Nucleotide-binding oligomerization domain-like receptor X1 (NLRX1)

Nucleotide-binding oligomerization domain-like receptor X1 (NLRX1) is a unique member of the NOD-like receptor family that localizes to the mitochondrial outer membrane and serves as a critical negative regulator of the innate immune response (UniProt Q86UT6). Unlike many other NLRs that promote inflammation, NLRX1 functions as an immune checkpoint by inhibiting the NF-kappaB and RIG-I/MAVS signaling pathways, thereby dampening the production of pro-inflammatory cytokines and Type I interferons (PubMed: 29439165). It also plays a significant role in maintaining mitochondrial homeostasis and regulating the production of reactive oxygen species (PubMed: 30634377). Due to its anti-inflammatory properties, NLRX1 has emerged as a promising therapeutic target for chronic inflammatory conditions, particularly inflammatory bowel diseases (IBD) like ulcerative colitis and Crohn's disease (PubMed: 31434667). Small molecule agonists, such as NX-13 and BT-11, have been developed to activate NLRX1 and restore immune balance in the gut, with NX-13 progressing through clinical trials for ulcerative colitis (Landos Biopharma). Beyond gastrointestinal health, NLRX1 is also implicated in the pathogenesis of respiratory diseases like COPD and certain cancers, making it a versatile target for drug development (PubMed: 32814557).

Other names

NOD-like receptor X1NOD9NLR family member X1NOD26CLR11.3

Agonism of NLRX1 to negatively regulate pro-inflammatory signaling pathways, such as NF-kappaB and RIG-I/MAVS, thereby reducing the production of inflammatory cytokines (PubMed: 31434667).