PPP6R3 encodes a regulatory subunit of protein phosphatase 6 (PP6), functioning as a scaffolding component that modulates PP6 activity in multiple cellular processes 1. The protein plays a critical role in innate immune signaling by promoting RIPK1-dependent PANoptosis, a lytic cell death pathway that serves as a host defense mechanism against pathogens that inhibit TAK1 1. Mechanistically, PPP6R3, along with other PP6 regulatory subunits (PPP6R1 and PPP6R2), works redundantly to regulate the phosphorylation state of RIPK1, promoting pro-death S166 auto-phosphorylation while reducing pro-survival S321 phosphorylation 1. PPP6R3 also participates in maintaining functional ER exit sites through spatial regulation of protein dephosphorylation, where the PPP6R3/PPP6C complex specifically dephosphorylates Sec16A to sustain proper secretory activity 2. In disease contexts, PPP6R3 has clinical significance in bone metabolism, as genome-wide association studies and transcriptome-wide association studies identify it as a putatively causal gene for bone mineral density regulation 34. Additionally, PPP6R3 gene fusions have been identified in various tumors, including aggressive nodular fasciitis cases and myoepithelioma-like tumors of the vulvar region 56. The gene also serves as a stable reference gene in inflammatory conditions like sepsis and SIRS 7.