Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3–NFS1 axis in doxorubicin-induced cardiotoxicity

Wang, Yifan; Wang, Yuehong; Zou, Zhiguo; Yuan, Ang; Xiao, Zemeng; Geng, Nan; Qiao, ZhiQing; Li, Wenli; Ying, Xiaoying; Lu, Xiyuan; Pu, Jun

doi:10.1016/j.cellsig.2023.110655

Cited by 21 publications

(15 citation statements)

References 80 publications

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“…However, with the addition of NaHS, rotenone-inhibited cell viability could be significantly reduced. In line with our findings, it has been widely shown that H 2 S protects cardiac cell death induced by various stressors [ 13 , 45 , 46 ]. Apoptosis significantly contributes to myocyte cell death in ischemic heart disease [ 41 , 42 ].…”

Section: Discussionsupporting

confidence: 92%

“…The knockout of CSE diminished a majority of H 2 S production in the heart, while cardiac H 2 S levels were not altered in 3MST deficient mice, suggesting that CSE acts as a major H 2 S-generating enzyme in cardiac cells [ 1 , 5 ]. Disrupted CSE expression and H 2 S generation have been found in a variety of vascular diseases, and enhanced CSE/H 2 S signal would be able to improve vascular functions and prevent vascular disorders [ 10 , 11 , 12 , 13 ]. Another important source of H 2 S is through non-enzymatic production from sulfur-containing molecules such as cysteine, thiosulfate, and persulfides [ 6 , 10 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…A plethora of literature over the past few decades has demonstrated that H 2 S plays significant protective roles in the cardiovascular system via the actions of inflammation inhibition, antioxidant regulation, vasodilation, and energy metabolism, etc. [ 1 , 2 , 10 , 11 , 12 , 13 ]. All these findings suggest that H 2 S can be a target for drug design to prevent and cure cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

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H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

Linjacki,

Wang,

Baath

et al. 2024

Cells

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Hydrogen sulfide (H2S) has been recently recognized as an important gasotransmitter with cardioprotections, and iron is vital for various cellular activities. This study explored the regulatory role of H2S on iron metabolism and mitochondrial functions in cultured rat cardiac cells. Rotenone, a mitochondrial complex I inhibitor, was used for establishing an in vitro model of ischemic cell damage. It was first found that rotenone induced oxidative stress and lipid peroxidation and decreased mitochondrial membrane potential and ATP generation, eventually causing cell death. The supplement of H2S at a physiologically relevant concentration protected from rotenone-induced ferroptotic cell death by reducing oxidative stress and mitochondrial damage, maintaining GPx4 expression and intracellular iron level. Deferiprone, an iron chelator, would also protect from rotenone-induced ferroptosis. Further studies demonstrated that H2S inhibited ABCB8-mediated iron efflux from mitochondria to cytosol and promoted NFS1-mediated Fe-S cluster biogenesis. It is also found that rotenone stimulated iron-dependent H2S generation. These results indicate that H2S would protect cardiac cells from ischemic damage through preserving mitochondrial functions and intracellular Fe-S cluster homeostasis.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

Linjacki,

Wang,

Baath

et al. 2024

Cells

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“…Furthermore, H2 has been shown to regulate anti-inflammatory and antioxidant activities, mitochondrial energy metabolism, endoplasmic reticulum stress, immune system function, and cell death processes (including apoptosis, autophagy, pyroptosis, ferroptosis, and circadian rhythms), thereby exhibiting therapeutic potential for various systemic diseases [ 253 – 256 ]. Hydrogen sulfide (H2S), on the other hand, mitigates mitochondrial damage and ferroptosis by modulating the OPA3-NFS1 axis induced by doxorubicin-induced cardiotoxicity [ 257 ]. In the context of heart failure, hydrogen sulfide modulates iron metabolism, reducing oxidative stress levels in myocardial cells, inhibiting myocardial iron death, and protecting cardiac function in aging rats [ 258 ].…”

Section: Molecular Mechanism Of Natural Products Regulating Ferroptos...mentioning

confidence: 99%

Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure

Zhang,

Luo,

et al. 2024

Eur J Med Res

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The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.

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“…In recent years, a number of studies had found that NFS1 was involved in the regulation of tumor progression. Researchers found that by targeting OPA3 NFS1 axis suppression iron death to protect the cardiac toxicity induced by dox(Wang Y et al 2023), depletion of NFS1, while targeting CAIX, enhanced ferroptosis and signi cantly inhibited tumor growth. In this study, we investigated that the differential expression of NFS1 in GC tissues may be related to the iron death pathway.…”

mentioning

confidence: 99%

Overexpression of ferroptosis-related gene NFS1 correlates with gastric cancer progression and tumor immune infiltration

Mao,

Shi,

Cui

et al. 2023

Preprint

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Gastric cancer (GC) is one of the malignant tumors with the highest incidence in the world, however finding better biomarkers remains a challenge. Cysteine desulfurase (NFS1) has been found to regulate the biological functions of a variety of tumors, but the study in GC remains to be explored. In our study, NFS1 expression was predicted by TCGA, GTEx, UALCAN, and HPA databases. And immunohistochemistry (IHC) was performed in 146 pairs of GC tissues and paired adjacent tissues to verify NFS1 expression. We found that NFS1 was up-regulated in GC tissues, which can be effectively diagnosed and dynamically monitored to evaluate the prognosis of GC patients. The results of immunohistochemistry showed that the strong positive immunostaining was related to the degree of differentiation and the depth of invasion of GC patients. Functional enrichment analysis indicated that NFS1 might play a role in ferroptosis and tumor microenvironment (TME), including regulating epithelial-mesenchymal transition, stromal response, and immune response. Moreover, the aberrant NFS1 expression was related to TMB, MSI, DNSss, RNAss, TME score in GC and drug sensitivity. In addition, in the NFS1 and immune correlation analysis, it was found that the expression level of NFS1 was correlated with a large number of immune cells and immune microenvironment characteristics. Our findings indicated that NFS1 was a potential diagnostic and prognostic biomarker associated with ferroptosis and TME, providing a new target for drug therapy and immunotherapy of specific cancers.

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Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3–NFS1 axis in doxorubicin-induced cardiotoxicity

Cited by 21 publications

References 80 publications

H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

H2S Protects from Rotenone-Induced Ferroptosis by Stabilizing Fe-S Clusters in Rat Cardiac Cells

Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure

Overexpression of ferroptosis-related gene NFS1 correlates with gastric cancer progression and tumor immune infiltration

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