The discovery of hormones dates back to the early 1900s42,43,44,45 (Fig. 1). In 1905, Ernest Starling coined the term ‘hormone’.44,45 In 1926, Tadeus Reichstein and Edward Calvin Kendall elucidated the structures of cortisone and thyroxine,46 while Adolf Butenandt and Edward Adelbert Doisy first isolated estrogen in 1929.47,48 became clear only after Elwood Jensen conducted a series of experiments in the late 1950s to determine how estrogen regulates reproductive organ maturation.49 The rise of molecular biology in the 1980s led to groundbreaking advances, including the cloning of the human glucocorticoid receptor (GR) and the identification of the first estrogen receptor, ERα, from the ESR1 gene.50,51,52 In 1985, Ronald Evans successfully cloned the human glucocorticoid receptor (GR),50,51 while Pierre Chambon’s lab identified the first estrogen receptor, ERα, from the ESR1gene.52 They found that these receptors shared similarities with v-erbA, a viral oncogene recognized as a thyroid hormone receptor (TR) transcribed from the THRA gene. This discovery resulted in the placement of steroid and thyroid hormone receptors into a single grouping. A sequence comparison revealed a conserved evolutionary framework, highlighting structural and functional features that predicted the development of the nuclear receptor superfamily. Each receptor contains DNA-binding, ligand-binding, and transactivation domains. Soon after, receptors for other binding factors, such as retinoic acid and vitamin D, were cloned, confirming the existence of a receptor superfamily unified by structure. The formal establishment of the NR superfamily represented a major milestone, bolstering the hypothesis that the development and physiology of all animal species might be regulated by related molecular processes.

Fig. 1 Historical timeline of nuclear receptor expression. Schematic timeline illustrating key milestones in the nuclear receptor research field. The timeline begins with the cloning of the first steroid hormone receptor cDNA and highlights significant advancements, culminating in recent discoveries enabled by “omics” technologies. Major breakthroughs and pivotal discoveries are annotated along the timeline Full size image

The therapeutic potential of NRs was recognized in the 1970s when it was shown that the estrogen blocker tamoxifen could inhibit ER-dependent breast cancer cells.53,54 In prostate cancer, multiple nuclear receptors have been shown to inhibit tumor growth, proliferation, and metastasis, leading to significant interest in targeting these receptors as therapeutic strategies.55,56,57 Dysfunction of NRs has been associated with specific diseases, such as infertility, obesity, and diabetes.58 As key drug targets, NRs are crucial in studying the pathological mechanisms of metabolic diseases and related drug development. Today, they represent a huge family of pharmaceutically targetable proteins. This review discusses the current knowledge on NR-based therapeutic intervention in different types of disease.

Family members

The known sequence of the human genome revealed that forty-eight human NRs detect ligands, such as hormones, and translocate them into the nucleus to function as transcription factors regulating gene expression.59 These receptors are classified into three main types on the basis of their ligand types or into eight subgroups on the basis of sequence homology.11,60 Type I receptors are steroid receptors, including the ER, AR, progesterone receptor (PR), mineralocorticoid receptor (MR) and GR.61,62 Their ligands are steroid hormones such as sex hormones, glucocorticoids and mineralocorticoids.63 Type II receptors are nonsteroid receptors, such as thyroid hormones (TRα and TRβ), retinoic acid receptors (RARα, β), vitamin D receptors (VDRs) and peroxisome proliferator-activated receptors (PPARα, β and γ).64 Type III receptors include orphan receptors whose endogenous ligands are unknown or that do not bind to any ligands, such as the testicular receptor and germ cell nuclear factor.65 Alternatively, NRs can be divided into eight subgroups that are similar to classical receptors but differ enough individually, named thyroid hormone receptor-like family, retinoid X receptor-like family, estrogen receptor like family, nerve growth factor IB-like family, steroidogenic factor-like family, germ cell nuclear factor-like family, and those with two DNA-binding domains, as well as recently identified typically structured NR (CgNR8A1) in metazoans such as mollusks, annelids, cnidarians, echinoderms and hemichordates.66,67

Structure

Except for the dose-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome, gene 1 (DAX1) and the small heterodimer partner (SHP), all NRs are typically single-chain polypeptides that share four or five functional domains,68 including the N-terminal transcription activation domain (NTD), the DNA-binding domain (DBD), the ligand-binding domain (LBD), the C-terminal transcription activation domain (CTD) and a hinge domain (H) that connects the DBD and LBD (Fig. 2).

Fig. 2 Diagram of the structural model of nuclear receptors. Nuclear receptors share four functional domains: the N-terminal transcription activation domain (NTD), the DNA binding domain (DBD), the ligand binding domain (LBD), and a hinge domain (H) that connects the DBD and LBD. Some NRs also contain a highly variable C-terminal transcription activation domain (CTD) Full size image

The NTD, which is located at the N-terminus and comprises 25–603 amino acids (AAs), contains the first of two transactivation regions (AF-1) and possesses transcriptional activator functions.69,70 The A/B domain is intrinsically disordered, which makes obtaining full-length 3D representations of the receptor difficult.71,72 The second identified subunit is the DBD, with 66–68 AAs, including two zinc fingers, which are typically obscured because of lower DNA affinity when the hormone is absent.73,74,75 Once a hormone is bound, the zinc fingers dock the hormone–receptor complex to hexanucleotide response elements located within NR-regulated promoters that determine the receptor’s regulatory specificity. The DBD also serves as an intermolecular interaction site for receptor dimerization.76 The LBD is located at the receptor’s C-terminus and contains 220–250 AAs.77 The LBD binds to the cognate hormone or ligand through an interior binding pocket.78,79 It also has an AF-2 site for recruiting various coactivating proteins, such as heat shock proteins (HSPs), to facilitate interactions with chromatin-remodeling proteins and the transactivation domain.80,81,82 The LBD plays a crucial role in mediating self-assembly reactions, such as dimerization or tetramerization, which are essential for high-affinity binding to DNA response elements.83 The DBD is connected to the LBD via a flexible domain, the ‘hinge’, which is related primarily to the nuclear localization signal of NRs and may influence the intracellular trafficking and subcellular distribution of the hormone‒receptor complex.84,85 The hinge region also contains a short NLS, and its phosphorylation is coupled to elevated transactivation.86,87

However, not all NRs have all four typical domains. Members of the NR0 subfamily, for example, frequently have neither a DBD nor an LBD in their structures.88 Among these, NRs with only the LBD and no DBD, such as Dax-1 and SHP, are nonetheless capable of binding to other transcription factors (TFs) and suppressing the expression of genes downstream. Finally, some NRs also possess a short, highly variable C-terminal domain (CTD or F domain) that often has unknown functions.89,90 However, current research has revealed a critical function of the F domain in the ERα reaction to select ER modulators (SERMs), particularly in SERM-mediated LBD dimerization and AF-1 activity.91

