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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.

Sekiya and colleagues demonstrate that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have an essential role in regulatory T cell development. Regulatory T cells (T reg cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in T reg cell development. Mice that lacked all Nr4a factors could not produce T reg cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the T reg cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4 + T cell fates in the thymus and thus contribute to immune homeostasis.

The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson’s disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1’s transcriptional function. Prostaglandins PGE1 and PGA1 have neuroprotective effects by enhancing the transcriptional activity of Nurr1 by directly binding to its ligand-binding domain and upregulating their target genes implicated in Parkinson’s disease.

CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. Here, we reconstitute a complete, recombinant human CCR4-NOT complex. Our reconstitution strategy permits strict compositional control to test mechanistic hypotheses with purified component variants. CCR4-NOT is more active and selective for poly(A) than the isolated exonucleases, CCR4a and CAF1, which have distinct deadenylation profiles in vitro. The exonucleases require at least two out of three conserved non-enzymatic modules (CAF40, NOT10:NOT11 or NOT) for full activity in CCR4-NOT. CAF40 and the NOT10:NOT11 module both bind RNA directly and stimulate deadenylation in a partially redundant manner. Linear motifs from different RNA-binding factors that recruit CCR4-NOT to specific mRNAs via protein-protein interactions with CAF40 can inhibit bulk deadenylation. We reveal an additional layer of regulatory complexity to the human deadenylation machinery, which may prime it either for general or target-specific degradation. The CCR4-NOT complex shortens poly(A) tails of messenger RNAs. By biochemical reconstitution of the entire human CCR4-NOT complex, the authors show the stimulatory roles of non-enzymatic subunits and the importance of the interaction between CAF40 and RNA binding proteins in targeted deadenylation.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.

Neurons from fibroblasts Three papers in this issue demonstrate the production of functional induced neuronal (iN) cells from human fibroblasts, a procedure that holds great promise for regenerative medicine. Pang et al . show that a combination of the three transcription factors Ascl1 (also known as Mash1 ), Brn2 (or Pou3f2 ) and Myt1l greatly enhances the neuronal differentiation of human embryonic stem cells. When combined with the basic helix–loop–helix transcription factor NeuroD1, these factors can also convert fetal and postnatal human fibroblasts into iN cells. Caiazzo et al . use a cocktail of three transcription factors to convert prenatal and adult mouse and human fibroblasts into functional dopaminergic neurons. The three are Mash1 , Nurr1 (or Nr4a2 ) and Lmx1a . Conversion is direct with no reversion to a progenitor cell stage, and it occurs in cells from Parkinson's disease patients as well as from healthy donors. Yoo et al . use an alternative approach. They show that microRNAs can have an instructive role in neural fate determination. Expression of miR-9/9* and miR-124 in human fibroblasts induces their conversion into functional neurons, and the process is facilitated by the addition of some neurogenic transcription factors. Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson’s disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons 1 , 2 . In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency 3 , 4 . However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled 5 . Here we identified a minimal set of three transcription factors— Mash1 (also known as Ascl1 ), Nurr1 (also known as Nr4a2 ) and Lmx1a —that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson’s disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies.

Parathyroid hormone (PTH) increases FGF23 mRNA and protein levels in vivo and in vitro. Here we tested whether the increased FGF23 expression by PTH is mediated by the orphan nuclear receptor Nurr1. PTH increased Nurr1 mRNA levels prior to elevation of FGF23 mRNA levels in UMR-106 rat osteoblast-like cells. Activation of PKA increased both FGF23 and Nurr1 mRNA levels. Modification of Nurr1 expression showed that Nurr1 is essential for the PTH-mediated increase in FGF23 and luciferase reporter gene experiments identified a functional promoter region containing several potential Nurr1 binding sites. Chromatin immunoprecipitation assays confirmed the binding of Nurr1 to these regions in the FGF23 promoter. In vivo, Nurr1 mRNA and protein levels were increased in calvaria from rats with experimental CKD together with high PTH and FGF23 expression. Calcimimetics decrease PTH and FGF23 levels in CKD patients. Importantly, in rats with experimental CKD, the calcimimetic R568 decreased PTH expression, calvaria Nurr1 mRNA and protein levels, and FGF23 mRNA. Immunohistochemistry for Nurr1 showed an increase in the number of Nurr1 expressing osteocytes in the femurs of rats with CKD and this was decreased by R568. Thus, the effect of PTH to increase FGF23 transcription is mediated by Nurr1 in vitro and in vivo. In CKD, calcimimetics decrease PTH, which in turn decreases Nurr1 and consequently FGF23.

NDRG1 protein engages with the orphan nuclear receptor NR4A1, effectively suppressing the transcriptional activity of NF-κB and influencing the inflammatory response. However, the specific roles of the NDRG family and NR4A transcription factors in inflammatory bowel disease (IBD) remain poorly defined, particularly regarding potential differential mechanisms between ulcerative colitis (UC) and Crohn’s disease (CD). We hypothesize that NDRG–NR4A interactions are differentially regulated in UC versus CD, contributing to disease-specific modulation of NF-κB signaling and inflammatory responses. Therefore, the aim was to analyze gene and protein expression of both protein families (NDRGs: NDRG1, NDRG2, NDRG3, and NDRG4; and NR4A: NR4A1, NR4A2, and NR4A3), their contributions to UC and CD, and their association with disease severity. In this cross-sectional and comparative study, we assess gene and protein expression of NR4A and NDRG1-4 in 38 UC patients, 10 CD patients, and 18 controls. Gene and protein expression levels were measured by RT-PCR (mucosa) and immunohistochemistry (colonic tissue), respectively. The colonic mucosa from remission UC patients showed upregulation of NDRG2 and the nuclear receptor genes NR4A1-3 compared with controls. NDRG4 was upregulated in active UC patients compared with controls. NDRG1 was downmodulated in active and remission UC patients compared with controls. All differences were statistically significant (p < 0.05). Decreased NR4A2 gene expression was associated with high-sensitivity C-reactive protein (p = 0.030) and erythrocyte sedimentation rate levels (p = 0.001). Our results provide the first evidence of differential alterations in the NDRG–NR4A axis in UC and CD, which could modulate NF κB signaling and the inflammatory profile differently in each disease, opening the possibility of new therapeutic options.

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.

There is a compelling need to develop disease-modifying therapies for Alzheimer’s disease (AD), the most common neuro-degenerative disorder. Together with recent progress in vector development for efficiently targeting the central nervous system, gene therapy has been suggested as a potential therapeutic modality to overcome the limited delivery of conventional types of drugs to and within the damaged brain. In addition, given increasing evidence of the strong link between glia and AD pathophysiology, therapeutic targets have been moving toward those addressing glial cell pathology. Nurr1 and Foxa2 are transcription/epigenetic regulators that have been reported to cooperatively regulate inflammatory and neurotrophic response in glial cells. In this study, we tested the therapeutic potential of Nurr1 and Foxa2 gene delivery to treat AD symptoms and pathologies. A series of functional, histologic, and transcriptome analyses revealed that the combined expression of Nurr1 and Foxa2 substantially ameliorated AD-associated amyloid β and Tau proteinopathy, cell senescence, synaptic loss, and neuro-inflammation in multiple in vitro and in vivo AD models. Intra-cranial delivery of Nurr1 and Foxa2 genes using adeno-associated virus (AAV) serotype 9 improved the memory and cognitive function of AD model mice. The therapeutic benefits of gene delivery were attained mainly by correcting pathologic glial function. These findings collectively indicate that AAV9-mediated Nurr1 and Foxa2 gene transfer could be an effective disease-modifying therapy for AD.