HM13 encodes signal peptide peptidase (SPP), an intramembrane protease that catalyzes the cleavage of signal peptides from secretory and membrane proteins within the endoplasmic reticulum 1. The enzyme is required for generating HLA-E epitopes from MHC class I signal peptides and processes various membrane proteins including PSEN1 and XBP1 213. HM13/SPP functions through ER-associated degradation (ERAD) mechanisms, promoting proteasomal degradation of metabolic regulators like heme oxygenase-1 4. The protein serves as a critical host factor for flavivirus replication, with knockout or proteolytic activity disruption markedly reducing replication of dengue virus, Zika virus, and other flaviviruses 5. Clinically, HM13 demonstrates significant disease relevance as it is upregulated in hepatocellular carcinoma and colorectal cancer, correlating with poor prognosis and enhanced tumor cell proliferation and migration 678. In cardiovascular disease, HM13/SPP promotes atherogenesis by enhancing foamy macrophage formation through ERAD-mediated degradation pathways 4. The enzyme shows promise as both a prognostic biomarker and therapeutic target, with HM13 expression serving as an independent predictor of survival in multiple cancer types and SPP inhibitors demonstrating potent antiviral activity 56.