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Key Points The nuclear receptors retinoic acid receptor-related orphan receptor-α (RORα), RORβ, RORγ, REV-ERBα and REV-ERBβ were originally identified as orphan receptors. RORα and RORβ constitutively activate transcription, whereas REV-ERBα and REV-ERBβ constitutively silence transcription. RORα and RORγ are now known to bind to sterols, with certain oxysterols having a very high affinity for these receptors. REV-ERBs have been found to bind to haem. REV-ERBs function as ligand-dependent (that is, haem-dependent) silencers of transcription. The role of the endogenous ligands for the RORs is less clear, as several sterols and oxysterols have been suggested to function as agonists or inverse agonists. The RORs and REV-ERBs have substantially overlapping functions as they usually recognize similar DNA response elements. These receptors have important roles in many physiological functions, including development, circadian rhythm, metabolism and immune function. Over the past several years, synthetic ligands have been designed that target RORs and REV-ERBs. Many of these have high potency and have been used to examine the utility of targeting RORs and REV-ERBs in animal models of human disease. Synthetic REV-ERB agonists alter the circadian rhythm and have beneficial effects on the metabolic profile in obese mice. REV-ERB agonists increase oxidative metabolism in the skeletal muscle and improve exercise endurance in mice. Synthetic inverse agonists of ROR (that either target RORγ alone or both RORα and RORγ) are effective in treating and preventing autoimmunity in mouse models. Additionally, they have beneficial effects on glucose and lipid metabolism. The continued refinement and development of synthetic ligands that target these former orphan nuclear receptors may yield novel therapeutics to treat a range of diseases in the future. This Review highlights recent progress in the development of ligands to target two classes of nuclear receptors — the REV-ERBs and retinoic acid receptor-related orphan receptors (RORs) — and describes how such ligands might be useful for treating disorders related to metabolism, immune function and the circadian rhythm. The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiological processes, including regulation of metabolism, development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacology indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders.

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies 1 , 2 . CAR T cells have been less effective against solid tumours 3 – 5 , in part because they enter a hyporesponsive (‘exhausted’ or ‘dysfunctional’) state 6 – 9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19 + tumour-bearing mice. CD8 + CAR + tumour-infiltrating lymphocytes and CD8 + endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells) 10 – 12 . CD8 + T cells from humans with cancer or chronic viral infections 13 – 15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors ( Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8 + effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy. Transfer of NR4A-deficient T cells expressing chimeric antigen receptors is shown to reduce tumour burden and increase survival by shifting T cell transcriptional programs away from exhaustion and towards increased effector function.

On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia–reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia–reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia–reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32–0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68–0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning–afternoon variation in hypoxia–reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia–reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia–reperfusion injury modulator CDKN1a/p21. Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité.

A subset of nuclear receptors (NRs) function as permissive heterodimers with retinoid X receptor (RXR), defined by transcriptional activation in response to RXR agonist ligands. Permissive NR-RXR activation is generally understood to operate through a classical pharmacological mechanism in which RXR agonist binding enhances coactivator recruitment to the heterodimer. However, we previously demonstrated that transcriptional activation of permissive Nurr1-RXRα (NR4A2-NR2B1) heterodimers by an RXR ligand set, which included pharmacological RXR agonists and selective Nurr1-RXRα agonists that function as antagonists of RXRα homodimers, is explained by a non-classical activation mechanism involving ligand-binding domain (LBD) heterodimer dissociation (Yu et al., 2023). Here, we extend mechanistic ligand profiling of the same RXR ligand set to the evolutionarily related Nur77-RXRγ (NR4A1-NR2B3) heterodimer. Biochemical and NMR protein-protein interaction profiling, together with cellular transcription studies, indicate that activation of Nur77-RXRγ transcription by the RXR ligand set, which lacks selective Nur77-RXRγ agonists, is consistent with contributions from both classical pharmacological activation and LBD heterodimer dissociation. However, reanalysis of our previously published data for Nurr1-RXRα revealed that inclusion of selective Nurr1-RXRα agonists was essential for elucidating the LBD heterodimer dissociation mechanism. Together, our findings highlight the importance of using a more functionally diverse RXR ligand set to define the mechanism of Nur77-RXRγ activation and to further evaluate whether LBD heterodimer dissociation represents a shared activation mechanism among NR4A-RXR heterodimers relevant to neurodegenerative and inflammatory diseases.

T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded by Nr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes including Il17a and Il17f. Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.

