Pharmacological inhibition of AKR1B1, but not of CBR1, exacerbated 4-HNE-mediated cytotoxicity.<h4>Conclusions</h4>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. The gene discussed is AKR1B1; the disease is Hyperglycemia.