Origins and evolution

NRs were thought to have evolved approximately 600 million years ago in the common ancestor of bilaterian animals, enabling them to sense and respond to internal and external signals.92 This evolution likely involved genetic amplification and mutation, contributing to the functional diversity of the NR superfamily.93 Most NR ligands are small, hydrophobic molecules that pass through cell membranes, although some, such as thyroid hormones, are actively transported into cells.94 While NRs were initially termed ligand-binding proteins, it remains debated whether their common ancestor bound ligands or functioned as constitutively active receptors. Over 50% of NRs are orphan receptors lacking known ligands, although some have been shown to bind metabolites, suggesting a role in sensing metabolic changes.95,96 The evolution of the LBD enabled interactions with small molecules and coregulators, increasing NR versatility.97 Gene duplication during early metazoan evolution expanded and specialized the NR superfamily into subfamilies such as steroid hormone receptors, thyroid hormone receptors, and orphan receptors. The coevolution of NRs and their ligands increases their physiological complexity. For example, vertebrate NRs, such as glucocorticoid and estrogen receptors, have evolved high specificity for steroid hormones, which are crucial for the stress response and reproduction.98

In 1992, a comparison of the DNA-binding domains of known NRs led to the construction of a phylogenetic tree, suggesting a common ancestor.99 By 1997, an alternative hypothesis emerged, suggesting that the original NR was an orphan receptor that gradually gained ligand-binding ability.100 The earliest NRs are believed to have evolved as orphan receptors that lack defined ligands and are involved in regulating fundamental processes such as metabolism and cellular signaling.101 Over time, orphan receptors adapt to regulate broader metabolic pathways, including lipid homeostasis and detoxification. A recent discovery of the NR7 subfamily has filled a critical gap in the understanding of the evolution of NR dimerization capabilities. Phylogenetically situated between class I NRs (monomers or homodimers) and class II NRs (heterodimers), the NR7 subfamily acts as a “missing link” in the transition from homodimerizing to heterodimerizing nuclear receptors.102

Mechanisms of action

Nuclear receptors can modulate gene expression through direct binding to target genes as well as through interactions with other NRs.103,104 The interplay between NR actions can be described at progressively more detailed levels, with various regulatory modes involved in upstream events that influence downstream gene transcription and crosstalk events at the DNA level that directly influence gene transcription.105 The existence or lack of physical connections between the relevant NRs could further alter the crosstalk mechanisms at the DNA level.

Crosstalk between nuclear signalings

Nuclear receptors can share overlapping arrays of target genes or regulate distinct genes that are part of the same downstream activity or pathway (Fig. 3). There is a wealth of experimental evidence to support endpoint modifications in gene expression that occur after NR crosstalk. The relationship between ERα and the PR was among the first observed examples of crosstalk between nuclear receptors.106 Estradiol-stimulated ERα activity was found to be suppressed by liganded PR isoforms, and the ligand, promoter and cell type were demonstrated to influence this suppressive crosstalk.106,107 Interactions between GRα and PPARα are critical in regulating shared subsets of target genes and different stages of signal transduction cascades involved in inflammatory and metabolic pathways.108,109 For example, both GRα and PPARγ have been shown to repress genes associated with TLR4- and TLR9-induced innate immune responses in primary peritoneal macrophages.110,111 However, there are significant differences in how these NRs achieve gene repression, which involves distinct transcriptional corepressor complexes. These variations in regulatory mechanisms highlight the complexity and specificity of gene regulation mediated by GRα and PPARγ in immune and metabolic contexts.

Fig. 3 Crosstalk modes of NR signaling. Various regulatory modes involved in NR signaling influence downstream gene transcription. For example, different types of nuclear receptor signaling can simultaneously regulate the expression of the same gene (Modes 1, 3 and 4) or regulate different genes belonging to the same pathway (Mode 2). Different nuclear receptors may share the same target genes (Mode 5). In addition, crosstalk between two NRs can influence each other’s gene or protein expression (Mode 6) Full size image

More complex types of crosstalk, such as reciprocal or unidirectional regulation of the expression of NR genes or proteins and ligand availability, can sometimes occur.112,113 For example, glucocorticoid-activated GRα was reported to upregulate PPARα mRNA expression.109,114 Conversely, fenofibrate-activated PPARα was shown to downregulate GRα expression at the posttranscriptional level in a time- and dose-dependent manner.115,116 In rodent adipocytes, antidiabetic PPARγ ligands increase the expression of PEPCK-C mRNA, which encodes the key glyceroneogenic enzyme EC4.1.1.32.117 In contrast, dexamethasone-activated GRα counteracted this induction at the transcriptional level. These results show that the processes involved in NR crosstalk are not unique; different pairs of nuclear receptors can interact through distinct crosstalk mechanisms according to the stimulus, expression level, cell type, pathway and genes involved. It is probable that many other modes of crosstalk will be uncovered as our knowledge expands to include other intracellular organelles and the shuttling of NRs.

Crosstalk between nuclear receptors at the DNA level

At the DNA level, NR crosstalk can take two primary forms13,118 (Fig. 4). In one scenario, NRs physically interact to regulate specific target genes (direct crosstalk). In another context, NRs do not actually connect but still engage in unidirectional or bidirectional interactions (indirect crosstalk). When two nuclear receptors interact directly, they can bind to DNA sequences that are either closely positioned or farther apart. Alternatively, they can bind DNA sequences through the action of other transcription factors. A well-known example of this is the peroxisome proliferator-activated receptor PPARs, which are of three types: PPARα, PPARβ/δ and PPARγ. Most of these proteins are heterodimers connected to retinoid X receptors (RXRs) that regulate gene transcription,119,120 but they can also be fine-tuned by pairing with a different ligand. Multiple coactivators can interact with heterodimer complexes to supplement and stabilize their activity in regulating lipid metabolism, adipogenesis and inflammation.121,122 Further instances of direct NR connections have been reported for steroid receptors. GRα and AR have many target genes in common due to the recognition of partial palindromic repeats of the sequence 5′-TGTTCT-3′.123 GRα–AR heterodimerization has been proposed as the mechanism underlying the mutual inhibition of the transcriptional activities of these two receptors, allowing for differential regulation of specific genes.124,125 Furthermore, AR and GR share significant similarities in the dimerization structure of their LBDs, which sheds new light on the previously reported structure of the GR LBD.126 The mechanisms of direct crosstalk may allow for dual NR ligand control, but the exact conditions for this process have not been determined. Context-specific influences, such as tissue or cell type and differentiation status, are likely to lead to different interaction patterns, resulting in varied biological responses.127,128

Fig. 4 Crosstalk modes at the DNA level. At the DNA level, nuclear receptors engage in crosstalk by indirectly or directly interacting with DNA. Part a outlines indirect regulation modes, where no physical interaction occurs, whereas Part b describes regulatory mechanisms involving direct physical interactions among nuclear receptors (NRs). Indirect regulation modes include: NR signaling pathways may compete for overlapping DNA-binding sites; NR heterodimer partners may cause redistribution or squelching; Components of the transcriptional machinery, such as RNA polymerase II (Pol II) and transcriptional coregulators, may cause redistribution or squelching; The alteration of shared coregulators can influence the activity of other NRs. One NR family member can act as a pioneering factor to facilitate chromatin loosening and enable the subsequent binding of other NRs. Direct physical interactions includes: Paired receptors may cooperate for direct DNA binding or through DNA looping; Direct crosstalk can occur with just one partner contacting the DNA; Two nuclear receptors engage in crosstalk through protein-protein interactions with other transcription factors (TFs); The sequestration of one or both NRs (originating from other modes, (f–i) away from the DNA due to heterodimer interactions Full size image

In the absence of an actual connection, NR signaling pathways can indirectly influence crosstalk through several mechanisms.129,130,131 They may compete for overlapping DNA-binding sites by redistributing shared proteins or parts of the transcriptional machinery, such as RNA polymerase II or transcriptional coregulators; by regulating the expression of shared coregulators; and by acting as pioneering factors that loosen chromatin to facilitate the binding of additional NRs. For example, peroxisome proliferator-activated receptor alpha (PPARα) binds to estrogen-related receptor (ERR) target genes in heart tissue through ERR response element motifs via a histone deacetylase SIRT1-dependent mechanism.132 RXR, the PPAR partner, can trigger PPAR-independent activities on PPAR response element (RE)-controlled genes via RXR homodimerization, adding another layer of control to an intricate metabolic pathway.133 Members of the PPAR and ERR subfamilies can be further connected through shared coregulators, including PGC1α and PGC1β, as well as through common regulators such as low-energy-sensing AMP kinase.134,135 For example, during adipocyte differentiation and osteoclastogenesis, PGC1β, a coregulator that is upregulated by ERRα, can be recruited by PPARγ and other transcriptional regulators to enhance their adipogenic properties.136 Reduced PGC1β expression levels due to downregulation of ERRα resulted in decreased transcriptional activity of PPARγ. These reports provide evidence for the existence of complex combinations of indirect regulatory modes.

