Journal Article

Differential Expression Profiles of Orphan Nuclear Receptors (NR4A) and N-myc Downstream-Regulated Gene Family (NDRG) in Patients with Inflammatory Bowel Disease

Barreto-Zuñiga, Rafael, Fonseca-Camarillo, Gabriela, Furuzawa-Carballeda, Janette, Martínez-Benítez, Braulio, Yamamoto-Furusho, Jesús K., Aguilar-León, Diana

2026

Overview

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.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Adult / Apoptosis / Cell growth / Colitis, Ulcerative - genetics / Colitis, Ulcerative - metabolism / Colitis, Ulcerative - pathology / Crohn Disease - genetics / Crohn Disease - metabolism / Crohn Disease - pathology / Crohn's disease / Dendritic cells / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Female / Gene expression / Gene Expression Regulation / Humans / Immune response / Inflammation / Inflammatory bowel disease / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - metabolism / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Male / Metabolism / Middle Aged / N-myc Downstream-Regulated Gene 1 Protein / Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics / Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism / Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics / Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism / Patients / Protein expression / Proteins / Receptors, Steroid - genetics / Receptors, Steroid - metabolism / Receptors, Thyroid Hormone - genetics / Receptors, Thyroid Hormone - metabolism / Remission (Medicine) / Transcription factors / Tumor Suppressor Proteins