Unmasking NLRX1: Exploring the broadening biological landscape of a mysterious mitochondrial sensor

The nucleotide-binding oligomerization domain-like receptor (NLR) family is an important family of cytoplasmic pathogen recognition receptors involved in innate immune defense. Among them, NLR family member X1 (NLRX1) stands out with its specific N-terminal targeting sequence that targets it to mitochondria and thereby couples immune regulation with mitochondrial function. Recent findings point to NLRX1 as an important negative regulator of inflammation and also a modulator of mitochondrial metabolism and autophagy. Recent research has amplified our knowledge of the multifunctional biological functions of NLRX1, which involve it in the pathogenesis and development of several inflammatory, autoimmune, metabolic, and cancerous disorders. Despite significant progress, the specific molecular mechanisms involved in NLRX1-regulated cellular homeostasis are still not fully elucidated. In this review, we compile and critically review the recent data on NLRX1, highlighting its molecular interactions, signaling pathways, and disease-modulating functional relevance. Integrating findings from recent experimental and clinical research, this review attempts to discern the general biological significance of NLRX1 as well as its promise as an emerging therapeutic target in the new era of advanced research.