Genomic and nongenomic mechanisms

The function of nuclear receptors can be achieved via genomic or nongenomic pathways (Fig. 5). Genomic mechanisms involve the direct regulation of gene expression through binding to DNA. This mechanism usually plays a critical role in long-term physiological processes, such as development, metabolism, and homeostasis. Nongenomic mechanisms involve rapid, transcription-independent actions of nuclear receptors. These processes occur within minutes and are crucial for swift cellular responses, such as ion channel modulation, cell migration, and acute stress responses.

Fig. 5 Nuclear receptors precisely regulate cell fate and metabolic processes. Nuclear receptors play crucial roles in regulating cell fate by influencing various cellular processes, including proliferation, differentiation, senescence and apoptosis, by acting as transcription factors. Additionally, members of the nuclear receptor family control the synthesis rates of different metabolic enzymes across various tissues, affecting processes such as glucose, lipid and bile acid metabolism, as well as adipocyte differentiation and plasma lipoprotein modulation. By regulating the balance between the storage, utilization and production of these macromolecules, nuclear receptors ensure metabolic flexibility, enabling the organism to adapt to fluctuations in energy availability and demand Full size image

Genomic mechanisms

Prior to binding to the specific DNA sequences of target genes known as hormone HREs to control transcription, NRs are typically in an inactive state and require activation through the binding of a cognate ligand.15,137 With many receptors, in the absence of ligands, molecular chaperone proteins such as heat shock protein 90 (HSP90) and HSP70 anchor them in the cytoplasm in an inactive state.138 Upon ligand binding, the NR undergoes a conformational shift that causes it to separate from the heat shock protein and become active.139 This allows the hormone–receptor complex to translocate into the cell nucleus after its nuclear localization sequence (NLS) has been revealed.140,141 Once inside, the complex binds to a specific sequence in the target gene known as an HRE to regulate its transcription. In addition to detaching the HSPs, ligand binding can promote receptor phosphorylation, which further enhances the ability of the receptor to bind to HREs.142 In general, NRs undergo a change from a non-DNA-binding form to a DNA-binding form upon activation, but some types, such as thyroid hormone receptors, retinoic acid receptors and retinoid X receptors, are retained in the nucleus regardless of their ligand binding status.143 They are already bound to HREs but complex with corepressor proteins, which makes them transcriptionally inactive.144,145 However, upon receiving ligand activation signals, the corepressor dissociates, and coactivator proteins are recruited. The NR/DNA complex then enlists more proteins, such as RNA polymerase, to aid in the transcription of DNA into mRNA.146,147,148

Nuclear receptors can directly bind DNA via three different modes, namely, homodimers, heterodimers, or monomers, depending on the type of NR.13 For example, glucocorticoid receptors (GRs) bind to HREs after forming homodimers.149,150 In contrast, retinoic acid receptor-related orphan receptor gamma (RORγ) binds as a monomer to the DNA response region to control gene transcription and expression.151,152 The retinoid X receptor (RXR) can either bind to itself as a homodimer or pair with other nuclear receptors as a heterodimer to activate downstream gene transcription.153,154,155 To make this process even more complicated, some NRs can form nonclassical heterodimers, which are only activated by outside ligands. Thus, unanticipated adverse effects could appear when developing therapeutics because NRs can operate through nonclassical routes.156,157,158,159

The identification of coregulatory proteins that interact with and control the transcriptional action of NRs in the mid-1990s was another pivotal development in our knowledge of the mechanism of action of NRs.160,161 These coregulators have a variety of functions, such as chromatin remodeling, which modifies the target gene’s transcriptional accessibility, or bridging, which maintains the binding of other coregulatory proteins.162 The intrinsic histone acetyltransferase (HAT) activity of coactivator proteins can promote gene transcription by reducing the affinity of histones for DNA.163 On the other hand, the recruitment of histone deacetylases (HDACs) by corepressor proteins increases the number of bonds between histones and DNA and suppresses gene transcription.164 These coactivators or corepressors enable nuclear receptors to function as inducible scaffolds that coordinate large transcriptional complexes, allowing different ligands to induce distinct receptor conformations.163,165 These changes could expose specific protein–protein interaction surfaces, making them available for coregulator binding. This hypothesis provides an explanation for how structurally different ligands, such as selective estrogen receptor modulators, could influence multiple genes in the same cell via the same receptor or how they could jointly regulate the expression of a single gene. Depending on the tissue-specific location of coregulators, the same ligand can also control specific genes in different tissues or at different developmental stages.166,167 Nuclear receptor/coregulator complexes that alter chromatin shape and DNA accessibility are produced by receptor-bound coregulators, which can also directly interact with the core RNA polymerase through their enzyme action. In addition, there is no set link between two distinct nuclear receptors, as they can change depending on the target genes and tissues that are engaged. Transcriptional regulation by NRs can be affected by epigenetic variables such as chromatin remodeling, DNA methylation and histone modification.168,169

Nongenomic mechanisms

In addition to acting as transcription factors in the nucleus to regulate target gene expression (genomic function), NRs can also operate through a molecular mechanism independent of transcriptional activity (nongenomic function)170,171,172 (Fig. 5, Fig. 6). This nongenomic role requires NRs to be localized to specific subcellular structures,173,174,175 where they directly interact with various intracellular proteins to rapidly regulate cellular stress responses and signal transduction pathways. Their subcellular translocation can occur either by alternative splicing or posttranslational modifications through free shuttling or with the assistance of other proteins.176,177 As an example, the plasma membrane is home to a truncated variant of the thyroid hormone receptor. This localization enables them to participate in several biological processes, including the endoplasmic reticulum stress response, apoptosis, autophagy, fatty acid oxidation within mitochondria and the regulation of centrosome homeostasis and cell mitosis. Nongenomic NR signaling frequently involves phosphorylation cascades mediated through pathways associated with AMPK, cAMP/PKA, PI3K/AKT, and Hippo/Yap and signaling via Wnt/β-catenin and MAPK.178,179,180,181,182,183

Fig. 6 Platelets are good models for investigating the possible nongenomic impacts of nuclear receptors. Because of their anucleate origin, well-characterized mechanisms, and quick reactions, platelets offer a model system for examining any non-genomic impacts of the NRs. Non-genomic roles of NRs include controlling intracellular calcium levels, ion channel function, kinase and phosphatase activity, and second messenger synthesis. It has been discovered that human platelets contain a number of NRs, and that certain NR agonists have anti-platelet actions through a range of mechanisms Full size image

