SSH1 (slingshot protein phosphatase 1) is a protein phosphatase that regulates actin filament dynamics by dephosphorylating and activating cofilin, which promotes actin depolymerization 1. SSH1 also inactivates LIMK1, a kinase that inhibits cofilin 1. Mechanistically, SSH1 controls actin cytoskeleton remodeling through the SSH1-cofilin axis. During T-cell activation, SSH1 rapidly polarizes to nascent synaptic contacts and mediates LIMK1 inactivation to enable F-actin rearrangements essential for TCR triggering and immunological synapse organization 1. In endothelial cells, the LRP2-SSH1-cofilin signaling cascade regulates actin dynamics to maintain barrier integrity against inflammation-induced vascular leakage 2. SH1 dysregulation contributes to multiple diseases. Mutations in SSH1 cause disseminated superficial actinic porokeratosis (DSAP), suggesting cytoskeleton disorganization in epidermal cells 3. SSH1 is upregulated in intrahepatic cholangiocarcinoma and promotes progression through p38 MAPK-CXCL8 axis activation, correlating with poor prognosis 4. In Alzheimer's disease, oxidative stress-activated SSH1 suppresses neuroprotective Nrf2 signaling by sequestering Nrf2 on actin filaments, independently of its phosphatase activity, promoting neurodegeneration 5. Clinically, SSH1 represents a therapeutic target in cancer immunotherapy, where MMP9-mediated SSH1 shedding from CD8+ T cells suppresses anti-tumor immunity in hepatocellular carcinoma 6, and in neuroinflammatory diseases like Alzheimer's disease.