Activation of the p62‐Keap1‐NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells

Sun, Xiaofang; Ou, Zhanhui; Chen, Ruochan; Niu, Xiaohua; Chen, De; Kang, Rui; Tang, Daolin

doi:10.1002/hep.28251

Cited by 1,519 publications

(1,377 citation statements)

References 36 publications

Supporting

Mentioning

1,334

Contrasting

Unclassified

Order By: Relevance

“…17 Knockdown of NRF2 and these NRF2-targeted genes accelerates erastin or sorafenib-induced ferroptosis in HCC cells. 17 In contrast, induction of HO-1 expression by erastin may promote cell death in HT1080 and fibroblasts, suggesting that HO-1 has a dual role in ferroptosis. 37 Measuring methods…”

Section: Molecular Biologymentioning

confidence: 99%

“…16 However, the expression of Rb (the prototype tumor suppressor gene) and NRF2 could inhibit sorafenib-induced ferroptosis in HCC. 14,17 The mechanism and action of sorafenib in ferroptosis may depend on the inhibition of system X c − function, but not on GPX4 activity (Figure 1a). 7 This process is associated with upregulated ER stress.…”

Section: Morphologymentioning

confidence: 99%

“…17 p62 interacts with the NRF2-binding site of Kelch-like ECHassociated protein 1 (Keap1) and competitively inhibits Keap1-NRF2 interaction, which is responsible for NRF2 protein stability following treatment with FINs (e.g., erastin, sorafenib, and BSO). 17 Upregulated NRF2 protein promotes transcription of genes encoding antioxidant proteins (e.g., quinone oxidoreductase 1 and heme oxygenase-1 (HO-1)) and iron metabolism proteins (e.g., FTH1) in ferroptosis. 17 Knockdown of NRF2 and these NRF2-targeted genes accelerates erastin or sorafenib-induced ferroptosis in HCC cells.…”

Section: Molecular Biologymentioning

confidence: 99%

“…17 Upregulated NRF2 protein promotes transcription of genes encoding antioxidant proteins (e.g., quinone oxidoreductase 1 and heme oxygenase-1 (HO-1)) and iron metabolism proteins (e.g., FTH1) in ferroptosis. 17 Knockdown of NRF2 and these NRF2-targeted genes accelerates erastin or sorafenib-induced ferroptosis in HCC cells. 17 In contrast, induction of HO-1 expression by erastin may promote cell death in HT1080 and fibroblasts, suggesting that HO-1 has a dual role in ferroptosis.…”

Section: Molecular Biologymentioning

confidence: 99%

“…3 The Iron Assay Kit provides a simple convenient means of measuring ferrous and/or ferric ions in samples. 17 ROS level: Erastin-treated HT1080 cells are accompanied by a prolonged period of lipid peroxidation detection by C11-BODIPY probe and shift the fluorescence from red to green, whereas ferroptosis inhibitors restrict this shift. In contrast, MitoSOX (a mitochondrial ROS probe) is not changed following erastin treatment.…”

Section: In Vitromentioning

confidence: 99%

See 4 more Smart Citations

Ferroptosis: process and function

et al. 2016

View full text Add to dashboard Cite

Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

show abstract

Section: Molecular Biologymentioning

confidence: 99%

Section: Morphologymentioning

confidence: 99%

Section: Molecular Biologymentioning

confidence: 99%

Section: Molecular Biologymentioning

confidence: 99%

Section: In Vitromentioning

confidence: 99%

See 3 more Smart Citations

Ferroptosis: process and function

et al. 2016

View full text Add to dashboard Cite

show abstract

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

et al. 2016

View full text Add to dashboard Cite

p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.

show abstract

Ferroptosis‐Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

Zhao

Guo

Zhou

et al. 2023

Adv Funct Materials

View full text Add to dashboard Cite

Hypertrophic scarring, an abnormal fibroproliferative wound-healing disease, has brought tremendous burden for global healthcare systems. To date, no satisfactory treatment of hypertrophic scarring is available yet. Ferroptosis, an iron-dependent form of cell death, has attracted much attention recently for the therapy of diseases featuring iron addiction. Intriguingly, myofibroblasts derived from hypertrophic scarring are found to exhibit a high iron state which appears to be sensitive to trigger ferroptosis for scarring treatment. Accordingly, in this study, a pH responsive self-assembly nanoplatform is designed by encapsulating silver nanoclusters (AgNCs) and Chinese herbal medicine trigonelline (TRG) into zeolitic imidazolate framework-8 (ZIF-8) for synergistic ferroptosis therapy against hypertrophic scarring. The fabricated AgNC/TRG/ZIF-8 composites exhibit good biocompatibility and pH responsive-degradation inside myofibroblasts. The ZIF-8 precursors can increase the generation of lipid reactive oxygen species and deplete intracellular glutathione (GSH). Also, AgNCs have the capability to consume GSH, while TRG can inhibit the activity of glutathione peroxidase. Consequently, the synergistic ferroptosis anti-scarring therapy can be effectively achieved. Furthermore, AgNC/TRG/ZIF-8-loaded microneedle patches made of gelatin methacrylate show remarkable therapeutic effect against hypertrophic scarring on a rabbit ear model. This study suggests the great potential of ferroptosis-mediated strategy for treating fibrotic skin diseases in future clinical application.

show abstract

Activation of the p62‐Keap1‐NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells

Cited by 1,519 publications

References 36 publications

Ferroptosis: process and function

Ferroptosis: process and function

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

Ferroptosis‐Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal–Organic Framework Microneedle Patch

Contact Info

Product

Resources

About