HM13 encodes signal peptide peptidase (SPP), an intramembrane aspartic protease localized to the endoplasmic reticulum that catalyzes proteolytic cleavage of signal peptides within the lipid bilayer 1. After signal peptidase removes signal peptides from precursor proteins, HM13/SPP cleaves them further, releasing peptide fragments into the cytoplasm 1. This activity is essential for generating HLA-E epitopes from MHC class I signal peptides, required for lymphocyte immune recognition 1. HM13/SPP also processes hepatitis C virus core protein and participates in ER-associated degradation (ERAD) of proteins including presenilin-1 and XBP1 isoform 1 2. In disease contexts, elevated HM13 expression is substantially associated with poor prognosis in hepatocellular carcinoma and colorectal cancer, where it promotes tumor cell proliferation and migration while suppressing apoptosis via PI3K/Akt and p53 pathway modulation 3 4. In macrophages, HM13/SPP overexpression enhances oxLDL-induced foamy macrophage formation and atherogenesis by promoting ERAD-mediated degradation of heme oxygenase-1 5. Clinically, HM13/SPP represents a host target for broad-spectrum flaviviral antivirals; SPP inhibitors demonstrate potent activity against dengue and Zika viruses at low nanomolar concentrations 6.