HSPB7 Deficiency Drives Aortic Aneurysm Progression in Marfan Syndrome Through Vascular Smooth Muscle Cell Phenotypic Switching.

Marfan syndrome (Mfs) arises from mutations in FBN1, predisposing individuals to thoracic aortic aneurysm (TAA) through abnormal smooth muscle cell behaviour. The role of HSPB7 in Mfs-related TAA remains poorly understood. By integrating multi-omics analysis with hiPSC-derived VSMCs from patients with Mfs, we elucidated the molecular landscape of Mfs-associated TAA. Analysis revealed immune cell infiltration, a reduced proportion of VSMCs, and altered intercellular communication. Pathway analyses indicated changes in cell adhesion, extracellular matrix (ECM) remodelling, and immune signalling, with downregulated metabolic pathways. Findings suggest structural, immune, and metabolic imbalances in Mfs-TAA pathogenesis. Downregulation of HSPB7 was associated with altered proliferation, migration, and metabolic activity. Overexpression of HSPB7 in patient-specific hiPSC-derived VSMCs attenuated these pathological features and promoted a more contractile phenotype. These findings suggest that HSPB7 may be involved in the regulation of VSMCs' phenotypic modulation in Mfs-TAA and provide mechanistic insight into disease-associated cellular alterations.