Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis

Gao, Gai; Xie, Zhishen; Li, Erwen; Yuan, Yu‐He; Fu, Yu; Wang, Pan; Zhang, Xiaowei; Qiao, Yu; Xu, Jiangyan; Hölscher, Christian; Wang, Hui; Zhang, Zhenqiang

doi:10.1007/s11418-021-01491-4

Cited by 81 publications

(56 citation statements)

References 68 publications

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“…Although tremendous effort has been devoted to NAFLD, the underlying mechanism remains elusive. It is widely accepted that iron overload is common in patients with NAFLD, and iron-induced lipid peroxide is one of the major contributors to NAFLD [ 63 , 64 ]. In addition, an iron imbalance is implicated in obesity and insulin resistance [ 65 ], both of which are typical characteristics of NAFLD patients.…”

Section: The Involvement Of Ferroptosis In Typical Liver Diseasesmentioning

confidence: 99%

“…Consistently, other investigations also discovered that some drugs like Ginkgolide B and dehydroabietic acid have beneficial effects on alleviating NASH severity through inhibiting ferroptosis. In these contexts, Nrf2 and GPx4 stand out as the major protective mechanisms [ 70 , 71 ]. Overall, these results implied that the regulation of ferroptosis in the context of NAFLD is an intriguing notion that deserves further investigation.…”

Section: The Involvement Of Ferroptosis In Typical Liver Diseasesmentioning

confidence: 99%

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Ferroptosis in liver disease: new insights into disease mechanisms

et al. 2021

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Characterized by excessive iron accumulation and lipid peroxidation, ferroptosis is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other well-known cell death. In recent years, ferroptosis has been quickly gaining attention in the field of liver diseases, as the liver is predisposed to oxidative injury and generally, excessive iron accumulation is a primary characteristic of most major liver diseases. In the current review, we first delineate three cellular defense mechanisms against ferroptosis (GPx4 in the mitochondria and cytosol, FSP1 on plasma membrane, and DHODH in mitochondria), along with four canonical modulators of ferroptosis (system Xc−, nuclear factor erythroid 2-related factor 2, p53, and GTP cyclohydrolase-1). Next, we review recent progress of ferroptosis studies delineating molecular mechanisms underlying the pathophysiology of several common liver diseases including ischemia/reperfusion-related injury (IRI), nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hemochromatosis (HH), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). Furthermore, we also highlight both challenges and promises that emerged from recent studies that should be addressed and pursued in future investigations before ferroptosis regulation could be adopted as an effective therapeutic target in clinical practice.

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Section: The Involvement Of Ferroptosis In Typical Liver Diseasesmentioning

confidence: 99%

Section: The Involvement Of Ferroptosis In Typical Liver Diseasesmentioning

confidence: 99%

Ferroptosis in liver disease: new insights into disease mechanisms

et al. 2021

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“…The Nrf2-mediated antioxidant response plays a key role in the regulation of ferroptosis [ 78 ]. Nrf2 can promote the expression of downstream HO-1, GSH, and GPX4, thereby eliminating the accumulation of ROS in the liver and reducing the level of malondialdehyde (MDA) [ 79 ]. In addition, activation of the Nrf2 pathway in the obese mouse model can reduce liver lipid accumulation and significantly improve the NAFLD of the mice [ 80 ].…”

Section: Mechanism Of Ferroptosis In Nafldmentioning

confidence: 99%

“…It has many benefits to the human body, such as being anti-tumor, anti-bacterial, anti-aging, and anti-inflammatory [ 106 , 107 , 108 ]. It has been reported that DA improved NAFLD in mice induced by HFD [ 79 ]. DA binds to Keap1 and then promotes the expression of HO-1, GSH, and GPX4 downstream of Nrf2, thereby eliminating the accumulation of ROS and reducing MDA.…”

Section: Drugs Targeting Ferroptosis In Liver Diseasesmentioning

confidence: 99%

Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies

Zhang

2021

Biomedicines

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Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Abnormal iron metabolism, lipid peroxidation, and accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) can all trigger ferroptosis. Emerging evidence indicates that ferroptosis plays a critical role in the pathological progression of NAFLD. Because the liver is the main organ for iron storage and lipid metabolism, ferroptosis is an ideal target for liver diseases. Inhibiting ferroptosis may become a new therapeutic strategy for the treatment of NAFLD. In this article, we describe the role of ferroptosis in the progression of NAFLD and its related mechanisms. This review will highlight further directions for the treatment of NAFLD and the selection of corresponding drugs that target ferroptosis.

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“…Exerting a positive effect of preventing lipotoxicity, poly-(rC)-binding protein 1 (PCBP1), as a cytosolic iron chaperonin, delay the progression of ferroprosis in mouse liver (Protchenko et al, 2020). Sestrin2 (Park et al, 2019), Ginkgolide B (GB) (Yang et al, 2020) and dehydroabietic acid (DA) (Gao et al, 2021) became operative in relieving MAFLD mainly through activating Nrf2 pathway to obstruct ferroptosis while enoyl coenzyme A hydratase 1 (ECH1) (considered as an ingredient in mitochondrial fatty acid β-oxidation) seemingly play a role of mediating the Erk expression (Liu B. et al, 2021). Conducted in clinical trials, several antioxidants, such as Vitamin E and pioglitazone, are also proved to ameliorate oxidation levels resulting in the improvement of steatosis, inflammation, ballooning and fibrosis in NASH patients (Sanyal et al, 2010;Bril et al, 2019).…”

Section: Ferroptosis and Metabolic Dysfunction-associated Fatty Liver Disease (Mafld)mentioning

confidence: 99%

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

Duan

Lin

et al. 2021

Front. Cell Dev. Biol.

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Ferroptosis is classified as an iron-dependent form of regulated cell death (RCD) attributed to the accumulation of lipid hydroperoxides and redox imbalance. In recent years, accumulating researches have suggested that ferroptosis may play a vital role in the development of diverse metabolic diseases, for example, diabetes and its complications (e.g., diabetic nephropathy, diabetic cardiomyopathy, diabetic myocardial ischemia/reperfusion injury and atherosclerosis [AS]), metabolic bone disease and adrenal injury. However, the specific physiopathological mechanism and precise therapeutic effect is still not clear. In this review, we summarized recent advances about the development of ferroptosis, focused on its potential character as the therapeutic target in metabolic diseases, and put forward our insights on this topic, largely to offer some help to forecast further directions.

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Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis

Cited by 81 publications

References 68 publications

Ferroptosis in liver disease: new insights into disease mechanisms

Ferroptosis in liver disease: new insights into disease mechanisms

Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

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