Metabolic dysfunction–associated steatotic hepatitis (MASH) is a chronic progressive liver disease that is highly prevalent worldwide. MASH is characterized by hepatic steatosis, inflammation, fibrosis, and liver damage, which eventually result in liver dysfunction due to cirrhosis or hepatocellular carcinoma. However, the cellular and molecular mechanisms underlying MASH progression remain largely unknown. Here, we found an increase of the Nr4a family of orphan nuclear receptor expression in intrahepatic T cells from mice with diet-induced MASH. Loss of Nr4a1 and Nr4a2 in T cell (dKO) ameliorated liver cell death and fibrosis, thereby mitigating liver dysfunction in MASH mice. dKO resulted in reduction of infiltrated macrophages and Th1/Th17 cells, whereas it led to a massive accumulation of Tregs in the liver of MASH mice. Combined single-cell RNA transcriptomic and TCR sequencing analysis revealed that intrahepatic dKO Tregs exhibited enhanced T cell immunoreceptor with Ig and ITIM domains (TIGIT) and IL-10 expression and were clonally expanded during MASH progression. Mechanistically, we found that dKO Tregs expressed high levels of basic leucine zipper ATF-like transcription factor (Batf), which promotes Treg cell proliferation and function upon TCR stimulation. Collectively, our findings not only provide an insight into the impact of intrahepatic Treg cells on MASH pathogenesis, but also suggest a therapeutic potential of targeting of the Nr4a family to treat the disease.

The nuclear receptors REV-ERBα and -β link circadian rhythms and metabolism. Like other nuclear receptors, REV-ERB activity can be regulated by ligands, including naturally occurring heme. A putative ligand, SR9009, has been reported to elicit a range of beneficial effects in healthy as well as diseased animal models and cell systems. However, the direct involvement of REV-ERBs in these effects of SR9009 has not been thoroughly assessed, as experiments were not performed in the complete absence of both proteins. Here, we report the generation of a mouse model for conditional genetic deletion of REV-ERBα and -β. We show that SR9009 can decrease cell viability, rewire cellular metabolism, and alter gene transcription in hepatocytes and embryonic stem cells lacking both REV-ERBα and -β. Thus, the effects of SR9009 cannot be used solely as surrogate for REV-ERB activity.

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules 1 . Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins 2 . Some BAs (approximately 5%) escape into the colon, where gut commensal bacteria convert them into various intestinal BAs 2 that are important hormones that regulate host cholesterol metabolism and energy balance via several nuclear receptors and/or G-protein-coupled receptors 3 , 4 . These receptors have pivotal roles in shaping host innate immune responses 1 , 5 . However, the effect of this host–microorganism biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic FOXP3 + regulatory T (T reg ) cells expressing the transcription factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this T reg cell population. Restoration of the intestinal BA pool increases colonic RORγ +  T reg cell counts and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunological homeostasis via the resulting metabolites. Both dietary and microbial factors influence the composition of the gut bile acid pool, which in turn modulates the frequencies and functionalities of RORγ-expressing colonic FOXP3 + regulatory T cells, contributing to protection from inflammatory colitis.

Circadian clocks regulate numerous physiological processes that vary across the day-night (diurnal) cycle, but if and how the circadian clock regulates the adaptive immune system is mostly unclear. lnterleukin-17–producing CD4⁺ T helper (T H 17) cells are proinflammatory immune cells that protect against bacterial and fungal infections at mucosal surfaces. Their lineage specification is regulated by the orphan nuclear receptor RORγt We show that the transcription factor NFIL3 suppresses T H 17 cell development by directly binding and repressing the Rorγt promoter. NFIL3 links T H 17 cell development to the circadian clock network through the transcription factor REV-ERBα. Accordingly, T H 17 lineage specification varies diurnally and is altered in Rev-erbα- ⁻ - mice. Light-cycle disruption elevated intestinal T H 17 cell frequencies and increased susceptibility to inflammatory disease. Thus, lineage specification of a key immune cell is under direct circadian control.

Background: The large and increasing number of chemicals released into the environment demands more efficient and cost-effective approaches for assessing environmental chemical toxicity. The U.S. Tox21 program has responded to this challenge by proposing alternative strategies for toxicity testing, among which the quantitative high-throughput screening (qHTS) paradigm has been adopted as the primary tool for generating data from screening large chemical libraries using a wide spectrum of assays. Objectives: The goal of this study was to develop methods to evaluate the data generated from these assays to guide future assay selection and prioritization for the Tox21 program. Methods: We examined the data from the Tox21 pilot-phase collection of approximately 3,000 environmental chemicals profiled in qHTS format against a panel of 10 human nuclear receptors (AR, ERα, FXR, GR, LXRβ, PPARγ, PPARδ, RXRα, TRβ, and VDR) for reproducibility, concordance of biological activity profiles with sequence homology of the receptor ligand binding domains, and structure-activity relationships. Results: We determined the assays to be appropriate in terms of biological relevance. We found better concordance for replicate compounds for the agonist-mode than for the antagonist-mode assays, likely due to interference of cytotoxicity in the latter assays. This exercise also enabled us to formulate data-driven strategies for discriminating true signals from artifacts, and to prioritize assays based on data quality. Conclusions: The results demonstrate the feasibility of qHTS to identify the potential for environmentally relevant chemicals to interact with key toxicity pathways related to human disease induction.