PPP6R2 is a regulatory subunit of protein phosphatase 6 (PP6) that functions as a scaffolding component of the PP6 holoenzyme complex. Mechanistically, PPP6R2 works redundantly with other PP6 regulatory subunits (PPP6R1 and PPP6R3) to promote RIPK1-dependent PANoptosis through dephosphorylation events that enhance pro-death S166 auto-phosphorylation of RIPK1 while reducing pro-survival S321 phosphorylation 1. The protein also participates in NF-κB regulation through PP6-mediated dephosphorylation of NFKBIE, opposing its degradation in TNF signaling [UniProt annotation supported by 24]. Disease relevance is emerging across multiple conditions: PPP6R2 was identified as a novel risk locus in multi-ancestry genome-wide association studies of Parkinson's disease 3, with variants detected in prodromal PD patients 4. Additionally, PPP6R2 shows altered expression in ophthalmoplegic myasthenia gravis 5 and developmental dysplasia of the hip 6. Obesity-associated DNA methylation changes at PPP6R2 may contribute to systemic inflammation in children 7. PPP6R2 also interacts with CC2D1A in hippocampal synapses, suggesting roles in synaptic function 8, and acts as an antiadhesive factor in colon cancer-endothelial interactions 9.