SREBP1-mediated lipogenesis promotes dedifferentiation and senescence of vascular smooth muscle cells through epigenetic remodeling

Real or simulated microgravity induces a senescence-like modification of carotid artery in both human and animal observations, with the mechanisms not fully elucidated. Here, we aim to elucidate the role of sterol regulatory element-binding protein 1 (SREBP1, encoded by Srebf1) mediated lipogenesis in the process. Pharmacological activation of SREBP1 directly triggers senescence-like transformation in vascular smooth muscle cells (VSMC), while silencing Srebf1 exerts an opposite effect. Mechanistically, SREBP1-mediated lipogenesis upregulates acetyl-CoA pool to increase histone acetylation, modifying the chromatin accessibility which limiting recruitment of SRF/myocardin complexes to CArG boxes of contractile genes and opening the chromatin accessibility of aging genes. Srebf1 knockdown and local delivery of lentivirus or AAV-mediated VSMC specific expressing sh-Srebf1 significantly attenuates the senescence-like transformation of VSMC both in vitro and in vivo. Our findings reveal a previously unrecognized feature of SREBP1-mediated lipogenesis in vascular biology and SM-induced carotid artery remodeling. Microgravity triggers carotid artery aging via SREBP1. This lipid regulator remodels chromatin by boosting acetyl-CoA, silencing contractile genes while activating aging pathways. Targeting SREBP1 blocks senescence, revealing a therapeutic strategy for spaceflight-associated vascular remodeling.