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 directs expression of genes that eliminate oxidants, along with their associated toxic byproducts, in a manner that is directly attuned to the level of stress endured. The Hayes lab undertakes research aimed at understanding the mechanisms by which cells overcome oxidative stress in order to minimise damage and recover their normal function. Based on this knowledge, the lab has utilized drugs in preclinical models of disease to demonstrate that activation of NRF2, and increased expression of the genes it controls, can ameliorate non-alcoholic steatohepatitis, diabetes mellitus, liver cirrhosis and initiation of hepatocellular carcinoma.

Early research in the Hayes lab focused on purifying and characterizing isoenzymes within the Alpha-, Mu-, Pi- and Theta-class glutathione S-transferase (GST) families of drug-metabolizing enzymes that protect against 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 previously reported to protect against the initiation of carcinogenesis [and have therefore been 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 occuring liver carcinogen aflatoxin B_1. Unexpectedly, the programme of work also led to the purification, characterization, cloning and 'discovery' of a previously unrecognised inducible aldo-keto reductase (AKR), which was the founding member of a 'new' 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 encoding these enzymes. Through a collaboration with Professor Masayuki Yamamoto (Tohoku University, Japan), the Hayes lab provided evidence that transcription factor NRF2 directs induction of GST, AKR and NQO1 genes by cancer chemopreventive agents, as well as genes encoding other detoxification enzymes and antioxidant enzymes associated with synthesis of glutathione. This, along with the efforts of others, led to the recognition that NRF2 is a master regulator of antioxidant systems in the cell.

More recently, the Hayes lab discovered that induction of cytoprotective genes by BHA is principally due to stabilisation of the NRF2 protein by blocking its proteasomal degradation. 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 (i.e., de-repression). Interestingly, KEAP1 contains multiple redox switches that 'sense' oxidative stressors, and controls the magnitude of induction of NRF2-target genes. By contrast, beta-TrCP requires phosphorylation of NRF2 by GSK-3 at a DSGIS motif within the transcription factor, done in 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 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 whether activation of NRF2 can suppresses fibrosis by bocking transforming growth factor-beta (TGF-beta) signalling that creates pulses of 'oxidants' (via NOX4) to drive fibrogenesis.

Dr Hayes is considered a leading researcher in the oxidative stress field through his lab's work on the biochemistry and molecular biology of NRF2. He is also 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 200 original research articles and at least 20 reviews, which according to the Google Scholar database have been cited more than 56000 times, giving an h-index of 100. 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.