APOL1 (apolipoprotein L1) is a serum protein with dual roles in innate immunity and lipid transport. As a component of trypanosome lytic factor, APOL1 kills Trypanosoma brucei by forming pores in parasite lysosomal membranes and inducing osmotic lysis 1. This trypanolytic function provided selective advantage in African populations, with certain APOL1 variants conferring parasite resistance 1. However, these protective APOL1 risk variants (G1 and G2 alleles) significantly increase susceptibility to kidney disease in individuals of African ancestry 2. Risk variants are associated with focal segmental glomerulosclerosis (FSGS), hypertension-associated end-stage kidney disease (ESKD), HIV-associated nephropathy, and collapsing glomerulopathy 23. The pathogenic mechanism involves interferon-γ-mediated induction of APOL1 expression in podocytes and endothelial cells, triggering pyroptotic cell death and vascular injury 4. In endothelial cells, APOL1 risk variants activate STING-mediated signaling and endothelin-1 production, leading to hypertension 5. Viral infections including COVID-19 and HIV amplify this inflammatory pathway, accelerating kidney disease progression 46. Clinical management requires identification of high-risk APOL1 genotypes and consideration of interferon/APOL1-targeted therapeutics.