Baicalin downregulates Thromboxane A2 receptor via SIRT1/NRF2 and NLRP3 pathways to attenuate Cyclosporine A-induced hypertension.

Cyclosporine A, an immunosuppressant, is clinically limited by its hypertensive and nephrotoxic effects. Baicalin, a bioactive flavonoid derived from Scutellaria baicalensis, effectively alleviates CsA-induced hypertension by downregulating the thromboxane A2 (TP) receptor via the SIRT1/NRF2 and NLRP3 pathways. Ex vivo, in vivo, and in vascular smooth muscle cells (VSMCs), baicalin markedly reversed CsA-induced vasoconstriction, elevated blood pressure, upregulation of TP receptor, KEAP-1, NLRP3, Caspase-1, IL-1β, and ASC, as well as downregulation of SIRT1, NRF2, HO-1, and NQO-1. Importantly, siRNA-mediated knockdown of SIRT1 or NLRP3 abolished baicalin's protective effects. CETSA and ITDRF-CETSA demonstrated that baicalin directly binds to and stabilizes SIRT1 and NLRP3. Molecular docking further confirmed strong binding affinity of baicalin to both TP receptor and SIRT1. Immunofluorescence revealed that baicalin significantly inhibited CsA-induced NLRP3/ASC speck formation. Collectively, baicalin may improve CsA-induced hypertension by downregulating the TP receptor through the SIRT1/NRF2 and NLRP3 pathways.