Several NRs have been found to propagate rapid nongenomic effects for cellular protection in addition to their defined genomic effects. Their nongenomic functions operate through the control of kinase/phosphatase activity,184,185 intracellular calcium levels,186,187 ion channel function188,189 and the production of second messengers.190 Accumulating data indicate that RXRα also possesses extranuclear nongenomic functions. Previous studies have demonstrated that RXRα engages in some nongenomic activities through the creation of heterodimers with Nur77.191 In response to specific apoptotic stimuli, RXRα-Nur77 heterodimers are translocated from the nucleus to the mitochondria, where they regulate apoptosis.192 Recent research has shown that truncated RXRα (tRXRα) has an important function in the PI3K/AKT signaling pathway, where it interacts with the p85α subunit to increase AKT activation and promote cell proliferation both in vitro and in vivo.193,194 Notably, glucocorticoids (GCs) manifested nearly instantaneous nongenomic effects through nonspecific interactions with cell membranes and targeted interactions with cytosolic GRs (cGRs) or membrane-bound GRs (mGRs).124,195,196 This rapid nongenomic action of GCs could also contribute to their anti-inflammatory effects through prolonged genomic processes, particularly in managing inflammatory diseases (Fig. 6).197,198 For example, recent studies revealed that GCs quickly enhanced the effects of bronchodilators used to treat allergic asthma.199 Other NRs, including PPARα, LXR and FXR, have also been reported to perform nongenomic functions.189,191,200 The possibility of turning NR ligands into effective medicines should be explored through the characterization of these extragenomic processes and the discovery of new binding partners and pathways in addition to their known genomic effects.

Platelets are useful models for investigating the potential nongenomic effects of NRs because they lack nuclei and possess well-characterized reactions.189,201 ERβ, but not ERα, is known to be expressed on human platelets and to affect their function.202 In addition, some studies have shown that platelets isolated from male rats exhibit a stronger aggregation response than those from female rats do, likely due to an increase in androgenic steroids.203,204 This conclusion was supported by findings that castration reduced platelet aggregation in male rats,205 an effect that was reversed with testosterone treatment.206 LXR and FXR ligands negatively regulate platelet function by inhibiting platelet signaling and the formation of procoagulant-coated platelets.207,208,209,210 For example, LXR ligands induce a procoagulant state in platelets, which is marked by the exposure of phosphatidylserine and α-granule contents on the surface of the platelet, coupled with mitochondrial membrane depolarization, reduced calcium mobilization and decreased affinity of integrin αIIbβ3, which ultimately inhibits platelet aggregation.209,211 Similarly, FXR ligands can cause platelet swelling and transformation into procoagulant-coated platelets, a process dependent on cyclophilin D activity.212 FXR ligands also increased cGMP levels, which increased PKG activity and VASP S239 phosphorylation, further suppressing platelet activation.189 Other studies have identified PPARα as a key mediator of the antiplatelet effects of statins and fenofibrate.213 Treating platelets with PPARα ligands, such as fenofibrate or statins (e.g., simvastatin), inhibited ADP-stimulated platelet activation by increasing intracellular cAMP levels through a PPARα-dependent mechanism.214 This role of PPARα was further confirmed by experiments showing that fenofibrate-induced inhibition of platelet activation and prolonged bleeding time were absent in PPARα-deficient mice215; the reversion of this inhibitory effect by the PPARα antagonist GW6471 further highlighted its dependence on PPARα.

Subsequent studies revealed the unexpected presence of retinoic acid receptors (RARs) in the cytosol of Sertoli cells, hepatic stellate cells and neurons.216,217,218 In Sertoli cells, RARα was found to be a substrate for small ubiquitin-like modifier-2 (SUMO-2), and its cytosolic or nuclear localization was influenced by a dynamic process of sumoylation and desumoylation.219,220 Additionally, in Sertoli and hepatic stellate cells, RARα is retained in the cytosol through interactions with the cytoplasmic adaptor for RAR and TR (CART1) protein or with cytoskeletal proteins that sequester the receptor outside the nucleus.144 Furthermore, in hippocampal neurons, independent studies have shown that RARα is exported to dendritic RNA granules, where it is associated with a specific subset of mRNAs and RNA-binding proteins.221,222,223 Interestingly, in response to retinoic acid (RA), this extranuclear pool of RARα rapidly initiates the local translation of the postsynaptic glutamate receptor GluR1, leading to an increase in synaptic strength.224,225 In light of this growing body of knowledge, understanding these nongenomic mechanisms can lead to the development of new therapeutic strategies that exploit the rapid and diverse roles of nuclear receptors outside of their traditional genomic functions. By targeting the nongenomic pathways of nuclear receptors, it may be possible to create drugs with faster onset times and more specific effects, thereby increasing the efficacy of treatments for various diseases.

Functions in physiology and pathology

Nuclear receptors are of key importance in physiology and pathology because they regulate multiple cellular functions (Fig. 5). For example, NHR-6, the only NR4A-type nuclear receptor in the roundworm Caenorhabditis elegans, has been implicated in the development of the nervous system.226 During development, the nervous system produces highly specialized neurons with distinct functional characteristics. A prime example is the C. elegans BAG chemosensory neurons.227 Under certain circumstances, BAG neurons sense the concentration of carbon dioxide in respiratory gas and translate it into reactions of attraction or repulsion; ETS-5 and its target gene NHR-6 are essential for this process.228 In contrast to ETS-5, which is engaged in both the attraction and avoidance of carbon dioxide, NHR-6 is an NR that is exclusively involved in the attraction process.229 These findings imply that gene regulatory mechanisms supported by NR subtypes have undergone evolutionary conservation. NHR-6 is necessary for BAGs to exhibit exceptional capacity to adaptively assign positive or negative valences to chemosensory stimuli, and it is a key modulator of the functional plasticity of the neural system.226 It is clear that NRs are of the greatest importance for the proper functioning of numerous processes in cellular lipid metabolism,230,231 energy homeostasis232 and the inflammatory response233; cell proliferation and differentiation are critically dependent on nuclear receptors.

Pathological changes in nuclear receptors, such as mutations, altered expression levels, or dysregulated activity, are linked to a wide range of diseases, including cancer, metabolic disorders, inflammation, and cardiovascular conditions. For example, the overexpression of ER in breast cancer drives tumor growth,234 whereas aberrant AR can cause therapy resistance in prostate cancer.235 Impaired PPAR function is associated with metabolic disorders such as obesity and type 2 diabetes,236 whereas dysregulated liver X receptors (LXRs) disrupt cholesterol homeostasis, exacerbating cardiovascular disease.237 Aberrant GR activity exacerbates inflammatory conditions and may induce corticosteroid resistance. Altered retinoid X receptor (RXR) function has been linked to neurodegenerative diseases such as Alzheimer’s disease. These pathological changes not only hold diagnostic and prognostic value but also serve as therapeutic targets. For example, ER, PR, and HER2 expression levels guide breast cancer classification and treatment, with SERMs such as tamoxifen proving effective in ER-positive patients. AR inhibitors are crucial in prostate cancer, where AR expression levels and mutations influence therapeutic outcomes. Additionally, radiolabeled ligands such as [F-18]-estradiol enable imaging of ER-positive tumors via PET scans,238 aiding in diagnosis and treatment monitoring. In summary, nuclear receptor alterations play a dual role in clinical practice as both therapeutic targets and biomarkers, underscoring their critical contribution to precision medicine and improved patient outcomes.

