PLCE1 (phospholipase C epsilon 1) is a bifunctional enzyme that mediates the production of second messengers diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), while also functioning as a Ras guanine-exchange factor (RasGEF) to regulate small GTPases. In podocytes, PLCE1 regulates lamellipodia formation downstream of AVIL to facilitate ARP2/3 complex assembly 1. The enzyme acts as an effector of heterotrimeric and small G-proteins, contributing to cell survival, growth, actin organization, and T-cell activation. PLCE1 mutations cause steroid-resistant nephrotic syndrome (SRNS), particularly congenital nephrotic syndrome, with specific mutations correlating with age of onset 2. PLCE1 was identified among the most frequently mutated genes in whole exome sequencing of SRNS patients 3 and is implicated in congenital nephrotic syndrome pathogenesis 4. Additionally, PLCE1 polymorphisms (rs2274223, rs3765524, rs3781264) are associated with esophageal squamous cell carcinoma (ESCC) susceptibility, with GG genotypes at rs2274223 conferring increased cancer risk 5. PLCE1 promotes ESCC progression by activating PKCα-mediated phosphorylation of E2F1 to upregulate MCM7 and miR-106b-5p, driving cell-cycle progression and tumor development 6. Genome-wide association studies identified PLCE1 as a novel locus associated with preeclampsia and gestational hypertension, implicating renal glomerular function in pregnancy complications 78.