Abstract Body: Background:Hypertension remains the leading cause of mortality worldwide. Aim:We hypothesize that ENaC-dependent sodium entry triggers inflammation and activates the Keap1-Nrf2 signaling axis in APCs, thereby contributing to SSBP. Method:We conducted Bulk RNAseq on human monocytes exposed to elevated sodium levels in vitro. Then, we utilized inpatient protocol and performed CITE-seq analysis on PBMCs. Further, we kept SV/129 mice on a high-salt (HS) diet for 3 weeks and performed flow cytometry and isolated APC MHCII from the spleen followed by western blotting. Further, we isolated the splenocytes from SV/129 mice and treated them with normal salt (NS), HS and HS+ML385 (Nrf2 inhibitor) for 48 hours, followed by flow cytometry. We also treated APC MHCII from SV/129 mice for 48 hours in either NS (150 mM) or HS media (190 mM) and performed western blotting. Results:We found that increase expression of Keap1 (1586.54+132.94 vs 2203.72+177.48, q=0.884), Nrf2 (5080.36+416.64 vs 5443.54+432.78, q=0.019) in bulk RNAseq analysis of high salt treated human monocyte compared to normal salt. We also found Nrf2 downstream antioxidant genes expression HO1 (14738.181+1476.12 vs 10365.18+1453.79, q= 3.21852E-08), NQO1 (539.54+114.16 vs 241.72+48.72, q= 1.20E-11), and SOD2 (92229.18+13434.17 vs 80566.72+12197.17, q=0.001) significantly decrease in high salt treated monocyte. Furthermore, the results of the CITE-seq experiment indicated that changes in the expression of the Nrf2 negatively correlate with SSBP (DBP; r=0.5726, p=0.025 and MAP; r=0.666, p=0.006) in salt-sensitive (SS) but not in salt-resistant (SR) patients. Compared to normal diet, high salt treated mice shows increase in the expression of keap1, Nrf2 in monocytes of the aorta and spleen. Moreover, compared to normal salt, high salt+ML385-induced a significant decrease in the expression of Nrf2 in monocytes of the spleen in flow cytometry analysis. We also found the keap1 (3.283±1.568, p=0.08) and Nrf2 (5.083± 2.407, p=0.04) expression increase in high salt treated APC MHCII compared to normal salt in invitro western blot analysis. We also found the keap1 (0.1061±0.046, p=0.063) expression increase in high salt diet APC MHCII compared to normal salt in invivo western blot analysis. Conclusion:These findings reveal a physiological link between inflammation and salt-sensitive hypertension through the Keap1-Nrf2 signaling axis in APCs and may provide a potential therapeutic target for the treatment of SSBP.