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]. Adaptation to oxidative stress entails activation of a genetic programme, controlled by the transcription factor NRF2, which directs the expression of genes that eliminate oxidants, and the toxic electrophilic by-products they generate, from the cell. 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. Based on this knowledge, the lab has utilized drugs that increase NRF2 activity [by blocking its protein degradation] in preclinical models of disease to demonstrate that activation of the transcription factor, and increased expression of the genes it controls, can ameliorate non-alcoholic steatohepatitis, diabetes mellitus, liver cirrhosis and hepatocellular carcinoma.

Early research in the Hayes lab focused on the glutathione S-transferase (GST) superfamily of drug-metabolizing enzymes that collectively protect against oxidative stress. Whilst characterizing the biochemical properties of different GSTs, and seeking to determine their genetic relationships, the lab discovered that many of the mouse enzymes are upregulated by the food preservative butylated hydroxyanisole (BHA), which had been shown by others to protect against cancer. This line of enquiry led the lab to identify inducible GST enzymes that inactivate the naturally occuring liver carcinogen aflatoxin B_1. Unexpectedly, it also led to the 'discovery' of a previously unrecognised family of inducible aldo-keto reductases (AKRs) that can reduce an aldehyde-containing metabolite of aflatoxin B₁.

Following identification of agents that upregulate GSTs and AKRs, the lab demonstrated these were co-induced with the prototypic stress-induced enzyme quinone reductase (NQO1), and so the lab next sought to determine the molecular basis for the co-induction of the genes encoding these enzymes. Through a collaboration with Professor Masayuki Yamamoto (Tohoku University, Japan), the Hayes lab provided evidence that transcription factor NRF2 directs induction by BHA (and other agents that protect against cancer) of GST, AKR and NQO1 genes, as well as genes encoding other detoxification enzymes and 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.

Later, the lab discovered that induction of cytoprotective genes by BHA 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 redox switches, 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. Current work in the lab seeks to establish the extent to which NRF2 controls redox signalling.

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 Google Scholar database have been cited more than 54000 times, giving an h-index of 98. 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.