Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4

Zhang, Xuyang; Huang, Zhaobo; Xie, Ziang; Chen, Yilei; Zheng, Zeyu; Wei, Xiaoan; Huang, Bao; Shan, Zhi; Liu, Junhui; Fan, Shunwu; Chen, Jian; Zhao, Fengdong

doi:10.1016/j.freeradbiomed.2020.08.029

Cited by 118 publications

(85 citation statements)

References 52 publications

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“…Ferroptosis is a newly discovered form of programmed death, which is different from other death procedures such as apoptosis, necrosis, and autophagy (17). The mechanism of iron death may be mainly related to lipid and lipid peroxide accumulation, amino acid antioxidant system imbalance, iron ion metabolism disorder, etc.…”

Section: Discussionmentioning

confidence: 99%

“…The role of GPX4 as the main regulator in the ferroptotic process is based on its unique function to reduce complex hydroperoxides including phospholipid hydroperoxides and cholesterol hydroperoxides to their corresponding counterparts, thereby interrupting the lipid peroxidation chain reaction (16). Numerous studies have shown that this mode of death is closely related to various diseases, including nervous system diseases, tumors, ischemiareperfusion injury diseases, as well as kidney injury and iron metabolism diseases (17). Recently, an increasing number of studies have found that ferroptosis is involved in the pathogenesis of NASH (18).…”

Section: Introductionmentioning

confidence: 99%

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ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation

Lü¹,

Qing²,

Yang³

et al. 2021

Ann Transl Med

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Background: ENO3 expression is upregulated in Non-alcoholic fatty liver disease (NAFLD) patient tissues, demonstrated that ENO3 might play crucial roles in NAFLD. However, the mechanism of ENO3 in NAFLD remains unclear. Therefore, this study aimed to investigate the regulatory mechanism of ENO3 in the progression of non-alcoholic steatohepatitis (NASH) in vivo and vitro NASH model. Methods: In vivo and vitro NASH model were established by methionine-choline deficient (MCD)-diet feeding and high free fatty acid (HFFA) induction in L02 cells. Loss and gain function of ENO3 and GPX4 was performed to study the mechanism in NASH. Western blot was used to detect the expression of ENO3 and GPX4. Hematoxylin and eosin (H&E), picrosirius Red and Oil Red O staining was used to evaluate histopathology of liver in NASH model. Ferroptosis indicators were measured by assay kits according to the manufacturer's instructions.Results: NASH mouse model was successfully established induced by MCD diet with steatosis, inflammatory infiltration, ballooning and fibrosis observed in the liver tissue. The expression of ENO3 and GPX4 was significantly elevated while ferroptosis was inhibited in NASH mice and cell model. Upregulation of both ENO3 and GPX4 could promote the lipid accumulation in L02 cells. In addition, overexpressed ENO3 attenuated the status of ferroptosis.Conclusions: In the present study, we demonstrate that ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevating GPX4 expression and lipid accumulation. These findings provided solid foundation for the mechanism of ferroptosis on the progression of NASH regulated by ENO3, suggesting that ENO3 may be a potential therapeutic target for NASH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation

Lü¹,

Qing²,

Yang³

et al. 2021

Ann Transl Med

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“…Further analysis reveals that the upstream of GPX4 is characterized by lower DNA methylation sites and elevated H3K4me3 and H3K27ac levels, suggesting that a high level of GPX4 in cancer may result from epigenetic regulation [28]. Upregulated methylation of GPX4 inhibits its expression thus leading to lipid ROS accumulation and following ferroptosis [85].…”

Section: The Epigenetic Regulation Of Redox-induced Ferroptosismentioning

confidence: 99%

The Molecular Mechanisms of Regulating Oxidative Stress-Induced Ferroptosis and Therapeutic Strategy in Tumors

Zhu

Xiong

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Ferroptosis is an atypical form of regulated cell death, which is different from apoptosis, necrosis, pyroptosis, and autophagy. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system’s failure. The sensitivity of ferroptosis is tightly regulated by a series of biological processes, the metabolism of iron, amino acids, and polyunsaturated fatty acids, and the interaction of glutathione (GSH), NADPH, coenzyme Q10 (CoQ10), and phospholipids. Elevated oxidative stress (ROS) level is a hallmark of cancer, and ferroptosis serves as a link between nutrition metabolism and redox biology. Targeting ferroptosis may be an effective and selective way for cancer therapy. The underlying molecular mechanism of ferroptosis occurrence is still not enough. This review will briefly summarize the process of ferroptosis and introduce critical molecules in the ferroptotic cascade. Furthermore, we reviewed the occurrence and regulation of reduction-oxidation (redox) for ferroptosis in cancer metabolism. The role of the tumor suppressor and the epigenetic regulator in tumor cell ferroptosis will also be described. Finally, old drugs that can be repurposed to induce ferroptosis will be characterized, aiming for drug repurposing and novel drug combinations for cancer therapy more efficiently and economically.

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“…[92,93,[95][96][97][98][99] Epidemiological retrospective and prospective clinical studies established homocysteine as a potent independent risk factor for atherothrombotic vascular disease. [91,92,100] Additionally, homocysteine increase superoxide (O 2 -) levels resulting in increased oxidative stress, causing an inflammatory state and increased atherosclerosis and ischemia reperfusion. Oxidative stress in return inhibits the cobalamine metabolism and enhances the cycle.…”

Section: Homocysteinementioning

confidence: 99%

“…Oxidative stress in return inhibits the cobalamine metabolism and enhances the cycle. [101,102] The frequency of hyperhomocysteienaemia as an independent risk factor for atherothrombotic vascular disease [91,92,100] was found in 66.4% and 1.6% of the urban elderly [57] and rural children respectively. Thus, although homocysteine measurement did not form part of the objectives in all our communities, prevalence of hyperhomocysteienaemia in the urban elderly (Gauteng) ( Table 2) and the rural children (EC) ( Table 3) is an additional confirmation of an increased risk for CVD in the low income South African population.…”

Section: Homocysteinementioning

confidence: 99%

Double Burden of Poverty and Cardiovascular Disease Risk among Low-Resource Communities in South Africa

Oldewage‐Theron¹,

Grobler²

2021

Lifestyle and Epidemiology - Poverty and Cardiovascular Diseases a Double Burden in African Populations [Working Title]

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Limited studies evaluating the prevalence of cardiovascular risk (CVR) in resource-poor black communities in South Africa (SA), exist. The objective of this chapter is to evaluate the prevalence of CVR in a cross-sectional studies in randomly selected low income children, adults and elderly in Gauteng, Free State and Eastern Cape, SA. The test panel of CVR markers included: anthropometry, lipid profile, blood pressure, fibrinogen, high sensitive–C–reactive protein (HS–CRP), homocysteine, vitamin B12, folate, glucose and dietary intakes. The main findings indicated high CVR with prevalence of overweight/obesity, Hypertension, hyperhomocysteinaemia, increased fibrinogen and HS-CRP, as well as low intakes of dietary fibre, vitamins B6 and B12, folate and polyunsaturated- and monounsaturated fatty acids, and high intakes of dietary sodium, saturated and trans fatty acids, and added sugars. Multiple CVR factors are present among all the communities. It can thus be concluded that a double burden of poverty and risk of CVD exists across the different age groups and geographical locations in these resource-poor communities.

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Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4

Cited by 118 publications

References 52 publications

ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation

ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation

The Molecular Mechanisms of Regulating Oxidative Stress-Induced Ferroptosis and Therapeutic Strategy in Tumors

Double Burden of Poverty and Cardiovascular Disease Risk among Low-Resource Communities in South Africa

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