oxidative stress.

## Key findings

- Hyperglycemia activates the polyol pathway in neuroblastoma cells, increasing AKR1B1 activity and sorbitol accumulation.
- Neuroblastoma cells lack ALDH1A1 and AKR1C3, showing incomplete 4-HNE detoxification capabilities.
- Inhibiting AKR1B1 worsens 4-HNE-induced cell death, highlighting its protective role in oxidative stress.

## Abstract

Background: Neuroblastoma (NB) progression is influenced by metabolic and redox adaptations. The polyol pathway, driven by aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD), is activated in hyperglycemic conditions, while detoxification of lipid peroxidation products such as 4-hydroxynonenal (4-HNE) involves carbonyl reductase 1 (CBR1) and AKR1B1. A systematic characterization of these enzymes under distinct metabolic and oxidative challenges in NB is currently lacking. Methods: Human neuroblastoma LAN-5 and SH-SY5Y cells were exposed to hyperglycemic medium to assess polyol pathway regulation, and to exogenous 4-HNE to model aldehyde-induced oxidative stress. Protein expression and enzyme activities were quantified. Cells were treated with Sorbinil or rutin during stress exposure, and viability was analyzed in 2D and 3D models. Results: Hyperglycemia increased AKR1B1 activity and sorbitol accumulation, indicating polyol pathway activation in NB cells. Both NB cell lines displayed an incomplete HNE-detoxifying enzyme profile, with absence of ALDH1A1 and AKR1C3 expression. Exposure to 4-HNE reduced NB cell viability both in 2D and 3D models. Pharmacological inhibition of AKR1B1, but not of CBR1, exacerbated 4-HNE-mediated cytotoxicity. Conclusions: While hyperglycemia stimulates the polyol pathway, aldehyde detoxification by AKR1B1 supports resistance to 4-HNE toxicity, demonstrating that AKR1B1 activity is essential to counteract HNE toxicity, and its impairment may increase the susceptibility of NB cells to oxidative damage.