Redefining nucleotide-binding oligomerization domain-like receptors: from immune sentinels to multifunctional...

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a large family of intracellular pattern recognition receptors primarily involved in innate immunity. Although canonical inflammasome-forming NLRs, such as NLRP3 and NLRC4, and microbial sensors, including NOD1 and NOD2, are well-characterized, the functions of many other NLRs remain poorly understood. This review article addresses this gap by highlighting the critical, context-dependent roles of these less-characterized NLRs beyond pathogen sensing. We classify these NLRs as immune modulators, regulators of autophagy and mitophagy, tissue-specific effectors, and reproductive mediators, expanding the traditional view of NLR functions. Understanding the diverse, context-dependent roles of NLRs across biological systems is essential to fully understand their complex regulatory networks and therapeutic potential, which extends beyond classical inflammasome functions.