Cell fate

Nuclear receptors are essential for regulating cell fate through their function as transcription factors with effects on proliferation,239 differentiation,240 senescence241 and apoptosis.242 Through nongenomic mechanisms, NRs modulate signaling pathways that determine whether a cell will continue to divide, differentiate into a specific cell type, or undergo programmed cell death.243

The ER has been the most studied ER, mainly because of the estrogen dependence of the growth of certain breast cancer cells. The function of estrogen receptor alpha (ERα/ER) defines the most common type of breast cancer.244,245 Numerous associated elements that function as regulators of estrogen-driven transcriptional pathways have been discovered, indicating that the ER cannot function solely by itself.246 Enhancer sequences are cis-regulatory ER binding sites that are located mainly away from transcriptional start sites, according to genome-wide profiling of chromatin binding.247 There is growing evidence that global enhancer activation is involved in tumor aneuploidy and carcinogenesis.248 Short DNA enhancer elements are crucial for maintaining a coordinated gene expression program specific to cell types during development and differentiation.249 Other nuclear receptor ligands, such as all-trans retinoic acid (atRA) and 1,25(OH)2D3, induce cell differentiation.250,251,252 RA, the primary bioactive metabolite of retinol (vit A), has a range of pleiotropic effects on cell growth and differentiation, which are important in adult physiology and embryonic development.253 Members of the NR class of transactivators, specifically the retinoic acid receptors RARα, RARβ and RARγ, are the main mediators of activity.254 For example, prostate cancer-induced bone formation is decreased, and the endothelial-to-osteoblast transition (EC-to-OSB) is inhibited when the retinoic acid receptor (RAR) is activated.255,256 Treatment with the RARγ agonist palovarotene, which has been tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited osteoblast mineralization and the EC-to-OSB transition in vitro. It also reduces the growth and formation of tumor-induced bone in several models of osteogenic prostate cancer.255 Compared with mature hepatocytes, hepatocytes induced in a 3D environment exhibited lower activity of the nuclear receptor THRB. The addition of THRB ligands during differentiation upregulated not only the expression of CYP3A4 but also the expression of multiple hepatocyte-related genes and increased histone acetylation; the induced differentiated hepatocytes were more similar to mature hepatocytes.21 In addition, the nuclear receptor Nur77 regulates the expression of genes involved in fatty acid absorption and transport, thereby blocking the uptake of exogenous fatty acids by cells and inhibiting the signaling pathways that promote breast cancer cell proliferation.27 These findings highlight the significant role of NRs in controlling cell growth and differentiation.

NRs have also been shown to be involved in cellular senescence and cell death processes. Three members of the NR4A1/Nur77/NGFIB orphan nuclear hormone receptor subfamily (NR4A1, NR4A2 and NR4A3) have been the most studied. NR4A2 was reported to maintain anchorage-independent growth, thereby reducing cell death, known as anoikis, in HeLa cells.257 Following acute kidney injury (AKI), Nur77 and its family members Nurr1 and Nor-1 stimulate epithelial apoptosis. A conformational shift in Bcl2 and an increase in proapoptotic Bcl-xS protein levels are involved in Nur77-mediated kidney damage.258 Furthermore, YAP controls the transcription, phosphorylation and mitochondrial localization of NR4A1 to mediate the proapoptotic and antitumor actions of the Hippo pathway. In turn, NR4A1 acts as a feedback inhibitor of YAP, leading to its destruction, which prevents YAP from participating in carcinogenesis and liver regeneration.259 In addition, Nur77 interacts with DNMT3b, increasing GLS1 promoter methylation and decreasing GLS1 expression and glutaminolysis, which leads to the induction of HSC senescence.260 Hepatocyte nuclear factor 4α (HNF4α, NR2A1), another strongly conserved NR superfamily member, suppresses prostate tumorigenesis by arresting the cell cycle at the G2/M phase and p21-driven cell senescence.261 NR subfamily 1 group I member 2 (NR1I2), also called PXR (pregnane-X receptor) or PAR (pregnane-activated receptor), has been implicated in blunting the expression of the proapoptotic genes TP53 and BAK1 (BCL2 antagonist/killer 1) to prevent apoptosis from toxic bile acids.262 The retinoid RXRα has been shown to suppress the production of ITPR2 and control calcium signaling via ITPR2 and the mitochondrial calcium uniporter (MCU). After reducing the degree of DNA damage, the overexpression of RXRα delays replicative senescence.263 ZBTB17, a zinc finger protein, was shown in another study to interact with RXRα. Notably, ZBTB17 knockdown initiates a series of events, including DNA damage, decreased mitochondrial membrane potential (MMP), RXRα-dependent intracellular calcium signaling and cellular senescence.264 Under metabolic and genotoxic stresses, LXR/CD38 activation promoted lysosomal cholesterol efflux and nicotinamide adenine dinucleotide (NAD+) depletion in macrophages, which caused cholesterol-induced macrophage senescence and neurodegeneration.265

Cellular metabolism

Members of the NR family control the pace at which different metabolic enzymes are synthesized in different tissues,266 which affects processes including the metabolism of glucose, lipids and bile acids; adipocyte differentiation; and plasma lipoprotein modulation.267,268 By influencing the balance between the storage, utilization and production of these macromolecules, NRs ensure metabolic flexibility, allowing the organism to adapt to fluctuations in energy availability and demand (Fig. 7). Their regulatory functions are particularly critical during periods of fasting, stress, or increased physical activity, where their precise control is essential for maintaining overall metabolic health.

Fig. 7 Examples of nuclear receptors involved in regulating metabolic pathways. Cellular metabolic pathways provide the energy and materials essential for cell survival. Nuclear receptors transcriptionally regulate genes that encode nutrient transporters and metabolic enzymes involved in these processes. The pathways include the following: 1. Glycolysis, 2. Pentose phosphate pathway (PPP), 3. Gluconeogenesis, 4. Lactate oxidation, 5. Autophagy, 6. Amino acid catabolism, 7. Redox homeostasis, 8. Mitochondrial biogenesis/dynamics, 9. Oxidative phosphorylation (OXPHOS), 10. Tricarboxylic acid (TCA) cycle, 11. Ketogenesis/ketolysis, 12. Glutaminolysis, 13. Ca2+ homeostasis, 14. Fatty acid oxidation (FAO), 15. Lipolysis Full size image

Glucose metabolism and gluconeogenesis

Glucose is the primary metabolic fuel for mammals and plays a crucial role in maintaining energy homeostasis.269,270 During the fed state, circulating glucose originates primarily from the absorption of nutrients in the intestines.271 However, under fasting or energy-demanding conditions, the body relies on two additional sources to maintain glucose levels: the breakdown of stored glycogen through glycogenolysis and the production of new glucose molecules via gluconeogenesis.272,273,274 These complex metabolic processes are intricately regulated, and NRs play a key role in coordinating them. As molecular sensors, NRs detect changes in the body’s energy status and modulate the expression of genes involved in glucose metabolism.275,276 The activation of PXR by its ligand, pregnenolone-16α-carbonitrile (PCN), impaired glucose tolerance by dysregulating glucose transporter 2 (GLUT2) function through two distinct mechanisms.277 First, it reduced the expression of GLUT2 in both mouse liver and wild-type hepatocytes. Second, it triggers the transport of GLUT2 from the plasma membrane to the cytosol in the liver, thereby suppressing glucose uptake in primary hepatocytes. Additionally, data mining of published chromatin immunoprecipitation/sequencing results revealed that the Glut2 gene is directly targeted by PXR. These findings may explain the diabetogenic effects of certain medications and environmental contaminants, positioning PXR in a potential novel diabetogenic pathway. At physiological concentrations found in the liver, glucose binds to and activates the transcriptional activity of LXRs, inducing the expression of LXR target genes with similar efficacy to that of oxysterols, which are well-known LXR ligands. Cholesterol homeostasis genes, which depend on LXR for their expression, were upregulated in the liver and intestines of fasted mice after refeeding with a glucose-rich diet,278 suggesting that glucose acted as an endogenous ligand for LXR.

