Abstract Body: Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state contributes to vascular remodelling in hypertension. While oxidative stress and microRNAs (miRNAs) modulate VSMC phenotype, the molecular profile of VSMCs in human hypertension remain undefined. This study aimed to characterize the proteomic, redox, and miRNA signature of VSMCs in human hypertension. VSMCs were isolated from resistance arteries of normotensive (NT) and hypertensive (HT) subjects. Expression of VSMC phenotypic markers and redox-related genes were assessed by immunoblotting and qPCR. Reactive oxygen species (ROS) was measured by Amplex red assay. Global and redox proteomic profiling was performed using tandem mass tag (TMT)-based LC-MS/MS, using isotope-labelled iodoacetamide to quantify cysteine oxidation. miRNA profiling and VSMC secretome were assessed using TaqMan Advanced miRNA arrays and Olink proteomics inflammation panel. In HT, VSMC exhibited reduced expression of contractile proteins (α-SMA, SM22, MYOCD; p<0.05) and increased KLF4 (NT:0.66±0.08, HT:2.83±0.73, p<0.05), indicating de-differentiation. ROS production was increased (NT:9.15±0.66, HT:13.28±1.24), along with Nox1 (NT:1.06±0.18, HT:1.83±0.29) and Nox5 (NT:1.25±0.32, HT:14.03±0.84) mRNA levels (p<0.05). Although Nrf2 mRNA was upregulated (NT:0.89±0.14, HT:1.34±0.07, p<0.05), levels of antioxidant enzymes (SOD1, SOD2, CAT, Trx1) remained unchanged, suggesting impaired redox balance. Proteomic analysis showed upregulation of extracellular matrix (ECM) and inflammatory proteins in HT (fold change>1.5, p<0.05), consistent with a pro-fibrotic/pro-inflammatory phenotype and increased cysteine oxidation, particularly in ECM components (fold change>1.5, p<0.05). miRNA profiling revealed 136 downregulated miRNAs in HT (fold change >1.5), including miR-145-5p, a key regulator of VSMC differentiation. Additionally, four Nox5-targeting miRNAs (miR-505-5p, miR-324-5p, miR-185-5p, miR-491-5p) were downregulated, linking miRNA dysregulation and oxidative stress. Secretome analysis confirmed increased release of pro-inflammatory and pro-fibrotic mediators in HT, including CXCL1/5/6, IL-6/8/24, MCP1–4, IL-18R1, CCL3, and CCL20 (p<0.05). In hypertension, VSMCs exhibit a distinct proteomic, oxidative, and miRNA signatures consistent with a pro-inflammatory, pro-fibrotic phenotype. These findings provide molecular insights into VSMC plasticity and vascular remodelling in human hypertension.