NLRX1 is a mitochondrial NOD-like receptor that serves as a critical regulator of innate immunity and mitochondrial homeostasis 1. As a negative regulator of inflammation, NLRX1 modulates antiviral responses by fine-tuning signaling through MAVS and other pattern recognition receptor pathways in a context-dependent manner, enabling balanced control of viral infections without excessive inflammation 2. Beyond immunity, NLRX1 orchestrates mitochondrial quality control by coupling mitochondrial dynamics (fission and fusion) with mitophagy through interaction with the zinc transporter SLC39A7, maintaining mitochondrial homeostasis and preventing cellular senescence 3. Mechanistically, NLRX1 localizes to the mitochondrial outer membrane where its leucine-rich repeat domain directly binds cytosolic acetyl-CoA, a key metabolic signaling molecule that regulates mitophagy activation 4. NLRX1 also promotes selective autophagy of damaged mitochondria and protein aggregates through interactions with autophagy machinery 5. Clinically, NLRX1 dysregulation is implicated in multiple pathologies including intervertebral disc degeneration, HIV-1 replication enhancement, and various inflammatory and metabolic diseases 36. The protein's unique mitochondrial localization and dual role as both immune modulator and metabolic gatekeeper distinguish it from canonical NLRs, positioning NLRX1 as an emerging therapeutic target 7.