Abstract Body: Preeclampsia is a severe pregnancy complication that disproportionately affects women of Sub-Saharan African ancestry. Genetic variants of apolipoprotein L1 (APOL1), originally evolved in response to Trypanosoma brucei, have been associated with kidney disease; however, their role in preeclampsia remains unclear. Inaxaplin (VX-147), a first-in-class APOL1 inhibitor, is currently in Phase 3 trials for APOL1-mediated kidney disease, but its therapeutic potential for APOL1-mediated preeclampsia has yet to be explored. This study investigates 1) whether APOL1 risk variants cause preeclampsia and 2) whether inaxaplin can mitigates APOL1-mediated preeclampsia. Due to the absence of APOL1 in rodents, transgenic mouse models carrying human APOL1 alleles were used: wild-type (G0/G0) and high-risk (G2/G2). Hallmarks of preeclampsia, including new-onset hypertension, proteinuria, and intrauterine grow restriction (IUGR) were assessed. Blood pressure (BP) was continuously monitored in conscious pregnant mice via implanted telemetry devices throughout gestation and confirmed by invasive transducer-based measurements under anesthesia on gestation day 18 (GD18). Proteinuria was quantified at GD18 using Coomassie blue staining and normalized by urine creatinine. Fetal weight was also recorded at GD18 to evaluate IUGR. Inaxaplin was administered via drinking water throughout the gestational period. We found that pregnant G2/G2 mice at GD18 exhibited higher BP 106.38 ± 5.50 vs. 89.84± 4.42 mmHg; n=9; p<0.01) and elevated urine albumin-creatinine ratio (944.98 ± 138.28 vs. 66.68 ± 43.78 mg/g; n=5-8; p<0.01) than pregnant G0/G0 mice. Additionally, G2/G2 fetuses had lower weights than G0/G0 fetuses (0.607 ± 0.169 vs.0.941 ± 0.138 g; n=51-95; p<0.01). Moreover, pregnancy acted as a “second hit”, increasing renal APOL1 mRNA expression by 68.6 ± 7.2% in G2/G2 and 60.2 ± 13.5% in G0/G0 mice. This was accompanied by elevated circulating IFN-γ, measured using the Proteome Profiler Cytokine Array, with levels rising by 99.2% in G2/G2 and 97.7% in G0/G0 mice (n=5; p<0.01). Furthermore, inaxaplin restored BP (93.49± 6.60 vs. 106.38± 5.50 mmHg; n=7-9; p<0.01) and fetal weight (1.051 ± 0.097 vs. 0.607 ± 0.169 g; n=10; p<0.01) and reduced albuminuria by 57.9±7.5% (n=5; p<0.01) in pregnant G2/G2 mice. These findings demonstrate that humanized APOL1 mice carrying high-risk alleles spontaneously develop preeclampsia, and that inaxaplin treatment mitigates APOL1-mediated preeclampsia.