Chrysophanol attenuates hepatitis B virus X protein-induced hepatic stellate cell fibrosis by regulating endoplasmic reticulum stress and ferroptosis

Kuo, Chan‐Yen; Chiu, Valeria; Hsieh, Po‐Chun; Chun-Yen, Huang; Huang, Shaohui; Tzeng, I‐Shiang; Tsai, Fu-Ming; Chen, Mao-Liang; Liu, Chien-Ting; Chen, Yi-Ru

doi:10.1016/j.jphs.2020.07.014

Cited by 65 publications

(50 citation statements)

References 65 publications

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“…Attractively, Li et al recently reported that artemether-induced ferroptosis alleviates liver fibrosis via IRP2/Iron/ROS axis [ 34 ]. Furthermore, Kuo et al found that chrysophanol attenuates liver fibrosis induced by hepatitis B virus X protein by regulating HSC ferroptosis [ 35 ]. Consistent with previous researches, we found that ferroptosis inducers significantly inhibited cell viability and alleviated CCl 4 -induced liver fibrosis by inducing HSC ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

et al. 2021

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Ferroptosis is a recently identified non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. However, the underlying exact mechanisms remain poorly understood. Here, we report that the total levels of N 6 -methyladenosine (m 6 A) modification are evidently increased upon exposure to ferroptosis-inducing compounds due to the upregulation of methylase METTL4 and the downregulation of demethylase FTO. Interestingly, RNA-seq shows that m 6 A modification appears to trigger autophagy activation by stabilizing BECN1 mRNA, which may be the potential mechanism for m 6 A modification-enhanced HSC ferroptosis. Importantly, YTHDF1 is identified as a key m 6 A reader protein for BECN1 mRNA stability, and knockdown of YTHDF1 could prevent BECN1 plasmid-induced HSC ferroptosis. Noteworthy, YTHDF1 promotes BECN1 mRNA stability and autophagy activation via recognizing the m 6 A binding site within BECN1 coding regions. In mice, erastin treatment alleviates liver fibrosis by inducing HSC ferroptosis. HSC-specific inhibition of m 6 A modification could impair erastin-induced HSC ferroptosis in murine liver fibrosis. Moreover, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis and m 6 A modification in advanced fibrotic patients with hepatocellular carcinoma (HCC) receiving sorafenib monotherapy. Attractively, the m 6 A modification upregulation, autophagy activation, and ferroptosis induction occur in human HSCs. Overall, these findings reveal novel signaling pathways and molecular mechanisms of ferroptosis, and also identify m 6 A modification-dependent ferroptosis as a potential target for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

et al. 2021

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“…The cells 1 × 10 6 were harvested and lysed according to a protocol described in our previous study [ 29 ]. Briefly, cells were collected, washed three times with PBS and lysed using RIPA lysis buffer (Pierce, Rockford, IL, USA), containing 1% Sigma protease cocktail, for 30 min at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Nephroprotective Role of Chrysophanol in Hypoxia/Reoxygenation-Induced Renal Cell Damage via Apoptosis, ER Stress, and Ferroptosis

et al. 2021

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Acute kidney injury (AKI) is caused by hypoxia-reoxygenation (H/R), which is a kidney injury produced by a variety of causes, resulting in the remaining portion of the kidney function being unable to maintain the balance for performing the tasks of waste excretion metabolism, and electrolyte and acid-base balance. Many studies have reported the use of Chinese medicine to slow down the progression and alleviate the complications of chronic renal failure. Chrysophanol is a component of Rheum officinale Baill, a traditional Chinese medicine that has been clinically used to treat renal disease. We aimed to study the nephroprotective effect of chrysophanol on hypoxia/ reoxygenation (H/R)-induced cell damage. The results showed that chrysophanol prevented H/R-induced apoptosis via downregulation of cleaved Caspase-3, p-JNK, and Bax but upregulation of Bcl-2 expression. In contrast, chrysophanol attenuated H/R-induced endoplasmic reticulum (ER) stress via the downregulation of CHOP and p-IRE1α expression. Our data demonstrated that chrysophanol alleviated H/R-induced lipid ROS accumulation and ferroptosis. Therefore, we propose that chrysophanol may have a protective effect against AKI by regulating apoptosis, ER stress, and ferroptosis.

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“…Chrysophanol helps reverse HBx-mediated inhibition of ferroptosisis via downregulation of GPX4 and SLC7A11. Therefore, chrysophanol could attenuate HBx-induced HSCs activation and ameliorate liver fibrosis 53 . Recently, dihydroorotate dehydrogenase (DHODH) was found to operate in parallel to GPX4 in mitochondrials to inhibit ferroptosis, which reduces ubiquinone to ubiquinol.…”

Section: Ferroptosis and Liver Fibrosismentioning

confidence: 99%

Ferroptosis and Liver Fibrosis

Pan¹,

Luo²,

Xia³

et al. 2021

Int. J. Med. Sci.

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Ferroptosis is an iron-dependent form of regulated cell death, which is characterized by a large amount of lipid peroxide accumulation and the imbalance of redox state in cells. Ferroptosis is usually accompanied with the dysfunction of lipid repair enzyme (glutathione peroxidase 4, GPX4), large masses of iron accumulation and lipid peroxidation of polyunsaturated fatty acids (PUFAs). Ferroptosis is related to several signaling pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion and p53 and Keap1/Nrf2 signaling pathways. A number of studies have indicated that ferroptosis is closely associated with acute renal failure, tumor, ischemia and reperfusion injury, neurodegenerative diseases and liver fibrosis. Liver fibrosis, which has long been a global health problem, still lacks effective treatment till now, and the discovery of ferroptosis provides a new insight into addressing this issue.

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Chrysophanol attenuates hepatitis B virus X protein-induced hepatic stellate cell fibrosis by regulating endoplasmic reticulum stress and ferroptosis

Cited by 65 publications

References 65 publications

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

Nephroprotective Role of Chrysophanol in Hypoxia/Reoxygenation-Induced Renal Cell Damage via Apoptosis, ER Stress, and Ferroptosis

Ferroptosis and Liver Fibrosis

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