NLRP12 is a cytosolic pattern recognition receptor that functions as a potent negative regulator of inflammation 1. Primarily expressed in dendritic cells and macrophages, NLRP12 suppresses canonical and non-canonical NF-κB and ERK signaling pathways 23. Mechanistically, NLRP12 targets NOD2 for proteasomal degradation, promoting bacterial tolerance 1, and inhibits RIG-I-mediated antiviral responses by modulating E3 ubiquitin ligase activity 4. Beyond classical inflammation, NLRP12 downregulates Wnt/β-catenin signaling via interaction with STK38 to suppress colorectal cancer progression 5. NLRP12 also serves as a key regulator of PANoptosis, an inflammatory cell death pathway, through assembly of NLRP12-PANoptosomes with regulation by hematopoietic cell kinase (HCK) 6. Disease-relevant dysregulation includes familial cold autoinflammatory syndrome 2 and broader associations with cancers, metabolic, and infectious diseases 7. Recent evidence indicates NLRP12 interacts with other NLR family members to form coordinated immune networks 8. Therapeutic targeting of NLRP12 shows promise for mitigating inflammation-associated pathology 6.