Nuclear orphan receptor subfamily 4 group A member 1 (NR4A1), an important regulator of hepatic glucose homeostasis, was found to interact with the nuclear glycerol kinase Gyk during hepatic gluconeogenesis in the unfed state and in diabetes. Gyk acts as a corepressor of NR4A1, which attenuates the expression of target genes involved in hepatic gluconeogenesis and obstructs blood glucose regulation.279 Nuclear receptor subfamily 5 group A member 2 (NR5A2 or LRH1) and steroidogenic factor 1 (SF1 or NR5A1) work synergistically as key regulators of glucose-sensing systems in hepatic and steroidogenic tissues.280 These receptors are essential for the normal processing of glucose after eating through direct control of GCK and HK1 transcription.281 FXR combines signals from PKA and FOXA2 for hepatic glucose metabolism and production through two regulatory arms.282 The first is the phosphorylation of FXR by protein kinase A, which induces glucagon, agonist-activated FXR and CREB to combine and activate gluconeogenic genes. The physical interaction between FXR and the glucagon-activated FOXA2 transcription factor constitutes the second arm, which prevents FXR from stimulating the anti-gluconeogenic nuclear receptor SHP. Foxa2 knockdown did not influence the expression of glucagon-induced or FXR agonist-boosted gluconeogenic genes, suggesting that distinct subsets of FXR-sensitive genes are controlled by the PKA and FOXA2 pathways.282

NR coregulators play crucial roles in the regulation of glucose metabolism. For example, NR corepressors (NCoRs) operate within multiprotein complexes containing histone deacetylase 3 (HDAC3) to inhibit transcription, primarily through repressive chromatin remodeling at target loci. This process ultimately drives glucocorticoid receptor-dependent activation of hepatic gluconeogenesis. In hepatocytes, the double knockout of both NCoR1 and NCoR2 mimicked the hepatomegaly and fatty liver phenotype observed in HDAC3 knockouts by preventing glucocorticoid receptor binding.283 Similarly, nuclear receptor coactivator 3 (NCOA3) regulates the transcription of tyrosine-protein kinase (Fyn) in a PPARγ-dependent manner. NCOA3 deficiency was shown to worsen diabetic kidney disease by exacerbating albuminuria, glomerular sclerosis, and podocyte injury and impairing autophagy.284

Bile acid, sterol and lipid metabolism

Increasing evidence suggests that NRs play critical roles not only in glucose metabolism but also in the regulation of sterol, bile acid and lipid metabolism.285,286,287 The three ERR isoforms, as well as PPARα and PPARδ, are the main transactivators of genes involved in mitochondrial bioenergetics and fatty acid oxidation (FAO) and are viewed as primary controllers of mitochondrial FAO.288,289 For example, in addition to being a regulator of mitochondrial function, ERRα was established as a major transcriptional regulator of lipid biosynthesis and a promoter of nonalcoholic fatty liver disease (NAFLD/NASH).290 Medium-chain specific acyl-CoA dehydrogenase (ACADM), the first-discovered target gene of ERRα, encodes the initial rate-limiting enzyme in mitochondrial FAO; the promoter is also targeted by PPARα.291 In addition, a muscle-specific protein induced by PGC-1 and ERRs, PERM1 (PGC-1/ERR-induced regulator in muscle-1), promoted mitochondrial biogenesis and metabolism in cardiomyocytes. In this study, PERM1 was shown to interact with the proximal regions of PPAR response elements (PPREs) in the endogenous promoters of genes involved in fatty acid oxidation, and further results revealed that PERM1 interacted with PPRE to promote transcription, partly in a PPARα- and PGC-1α-dependent manner.292

PPARα is also a key regulator of fatty acid oxidation and can induce spontaneous fatty liver and hyperlipidemia in mice fed a standard diet. For example, during the early night, fasting mice exhibited acute PPARα-dependent hepatocyte activity, accompanied by increased circulating free fatty acids that could be further stimulated by adipocyte lipolysis. However, fasting resulted in mild hypoglycemia and hypothermia in PPARαhep−/− mice, suggesting a role of PPARα activity in nonhepatic tissues.293 Liver-specific inactivation of Vps15, the essential regulatory subunit of class 3 PI3K, elicited mitochondrial depletion and failure to oxidize fatty acids through blunting of the transcriptional activity of PPARα. Vps15 deficiency led to the accumulation of the PPARα repressors HDAC3 and nuclear receptor corepressor 1 (NCoR1) in the liver due to disrupted autophagy. Activation of PPARα or inhibition of HDAC3 restored mitochondrial biogenesis and FAO in Vps15-deficient hepatocytes, revealing functions for class 3 PI3K and autophagy in the transcriptional coordination of mitochondrial metabolism.294 In addition, hepatic Ncor1 deletion in mice retarded atherosclerosis development by reprogramming bile acid metabolism and enhancing fecal cholesterol excretion, resulting in reduced plasma cholesterol levels and decreased hepatic cholesterol content in liver-specific Ncor1 knockout mice compared with those in controls fed an atherogenic diet for twelve weeks.295

NR4A1 was identified as a previously unrecognized constitutive regulator of adipocyte progenitor (AP) quiescence.296 In ex vivo experiments, NR4A1 gain-of-function reduced adipogenesis, whereas its loss-of-function increased adipogenesis.296 Compared with control mice, NR4A1 knockout mice fed a high-fat diet were more prone to obesity, with increased gene expression of PPARγ and FAS. Conversely, NR4A1 overexpression in 3T3-L1 preadipocytes inhibited adipogenesis. NR4A1 upregulated GATA binding protein 2 (GATA2), which in turn inhibited PPARγ. NR4A1 also suppressed sterol regulatory element-binding protein 1 (SREBP1) and its downstream target fatty acid synthase (FAS) by upregulating p53. Overall, NR4A1 inhibits adipocyte differentiation and lipid accumulation by increasing the expression of GATA2 and p53.297 Nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in the liver and intestine, and its transcriptional activity can be increased by fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling. FGF19 and SHP were observed to inhibit SREBF2 (sterol regulatory element binding transcription factor 2), which led to a reduction in intestinal NPC1L1 expression, cholesterol absorption and hypercholesterolemia.298 Another member of the nuclear receptor family, NR1A1, was reported to influence hepatic autophagy, lipid metabolism and adipocyte homeostasis by interacting with MED1 through a bridge formed by PGC1α.299,300

