Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis

Zhang, Minyi; Zhang, Tao; Song, Chenglin; Qu, Jiao; Gu, Yanpin; Liu, Songjun; Li, Haibo; Xiao, Wei; Kong, Ling-Dong; Sun, Yang; Lv, Wen

doi:10.1016/j.jep.2021.114064

Cited by 30 publications

(21 citation statements)

References 29 publications

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“…When ferroptosis occurs, increasing p62 promotes the autophagy degradation of Keap1, which facilitates Nrf2 to be released into the nucleus. Nrf2 activates downstream transcription factors such as HO-1, which further restrains the production of ROS, thus inhibiting ferroptosis ( Sun et al, 2020 ; Zhang et al, 2021 ). In agreement with previous studies, we found that the p62-Keap1-Nrf2 signaling axis was stimulated in neuronal ferroptosis both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Xia

Zhang

et al. 2022

Front. Aging Neurosci.

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BackgroundSpinal cord injury (SCI) is a severe traumatic disorder of the central nervous system (CNS) that causes irreversible damage to the nervous tissue. The consequent hemorrhage contributed by trauma induces neuronal ferroptosis post SCI, which is an important death mode to mediate neuronal loss. Growth differentiation factor 15 (GDF15) is a cytokine that regulates cell proliferation, differentiation, and death. However, the specific role of GDF15 in neuronal ferroptosis post SCI remains unknown.Materials and MethodsNeuronal ferroptosis in vitro was measured by detection of lipid peroxidation, glutathione, iron content, and reactive oxidative stress. In vivo, western blotting and immunofluorescence (IF) staining was utilized to measure ferroptosis post SCI. IF staining, TUNEL staining, hematoxylin-eosin staining, and Nissl staining were used to measure neurological damage. Finally, locomotor function recovery was analyzed using the Basso Mouse Scale and Louisville Swim Scale.ResultsGDF15 was significantly increased in neuronal ferroptosis and silencing GDF15 aggravated ferroptosis both in vitro and in vivo. Besides, GDF15-mediated inhibition of neuronal ferroptosis is through p62-dependent Keap1-Nrf2 pathway. In SCI mice, knockdown of GDF15 significantly exacerbated neuronal death, interfered with axon regeneration and remyelination, aggravated ferroptosis-mediated neuroinflammation, and restrained locomotor recovery.ConclusionGDF15 effectively alleviated neuronal ferroptosis post SCI via the p62-Keap1-Nrf2 signaling pathway and promoted locomotor recovery of SCI mice, which is suggested as a potential target on SCI pathogenesis and treatment.

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Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Xia

Zhang

et al. 2022

Front. Aging Neurosci.

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“…Nrf2 inhibits ferroptosis mainly by activating iron metabolism-related genes (SLC40A1 and MT1G), GSH metabolism-related genes (SLC7A11 and GCLM), and ROS detoxification enzymes (AKR1C1 and NQO1) in many cancers (Chen et al, 2021b). As previously revealed, the p62-Keap1-Nrf2 signaling pathway played an important role in promoting estrogen-induced endometrial hyperplasia by inhibiting ferroptosis (Zhang M et al, 2021). On one hand, Nrf2 regulated the expression of glutathione-dependent lipid antioxidant (GPX4) directly or indirectly, while GPX4 overexpression resulted in ferroptosis inhibition (Fan et al, 2017); on the other hand, the overexpression of Nrf2 was found to promote the expression of solute carrier family 7 member 11 (SLC7A11) and increase the GSH level to inhibit ferroptosis (Song and Long, 2020).…”

Section: Ferroptosis and Initiation Of Endometrial Cancermentioning

confidence: 77%

Ferroptosis: Opportunities and Challenges in Treating Endometrial Cancer

Zhang

et al. 2022

Front. Mol. Biosci.

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Ferroptosis, a new way of cell death, is involved in many cancers. A growing number of studies have focused on the unique role of ferroptosis on endometrial cancer. In this study, we made a comprehensive review of the relevant articles published to get deep insights in the association of ferroptosis with endometrial cancer and to present a summary of the roles of different ferroptosis-associated genes. Accordingly, we made an evaluation of the relationships between the ferroptosis-associated genes and TNM stage, tumor grade, histological type, primary therapy outcome, invasion and recurrence of tumor, and accessing the different prognosis molecular typing based on ferroptosis-associated genes. In addition, we presented an introduction of the common drugs, which targeted ferroptosis in endometrial cancer. In so doing, we clarified the opportunities and challenges of ferroptosis activator application in treating endometrial cancer, with a view to provide a novel approach to the disease.

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“…Iron has a unique role and function in the female reproductive system, and iron disorders are found in many gynecological diseases ( Ng et al, 2020 ). According to reports, iron-mediated cell death (ferroptosis) is closely related to endometriosis, repeated implantation failure, endometrial hyperplasia, and many other endometrial diseases, which can be used as treatment target ( Bielfeld et al, 2019 ; Ng et al, 2020 ; Zhang et al, 2021 ). However, the role of ferroptosis in EC remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of a Ferroptosis-Related Prognostic Model for Endometrial Cancer

Wang

Chen

et al. 2021

Front. Genet.

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Guizhi Fuling Capsule ameliorates endometrial hyperplasia through promoting p62-Keap1-NRF2-mediated ferroptosis

Cited by 30 publications

References 29 publications

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Ferroptosis: Opportunities and Challenges in Treating Endometrial Cancer

Construction and Validation of a Ferroptosis-Related Prognostic Model for Endometrial Cancer

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