PANoptosis fuels the fire of arthritis.

Innate immune cell death is critical for host defense but drives inflammatory disease when dysregulated. In this issue of Immunity, Huang et al. report that the complement protein C1q activates macrophage mitochondrial SARM1 to deplete NAD+ and produce cADPR, triggering NLRC5/NLRP12-PANoptosome formation, PANoptosis, and synovial inflammation in rheumatoid arthritis; targeting this pathway reduces inflammation.