The expression of RORα/β/γ and REV-ERBα/β in the liver follows circadian rhythms. The liver genome contains high-order transcriptionally repressive hubs where REV-ERBα condensates are found, and these hubs are strongly associated with circadian gene repression.301,302,303 In mouse models, RORs bind to ROREs at night, whereas REV-ERBα/β bind to ROREs during the day to decrease lipogenesis. In the liver, REV-ERBα and REV-ERBβ work in concert, increasing the ability of HDAC3 and NCoR to control SREBP activity and maintain lipid homeostasis. They also affect cytochrome P4507A1 expression levels, which helps to maintain the equilibrium of bile acid metabolism.304 RORγ serves as a crucial activator of the entire cholesterol biosynthesis program, controlling SREBP2 by binding to genes involved in cholesterol biosynthesis and facilitating SREBP2 recruitment. At the loci of genes involved in cholesterol production, RORγ inhibition decreases chromatin acetylation and disrupts its connection with SREBP2. In immunocompetent animals and patient-derived xenografts, RORγ antagonists induce tumor regression.305

The regulation of bile acids, sterols and lipids is also associated with many other types of nuclear receptors. Through the regulation of Akr1b7 transcription, the nuclear receptor PXR effectively reduces AKI by increasing reactive oxygen species (ROS) generation, mitochondrial autophagy and mitochondrial dysfunction in lipid metabolism.306 It was recently demonstrated that the function of FXR in BA homeostasis depends on the phosphorylation of Tyr-67 by the FGF15/19 signaling-activated nonreceptor tyrosine kinase Src. According to Byun and colleagues, hepatic FXR phosphorylation by FGF15/19-induced Src preserves cholesterol homeostasis and protects against atherosclerosis.307 PXR activation upregulated intermediates in the Kandutsch–Russell cholesterol synthesis pathway in the liver and induced a number of cholesterol synthesis genes, including the rate-limiting HMRCR. In both mice and humans, PXR activation increased the level of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL absorption. A new regulator of PCSK9 and cholesterol synthesis, the PXR-SREBP2 pathway, also serves as a molecular mechanism for drug- and chemical-induced hypercholesterolemia.308

Mitochondria, OxPhos and the TCA cycle

Mitochondria serve as vital energetic and biosynthetic signaling hubs, taking in substrates from the cytoplasm to generate bioenergetic and biosynthetic building blocks.309 This process is achieved through the coordinated activity of several key metabolic pathways, including the electron transport chain (ETC), oxidative phosphorylation (OxPhos), the tricarboxylic acid (TCA) cycle, glycolysis, glutaminolysis and fatty acid oxidation (FAO). These pathways not only produce ATP but also provide intermediates essential for biosynthesis. Crucially, the function of mitochondria is tightly regulated by various nuclear receptors, which modulate gene expression to ensure proper mitochondrial activity and metabolic balance.

Several nuclear receptors are involved in regulating genes associated with the TCA cycle and OxPhos, including estrogen-related receptor alpha (ERRα), NUR77 (NR6A1) and PPARγ.310,311,312 One of the first major datasets used to highlight the role of ERRα in OxPhos regulation was a study that integrated PGC1α-induced GW transcriptional profiling with a software approach to identify cis-regulatory sequences.313,314 Mice lacking both ERRα and ERRγ presented the most extensive and profound disruption in skeletal muscle gene expression, with the ‘mitochondrial function’ pathway genes involved in OxPhos and the TCA cycle being the most significantly affected. Moreover, mice deficient in ERRβ and ERRγ exhibit impairments in lipid metabolism and branched-chain amino acid metabolism, specifically in the soleus muscle.315 Similarly, muscle-specific deletion of Esrrg (the gene encoding ERRγ) in mice reduces exercise capacity because of deficient mitochondrial activity.316 adipocytes lacking all ERR isoforms exhibited significant downregulation of genes involved in oxidative metabolic pathways, including those controlling the TCA cycle and OxPhos, leading to marked reductions in mitochondrial content and oxidative capacity.317 These results suggest that many mitochondrial actions are mediated through the stimulation of ERR expression and activity, underscoring the critical role of ERR in mitochondrial energy metabolism across various tissues.

The nuclear receptor Nur77 (also known as TR3 or NGFI-B), encoded by Nr4a1, belongs to the steroid/thyroid/retinoid superfamily and serves as a key regulator of energy metabolism. Nur77 is phosphorylated by ERK2 and translocated to the mitochondria upon glucose deprivation. Mitochondrial Nur77 binds to TPβ, a rate-limiting enzyme in FAO, to protect it from oxidation. This promoted the metabolic adaptation of melanoma cells by evading ROS-induced cell death.318 Ubiquitinated mitochondrial Nur77 interacts with the ubiquitin-binding domain of p62/SQSTM1 to form condensates capable of sequestering damaged mitochondria. An additional interaction between the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1 allows tethering of clustered mitochondria to the autophagy machinery, which endows Nur77-p62/SQSTM1 condensates with the magnitude and liquidity to act on the mitochondria.319 In response to the pathological accumulation of α-synuclein (α-syn) fibrils in Parkinson’s disease (PD), Nur77 is translocated from the cytoplasm to the mitochondria to improve PHB-mediated mitophagy by regulating c-Abl phosphorylation. Nur77 overexpression alleviated the expression of pS129-α-syn and protected dopamine (DA) neurons from the loss of α-syn in PD.320

NR1D1 (nuclear receptor subfamily 1 group D member 1) is the most highly upregulated nuclear receptor in abdominal aortic aneurysm (AAA) tissues. Knockout of Nr1d1 in vascular smooth muscle cells (VSMCs), but not in endothelial or myeloid cells, led to significant inhibition of AAA formation. Mechanistic investigations revealed that ACO2 (aconitase-2), a key enzyme in the TCA cycle, is a direct transcriptional target of NR1D1. By repressing ACO2, NR1D1 modulates mitochondrial metabolism. In the absence of NR1D1, ACO2 expression is restored, which subsequently corrects mitochondrial dysfunction during the early stages of Ang II infusion, even prior to the onset of AAA development.321

Catabolism of amino acids

Amino acid catabolism is vital during starvation to sustain glucose levels and provide alternative carbon sources, primarily in the liver but also in the kidneys, muscles and adipose tissue.322 This process involves transamination and oxidative deamination in the cytoplasm, producing metabolites such as α-ketoglutarate, pyruvate and acetyl-CoA, which feed into the TCA cycle.323 An essential NR in AA catabolism is ERRα, which is active in regulating genes involved in amino acid uptake and branched-chain amino acid metabolism.324 ERRα is also linked to reduced leucine oxidation under energy-demanding conditions.325 PPARα and HNF4α also regulate amino acid utilization. PPARα, in the presence of RXRα, inhibited HNF4α activity, suppressing serine dehydratase expression by promoting HNF4α degradation via the proteasome pathway. In PPARα-knockout mice, HNF4α levels and amino acid catabolizing enzyme (AACE) expression are elevated.326 In response to amino acid deficiency (AAD), MEF2D (myocyte enhancer factor 2D) and NR4A1 induce FAM134B2 expression and promote FAM134B2-mediated reticulophagy to maintain intracellular amino acid levels.327

