Nucleotide-binding oligomerization domain, leucine-rich repeat-containing X1 (NLRX1) is a novel NLR family member and a crucial regulator of inflammation across various diseases. Its expression in the CNS positions NLRX1 as a promising target for making it a potential target for neuroinflammation. Parkinson’s disease (PD) is characterized by progressive dopaminergic neuronal loss, mitochondrial dysfunction, and neuroinflammation. NLRX1's ability to mitigate inflammation makes it as a potential target for therapeutic intervention in PD, with NLRX1 agonists, such as NX-13 (Landos Biopharma) being developed for inflammatory diseases such a IBD and MS. NLRX1 has been shown to suppress inflammasome activation in peripheral inflammation and infectious diseases through various mechanisms, such as binding to proteins involved in mitochondrial function and inflammasome oligomerization. The specific binding partners of NLRX1 in neuroinflammation, however, remain to be fully characterized. This study sought to identify proteins that interact with NLRX1 in immune cells and neurons under PD conditions using in vitro models of neuroinflammation and neuronal death. Using THP-1 macrophages, we identified novel NLRX1 interactions with TRIM21, PRDX3, PSMD4, and TOMM70, along with the known interaction of NLRX1-TUFM. Notably, there was a significant enrichment of NLRX1 interaction with PSMD4 and TOMM70 in activated macrophages. PSMD4, a component of the 26S proteasome, suggests a mechanism for the proteasomal degradation of NLRX1, while TOMM70's role in mitochondrial protein import indicates a direct link to mitochondrial function. Our results provide new insights into the mechanisms by which NLRX1 could regulate neuroinflammation in immune cells during PD.