PPP6C encodes the catalytic subunit of protein phosphatase 6 (PP6), a serine/threonine phosphatase with pleiotropic regulatory functions. PP6 primarily functions in cell cycle regulation, immune signaling, and metabolic homeostasis through dephosphorylation of key substrates. Mechanistically, PPP6C regulates G1/S phase transition partly through control of cyclin D1 1, and during mitosis controls spindle positioning 2. PPP6C negatively regulates innate immunity by dephosphorylating cGAS and STING1, with cGAS dephosphorylation at Ser-435 impairing GTP binding and inactivation 3. Hepatically, PPP6C dephosphorylates tuberous sclerosis complex 2 (TSC2) at Ser939 and Thr1462 to inhibit mTORC1, mediating fibroblast growth factor 21 (FGF21) signaling in metabolic dysfunction-associated steatohepatitis (MASH) 4. In psoriatic keratinocytes, IL-17-induced PPP6C downregulation causes C/EBP-β phosphorylation, activating arginase-1 and polyamine production that promotes self-RNA sensing 5. Additionally, PPP6C is essential for neuronal development and survival, as neuron-specific knockout causes neonatal lethality and decreased cortical neuron numbers 6. Disease relevance: PPP6C mutations are identified as cancer driver mutations in melanoma 7, basal cell carcinoma 8, and glioma, where PPP6C expression correlates with tumor grade 9. Therapeutically, PPP6C represents a target for MASH treatment through FGF21-mediated pathway activation 4, and arginase inhibitors targeting PPP6C dysfunction show promise in psoriasis 5.