Inflammation and immunity

Compelling evidence suggests that NRs can regulate inflammation and immunity, contributing to the pathogenesis of human diseases. For example, Nur77 binds to LPS, acting as an LPS receptor protein and playing a role in macrophage pyroptosis. Further research indicated that Nur77-LPS interactions activated NLRP3, resulting in the formation of an atypical inflammasome. These findings demonstrated that Nur77 promotes NLRP3 inflammasome activation, enhancing the host immune response to endotoxins.174 Similarly, Nur77 was identified as a key transcriptional regulator of the proinflammatory metabolic switch in macrophages. IDH expression was not downregulated in Nur77-deficient macrophages, which led to increased levels of succinate and other TCA cycle metabolites, independent of glutamine, resulting in increased nitric oxide and proinflammatory cytokine production in an SDH-dependent manner. Thus, Nur77 promotes an anti-inflammatory metabolic state in macrophages, offering protection against chronic inflammatory diseases such as atherosclerosis.328 Another nuclear receptor, RORα, regulates hepatic macrophage polarization and inflammation by inducing kruppel-like factor 4 (KLF4) expression. In myeloid-specific RORα-deficient animals, Kupffer cells (KCs) and bone marrow-derived macrophages fail to undergo M2 polarization, rendering them more susceptible to high-fat-diet-induced nonalcoholic steatohepatitis (NASH).329 Additionally, the orphan nuclear receptor TLX directly bound to the CD274 (PD-L1) gene promoter, showing a strong positive correlation with PD-L1 overexpression. Suppressing TLX significantly reduced the in vivo growth of glioma allografts and xenografts, preserved the antitumor immune response and markedly decreased the number of PD-L1-positive cells and glioma-associated macrophages.330 Nuclear receptor subfamily 1 group D member 1 (NR1D1) acts as a transcriptional repressor and plays a key role in regulating inflammation. The activation of NR1D1 decreased the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs), whereas NR1D1 silencing had the opposite effect. Additionally, NR1D1 activation reduces ROS production and increases the generation of Nrf2-associated antioxidant enzymes.331

NRs also play crucial roles in modulating immune responses by directly regulating the function and activity of immune cells, such as influencing their development, differentiation and activation. For example, overexpression of NR4A1 inhibited the development of effector T cells through binding to the transcription factor AP-1 and inhibited its promotion of the expression of effector genes. NR4A1 binding encouraged the acetylation of histone 3 at lysine 27 (H3K27ac), which activated genes linked to tolerance. Deletion of NR4A1 increases immunity against tumors and chronic viruses, overcomes T-cell tolerance and enhances effector function.332 Similarly, another study revealed that NR4A triple knockout CAR-T lymphocytes presented traits and gene expression profiles typical of CD8+ effector T cells. The chromatin regions in these cells were enriched in binding motifs for transcription factors involved in T-cell activation, such as NF-κB and AP-1.333 These studies suggest that NR4A is a major regulator involved in the induction of T-cell dysfunction and that NR4A inhibition is a promising approach for cancer immunotherapy.

RARs and RA signaling play crucial roles in immune responses, influencing immune tolerance, tissue homing, lymph node formation and protective immunity.334 RARs include RARα, RARβ and RARγ, which are encoded by different genes with unique transcriptional variants and isoforms. In the resting state, RARα binds to transcriptional repressors to inhibit gene expression. However, upon binding to RA, RARα tends to bind to transcriptional activators, promoting gene expression334 RAR signaling has been shown to regulate immunity. For example, following TCR stimulation, extranuclear RARα is rapidly phosphorylated and recruited to the TCR signalosome. RA disrupted extranuclear RARα signaling, leading to reduced TCR activation and increased conversion of FOXP3+ regulatory T cells. RA is translocated to the nucleus by CRABP2, which is upregulated by TCR activation. Deletion of Crabp2 resulted in increased cytoplasmic RA, disrupting signalosome-associated RARα and consequently weakening autoimmune responses while diminishing antipathogen immunity.335

Temporal expression changes

The expression of nuclear receptors is not only related to tissue, sex, and disease but also varies across different age groups within the same individual.336 These variations reflect developmental needs, metabolic changes, hormonal shifts, and adaptations to aging-related physiological demands. Generally, developmental NRs such as RARs, PPARs and RXRs are highly expressed during embryogenesis and early development to support rapid growth, differentiation, and development.337 During adolescence, ARs, ERα and ERβ are elevated to correlate with puberty and the onset of secondary sexual characteristics, whereas GRs act to moderate stress responses and energy metabolism during periods of rapid physical and emotional development. PPARs, LXRs, and FXRs live in adult individuals to maintain lipid and glucose homeostasis, supporting metabolic stability during peak years of physical activity and reproductive capability. Diet, exercise, and stress significantly modulate NR expression, affecting metabolic and endocrine balance during this period. The expression of these NRs decreases with increasing age, which causes impaired lipid metabolism and insulin sensitivity, cholesterol and bile acid metabolism, and calcium homeostasis and immune function, leading to an increased risk of metabolic syndrome, compromised organ function and chronic inflammation. For example, Nr4a1 is reduced in peripheral blood mononuclear cells and CA1 pyramidal neurons with aging, which impairs cognition and excitatory synaptic function.338 Monitoring age-specific NR expression patterns could guide personalized therapies to optimize metabolic health and prevent age-related diseases.

Degradation and metabolic cycling

The metabolic cycling process of NRs, including their synthesis, activation, degradation, and recycling, is integral to maintaining homeostasis and ensuring that NRs can adapt to changing physiological demands. Since the activation and transcriptional regulation of nuclear receptors have been discussed above, we mainly emphasize their degradation and recycling. The degradation of nuclear receptors is a highly regulated process that involves proteasomal and lysosomal pathways, ensuring the dynamic control of receptor levels in response to physiological and environmental cues. Ligand binding can either stabilize or destabilize NRs by inducing conformational changes that influence ubiquitination.339,340 In addition, posttranslational modifications (PTMs), such as phosphorylation,341 SUMOylation342 and acetylation,343 modify NR degradation rates by altering their interaction with ubiquitin ligases or stabilizing proteins. Moreover, many NRs, such as REV-ERBs and PPARs, exhibit circadian cycling, with their expression and activity oscillating in a 24-hour rhythm to align with metabolic needs.344,345 These rhythms are coregulated by core circadian clock genes (e.g., CLOCK and BMAL1), which synchronize metabolic functions with environmental cycles such as light and feeding. Altogether, cycling of NRs ensures appropriate receptor levels, preventing excessive or prolonged signaling that could lead to cellular dysfunction.

Alterations cause by aging

With aging, the efficiency of key regulatory pathways declines, leading to altered NR turnover, disrupted signaling, and increased susceptibility to age-related diseases.346 Proteasomal dysfunction, a hallmark of aging, impairs the degradation of damaged or misfolded proteins, including NRs. This results in the accumulation of inactive or malfunctioning receptors, which disrupt signaling and contribute to metabolic and endocrine dysregulation, key features of aging. These disruptions play a central role in the development of diseases such as obesity, diabetes, cardiovascular conditions, and neurodegenerative disorders.347,348 Additionally, aging reduces autophagic flux, hindering the clearance of damaged proteins, including aggregated NRs. As autophagy becomes less efficient with age, NR aggregates persist, disrupting receptor signaling and promoting chronic inflammation, mitochondrial dysfunction, and cellular stress.349,350 These factors are implicated in the progression of age-related diseases like Alzheimer’s, diabetes, and frailty. Oxidative stress also contributes to aging-related cellular damage by directly modifying NRs. ROS cause conformational changes in NRs, preventing their proper ubiquitination and degradation. This oxidation makes NRs resistant to degradation, leading to the accumulation of damaged receptors and further dysfunction in signaling pathways.351 Understanding these age-related changes offers valuable insights for developing targeted therapies to restore NR homeostasis and mitigate aging-associated disorders.