CTSS indirectly modulates NF-κB through distinct pathways (1): Degrading silent information regulator 1 (SIRT1) (an NF-κB suppressor), where CTSS inhibition stabilizes SIRT1 to repress NF-κB in hepatitis (19) (2); Activating PU.1/p38-NF-κB signaling in macrophages to drive IL-6-mediated periodontitis (48). Here, SPI1 is linked to periodontitis.