Frontiers in cardiovascular medicine · 2026
OTUD7B exacerbates atherosclerosis by promoting RIPK1-dependent vascular smooth muscle cell necroptosis.
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Yu Linfei, Wang Yulong, Li Yiheng, Zhang Yu
Аннотация
BACKGROUND: Atherosclerosis is a vascular disease characterized by lipid deposition, chronic inflammation, and cell death. Necroptosis, a form of programmed necrosis, plays a critical role in atherosclerosis progression. This study investigates the expression of the deubiquitinating enzyme OTUD7B in atherosclerosis and its mechanism in regulating vascular injury via the RIPK1-mediated necroptosis pathway.
METHODS: An atherosclerosis model was established in mice fed a high-fat diet combined with partial carotid ligation. OTUD7B and necroptosis-related proteins RIPK1, RIPK3, and phosphorylated MLKL (p-MLKL) were detected in arterial tissues. In vitro, a necroptosis model was induced in human aortic smooth muscle cells (HA-SMCs) using the TSZ protocol. OTUD7B was knocked down to assess cell viability, inflammatory cytokine levels, and necroptosis. OTUD7B knockdown and RIPK1 co-overexpression were employed to validate its protective effects and dependency in vivo.
RESULTS: OTUD7B was significantly upregulated in plaques of atherosclerosis mice, concomitant with increased expression and phosphorylation of RIPK1 and RIPK3, as well as elevated p-MLKL levels. TUNEL staining and ELISA confirmed elevated necroptosis and inflammation. In vitro, OTUD7B knockdown markedly alleviated HA-SMC injury, suppressed the expression and phosphorylation of necroptosis markers, and reduced IL-1β/TNF-α release. In vivo OTUD7B knockdown attenuated plaque formation, lipid deposition, necroptosis, and inflammation. Mechanistically, RIPK1 overexpression significantly reversed the protective effects of OTUD7B knockdown, restoring RIPK1/RIPK3 phosphorylation and downstream signaling, indicating its functional dependency on the RIPK1 pathway. Co-immunoprecipitation further confirmed a direct OTUD7B-RIPK1 interaction, facilitating downstream signaling activation.
CONCLUSION: OTUD7B exacerbates necroptosis and inflammation in vascular smooth muscle cells by activating the RIPK1-RIPK3-MLKL axis, thereby playing a detrimental role in AS. This study identifies OTUD7B as a potential therapeutic target for atherosclerosis intervention.
METHODS: An atherosclerosis model was established in mice fed a high-fat diet combined with partial carotid ligation. OTUD7B and necroptosis-related proteins RIPK1, RIPK3, and phosphorylated MLKL (p-MLKL) were detected in arterial tissues. In vitro, a necroptosis model was induced in human aortic smooth muscle cells (HA-SMCs) using the TSZ protocol. OTUD7B was knocked down to assess cell viability, inflammatory cytokine levels, and necroptosis. OTUD7B knockdown and RIPK1 co-overexpression were employed to validate its protective effects and dependency in vivo.
RESULTS: OTUD7B was significantly upregulated in plaques of atherosclerosis mice, concomitant with increased expression and phosphorylation of RIPK1 and RIPK3, as well as elevated p-MLKL levels. TUNEL staining and ELISA confirmed elevated necroptosis and inflammation. In vitro, OTUD7B knockdown markedly alleviated HA-SMC injury, suppressed the expression and phosphorylation of necroptosis markers, and reduced IL-1β/TNF-α release. In vivo OTUD7B knockdown attenuated plaque formation, lipid deposition, necroptosis, and inflammation. Mechanistically, RIPK1 overexpression significantly reversed the protective effects of OTUD7B knockdown, restoring RIPK1/RIPK3 phosphorylation and downstream signaling, indicating its functional dependency on the RIPK1 pathway. Co-immunoprecipitation further confirmed a direct OTUD7B-RIPK1 interaction, facilitating downstream signaling activation.
CONCLUSION: OTUD7B exacerbates necroptosis and inflammation in vascular smooth muscle cells by activating the RIPK1-RIPK3-MLKL axis, thereby playing a detrimental role in AS. This study identifies OTUD7B as a potential therapeutic target for atherosclerosis intervention.