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]. Cellular adaptation to oxidative stress entails activation of a genetic programme, controlled by the transcription factor NRF2, which orchestrates expression of genes that eliminate oxidants, along with their associated toxic byproducts, in a manner that is attuned to the level of stress endured. The Hayes lab undertakes research aimed at understanding the mechanisms by which cells overcome oxidative stress to minimise damage and recover their normal function, thereby preventing degenerative disease.

Early research in the lab focused on characterizing the complex superfamily of glutathione S-transferase (GST) drug-metabolizing enzymes that protect against harmful chemicals and the byproducts of oxidative stress. During this programme of work, the lab discovered that the abundance of many class Alpha, class Mu and class Pi GSTs in mouse and rat livers was markedly increased by consumption of diet containing the food preservatives butylated hydroxyanisole (BHA) and ethoxyquin, which had been reported by others to protect against the initiation of carcinogenesis [therefore called 'cancer chemopreventive' agents]. This line of enquiry led the lab, in collaboration with Dr Gordon Neal (MRC Toxicology Unit, UK), to identify and purify inducible GSTs that inactivate the naturally occurring liver carcinogen aflatoxin B_1. Unexpectedly, the programme of work also led to the purification, characterization and cloning of a previously unknown inducible aldo-keto reductase (AKR), which was the founding member of a previously unrecognised family of AKRs [i.e., AKR7s] that can detoxify an aldehyde-containing metabolite of aflatoxin B₁.

Following identification of cancer chemopreventive agents that upregulate GSTs and AKRs, the lab demonstrated these were co-induced with the cytoprotective drug-metabolising enzyme quinone reductase (NQO1) and so next sought to determine the molecular basis for co-regulation of the genes that encode them. Through a collaboration with Professor Masayuki Yamamoto (Tohoku University, Japan), the Hayes lab provided evidence that transcription factor NRF2 controls both the basal and inducible expression of GST, AKR and NQO1 genes, as well as genes encoding antioxidant enzymes associated with synthesis of glutathione. This, along with the efforts of other research groups, led to the recognition that NRF2 is a master regulator of antioxidant systems in the cell.

Subsequently, the lab discovered that induction of cytoprotective genes by BHA is principally due to stabilisation of the NRF2 protein by blocking its rapid proteasomal degradation that occurs under normal non-stressed conditions (i.e., by de-repression). They provided evidence that the instability of NRF2 is dictated by the ubiquitin ligase substate adaptors KEAP1 and beta-TrCP. Induction of NRF2-target genes by chemopreventive agents is primarily due to alleviation of repression of NRF2 by KEAP1 that occurs under normal unstressed conditions. By contrast, beta-TrCP requires phosphorylation of NRF2 by GSK-3 at a DSGIS motif within the transcription factor, identified through a collaboration with Professor Antonio Cuadrado (Autonomous University of Madrid, Spain), and it controls the duration of induction of NRF2-target genes.

These discoveries about NRF2 function and suppression of its activity by KEAP1 and beta-TrCP have opened 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. For example, using preclinical models of disease, the lab has employed pharmacological inhibitors of KEAP1 to demonstrate that increased expression of NRF2-target genes can ameliorate non-alcoholic steatohepatitis (now called, metabolic dysfunction-associated steatohepatitis), diabetes mellitus, liver cirrhosis and initiation of hepatocellular carcinoma. Current work in the lab seeks to establish whether activation of NRF2 can suppresses fibrosis by bocking oxidative stress that drives fibrogenesis.

Dr Hayes is a world leading researcher in the oxidative stress field through his lab's work on the biochemistry and molecular biology of NRF2, as evidenced by several seminal reviews he has written on the subject, and the high level of citations of papers published by the lab. For similar reasons, he has also been considered a leader in the toxicology/drug metabolism and cancer chemoprevention fields from the extensive biochemical characterization of GST and AKR isoenzymes undertaken by his lab. He has published over 220 original research articles and at least 20 reviews, which according to the Google Scholar database have been cited more than 58000 times, giving an h-index of 101. 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 he 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.