PRKCI encodes protein kinase C iota (PKCι), an atypical, calcium- and diacylglycerol-independent serine/threonine kinase with multifunctional roles in cell survival, differentiation, and polarity. 1 The protein functions as a general protective factor against apoptosis through multiple mechanisms: it phosphorylates and inhibits pro-apoptotic factors like BAD in glioblastoma cells, and prevents amyloid beta-induced neuronal death. 1 PKCι regulates epithelial cell polarity by phosphorylating EZR and organizing apical domains, while also modulating microtubule dynamics in the early secretory pathway. Clinically, PRKCI exhibits significant oncogenic activity across multiple cancers. In colorectal cancer, PKCι phosphorylates and stabilizes Tgfbr1, promoting epithelial-to-mesenchymal transition and metastasis; PKCι knockout reduced liver and lung metastases in mouse models. 2 In pancreatic cancer, PKCι promotes autophagy required for KrasG12D-mediated progression; its ablation blocked adenocarcinoma development despite increased neoplasia formation. 3 Circulating PRKCI variants show disease associations: the rs546950 polymorphism decreased prostate cancer risk in an Iranian population. 1 Dysregulation of circular RNA PRKCI (circ-PRKCI) occurs in papillary thyroid cancer and prostate cancer, where it promotes cell proliferation, glycolysis, and metastasis through competing endogenous RNA mechanisms with microRNAs. 4 5 In sepsis, decreased circ-PRKCI expression correlates with disease severity and 28-day mortality risk, and protecting against ferroptosis in acute lung injury. 6 7 These findings establish PKCι as both a critical oncogenic driver and a biomarker with therapeutic potential.