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BRITISH JOURNAL OF PHARMACOLOGY · 2024 · IF 6.8

The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination

Yun Zhao,Guobin Zheng,Shu Yang,Shangjing Liu,Yifan Wu,Yaodong Miao,Zhen Liang,Yunqing Hua,Jing Zhang,Jia Shi,Dan Li,Yanfei Cheng,Yunsha Zhang,Yuanli Chen,Guanwei Fan,Chuanrui Ma

Background and purpose Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS ( Panax notoginseng saponins ), containing the main active ingredients of Panax notoginseng , exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s). Experimental approach The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE −/− mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2 −/− macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2 −/− mice treated with high-fat diet (HFD) and AAV-PCSK9. Key results PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro. Conclusion and implications PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS. Graphical

CAS / MDL: 540-69-2

研究领域: 心血管疾病 · 药理学 · 细胞生物学 · 分子生物学

✓ 已验证产品关联 DOI PubMed 高影响因子

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Cell Death Discovery · 2026 · IF 10.4

Hepatic Usp2 orchestrates de novo lipogenesis through G3bp2 stabilization and β-catenin activation

Wang Wei,Wang Hui,Liu Yihan,Cui Siyuan,Tang Chuanxi,Wang Mengxue,Mu Chunyan,Li Jingyu,Ye Xianlong,Liang Xinmiao,Zhu Shenglong

The escalating global burden of metabolic diseases including obesity, type 2 diabetes, and metabolic dysfunction-associated fatty liver disease (MAFLD)-highlights an urgent need to identify new therapeutic targets. Although elevated hepatic de novo lipogenesis (DNL) is a hallmark of metabolic dysfunction, targeting its core transcriptional and enzymatic components has proven clinically challenging. Here, using a multi-model comparative transcriptomic strategy, we identify ubiquitin-specific protease 2 (Usp2) as a consistently upregulated gene strongly correlated with steatosis severity. Functional studies demonstrate that Usp2 promotes hepatic lipid accumulation both in vitro and in vivo. Mechanistically, Usp2 directly interacts with the RNA-binding protein G3bp2 and stabilizes it via K63-linked deubiquitination, leading to activation of β-catenin signaling and subsequent upregulation of key lipogenic genes, including Fasn, Scd1, and Plin2. These findings establish the Usp2-G3bp2-β-catenin axis as a previously unrecognized regulatory pathway driving hepatic lipogenesis and nominate Usp2 as a potential therapeutic target in metabolic disease.

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The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination

Hepatic Usp2 orchestrates de novo lipogenesis through G3bp2 stabilization and β-catenin activation