Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Baicalein attenuates atherogenesis by suppressing endothelial pyroptosis via cylindromatosis-mediated tumor necrosis factor receptor-associated factor 6 deubiquitination.
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Jiang Yue, Sun Ying, Li Jing, Ma Chaoyuan, Chen Hongli, Tang Rongrong, Zuo Xu
Аннотация
BACKGROUND: Endothelial pyroptosis is a critical contributor to the development of atherosclerosis. Baicalein (BAI) exhibits anti-atherosclerotic potential; however, whether it alleviates atherosclerosis by modulating endothelial pyroptosis and the underlying molecular mechanisms remain unclear.
PURPOSE: This study aimed to elucidate the mechanism by which baicalein attenuates atherosclerosis, with a particular focus on Cylindromatosis (CYLD)-mediated deubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6).
METHODS: Atherosclerosis was induced in ApoE⁻/⁻ mice, and ox-LDL was used to trigger pyroptosis in HUVECs. Serum lipid levels were measured, and aortic pathological changes were evaluated by Oil Red O, H&E, and Masson's trichrome staining. Endothelial injury, inflammasome activation, Gasdermin D cleavage, and TRAF6 ubiquitination were assessed using immunofluorescence, immunohistochemistry, western blotting, and co-immunoprecipitation. Pyroptosis was quantified by flow cytometry. CYLD knockdown, molecular docking, microscale thermophoresis (MST), and cellular thermal shift assays (CETSA) were performed to verify the interaction between baicalein and CYLD.
RESULTS: Baicalein significantly alleviated dyslipidemia, reduced aortic lipid deposition and plaque formation, and increased collagen content in ApoE⁻/⁻ mice. Baicalein also attenuated endothelial injury and suppressed the elevated expression of NF-κB, NLRP3, Caspase-1, and Gasdermin D in aortic tissues. In vitro, baicalein improved ox-LDL-induced HUVEC injury and markedly inhibited pyroptosis. Mechanistically, baicalein reduced TRAF6 ubiquitination by targeting CYLD, thereby suppressing Caspase-1 activation and Gasdermin D cleavage. Molecular interaction analyses confirmed direct binding of baicalein to the CYLD protein.
CONCLUSIONS: This study demonstrates that baicalein attenuates atherosclerosis by inhibiting endothelial pyroptosis through the CYLD-TRAF6-Caspase-1/Gasdermin D signaling axis, highlighting CYLD as a potential therapeutic target for atherosclerosis.
PURPOSE: This study aimed to elucidate the mechanism by which baicalein attenuates atherosclerosis, with a particular focus on Cylindromatosis (CYLD)-mediated deubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6).
METHODS: Atherosclerosis was induced in ApoE⁻/⁻ mice, and ox-LDL was used to trigger pyroptosis in HUVECs. Serum lipid levels were measured, and aortic pathological changes were evaluated by Oil Red O, H&E, and Masson's trichrome staining. Endothelial injury, inflammasome activation, Gasdermin D cleavage, and TRAF6 ubiquitination were assessed using immunofluorescence, immunohistochemistry, western blotting, and co-immunoprecipitation. Pyroptosis was quantified by flow cytometry. CYLD knockdown, molecular docking, microscale thermophoresis (MST), and cellular thermal shift assays (CETSA) were performed to verify the interaction between baicalein and CYLD.
RESULTS: Baicalein significantly alleviated dyslipidemia, reduced aortic lipid deposition and plaque formation, and increased collagen content in ApoE⁻/⁻ mice. Baicalein also attenuated endothelial injury and suppressed the elevated expression of NF-κB, NLRP3, Caspase-1, and Gasdermin D in aortic tissues. In vitro, baicalein improved ox-LDL-induced HUVEC injury and markedly inhibited pyroptosis. Mechanistically, baicalein reduced TRAF6 ubiquitination by targeting CYLD, thereby suppressing Caspase-1 activation and Gasdermin D cleavage. Molecular interaction analyses confirmed direct binding of baicalein to the CYLD protein.
CONCLUSIONS: This study demonstrates that baicalein attenuates atherosclerosis by inhibiting endothelial pyroptosis through the CYLD-TRAF6-Caspase-1/Gasdermin D signaling axis, highlighting CYLD as a potential therapeutic target for atherosclerosis.