RGS14 is a multifunctional scaffolding protein that integrates G protein, Ras/ERK, and calcium signaling pathways 1. Mechanistically, RGS14 functions as a GTPase-activating protein (GAP) on select Gαi subunits and a GDP-dissociation inhibitor (GDI), thereby suppressing G protein-coupled receptor signaling cascades 2. In the brain, RGS14 is highly expressed in postsynaptic spines of CA2 hippocampal pyramidal neurons and limbic structures, where it acts as a natural suppressor of synaptic plasticity and long-term potentiation (LTP), thereby restraining spatial learning and object memory 21. RGS14 functions as a nucleocytoplasmic shuttling protein; genetic variants disrupting its nuclear export impair LTP inhibition but preserve spatial learning, suggesting distinct nuclear functions 3. Beyond neurobiology, RGS14 regulates spermatogonial stem cell proliferation through GNAI3 binding and PLPP2/MAPK pathway activation; RGS14 downregulation contributes to non-obstructive azoospermia pathogenesis 4. RGS14 also limits seizure-induced mitochondrial oxidative stress in hippocampus by supporting SOD2 induction and microglial activation 5. Clinically, RGS14 is overexpressed in hepatocellular carcinoma, promoting tumor progression through cAMP/PKA/CREB and ECM-receptor interaction pathway activation 67.