Cardiovascular disease, diabetes, cancer and most forms of neurodegenerative disease are triggered and/or driven by chronic oxidative stress [i.e., an excess in the abundance of oxidants relative to the levels of antioxidants]. The Hayes lab undertakes research aimed at understanding the mechanisms by which cells perceive, adapt to, and overcome oxidative stress in order to minimise damage, restore homeostasis and recover their normal function. Adaptation to oxidative stress entails activation of a genetic programme, controlled by the transcription factor NRF2, which directs the expression of genes that eliminate from the cell oxidants and the toxic electrophilic by-products they generate. The lab also studies signalling pathways responsible for downregulating NRF2 because this impairs cellular adaptation to oxidative stress.

Dr Hayes' early research, at the University of Edinburgh, focused on a complex family of drug-metabolising enzymes called glutathione S-transferases (GSTs), which detoxify xenobiotics and protect against oxidative stress. During this time, his lab identified GSTs that are induced by agents which protect against carcinogenesis, such as the synthetic antioxidant food preservatives butylated hydroxyanisole and ethoxyquin. This line of enquiry led them to identify previously unrecognised inducible GST enzymes that inactivate the ultimate epoxidated carcinogenic form of a potent natural mycotoxin called aflatoxin B₁ (typically found in maize and peanuts stored under humid conditions), and so the induction of these GSTs prevents initiation of liver cancer caused by exposure to this carcinogen. 

Upon moving to the University of Dundee, the Hayes lab's research initially focused on a previously unrecognised family of inducible aldo-keto reductases (AKRs) that they had 'discovered' through finding the founding member reduced an aldehyde-containing metabolite of aflatoxin B₁. Thereafter, the lab provided evidence that transcription factor NRF2 directs induction by butylated hydroxyanisole (and other cancer preventive agents) of GST and AKR genes, as well as genes encoding enzymes associated with synthesis of the antioxidant glutathione. This, along with the efforts of others, led to the recognition that NRF2 is a master regulator of antioxidant and cytoprotective systems in the cell that orchestrate adaptation to oxidative stress. Also, the lab discovered that the induction of cytoprotective genes by butylated hydroxyanisole and thiol-reactive electrophiles is principally due to stabilisation of NRF2 by blocking its proteasomal degradation. They provided evidence that the instability of NRF2 protein is dictated by the ubiquitin ligase substate adaptors KEAP1 and beta-TrCP, with the former containing multiple thiol-based oxidative stress sensors, and the latter requiring phosphorylation of NRF2 by GSK-3 at a DSGIS motif within the transcription factor. These discoveries about NRF2 function and suppression of its activity by KEAP1 and beta-TrCP have opened up novel ways of attenuating oxidative stress that entails antagonism of ubiquitylation of NRF2 by KEAP1 and/or beta-TrCP, or inhibition of kinases that phosphorylate the DSGIS motif.

Based on understanding adaptation to oxidative stress, the lab has utilized drugs that increase expression of antioxidant and cytoprotective genes to ameliorate various forms of liver disease associated with oxidative stress and inflammation, such as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma, as well as type II diabetes mellitus.

Dr Hayes has been considered a leading researcher in the oxidative stress field through the lab's work on the molecular biology of NRF2 and the biochemistry of GSTs and AKRs. Similarly, he is also considered a leader in the drug metabolism and cancer chemoprevention fields from publications on NRF2, and detoxification by GST and AKR enzymes. His lab has published over 200 original research articles and at least 20 reviews, which according to the Web of Science 'Core Collection' database have been cited over 34000 times, giving an h-index of 85, and according to the Google Scholar database have been cited more than 50000 times, giving an h-index of 97. According to the academic research portal Research.com [based on data collected in December 2021], Dr Hayes has been calculated to have a D-index of 90 within the disciplines of Biology and Biochemistry, and this ranks his lab at position 69 in the UK and 1083 in the world in these academic disciplines. Dr Hayes has participated in the organization of many international scientific conferences. His lab has benefitted from numerous collaborations with other researchers, for which Dr Hayes is hugely indebted. Dr Hayes was elected a Fellow of the Royal Society of Edinburgh (equivalent to the National Academy of Scotland) in May 2008, and a Fellow of the Society of Biology in September 2008.