bims-nurfca 2024-01-07 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2024‒01‒07
eleven papers selected by
Caner Geyik, Istinye University

Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.
NRF2 promotes radiation resistance by cooperating with TOPBP1 to activate the ATR-CHK1 signaling pathway.
Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.
Interplay of oxidative stress, cellular communication and signaling pathways in cancer.
DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.
Arenobufagin regulates the p62-Keap1-Nrf2 pathway to induce autophagy-dependent ferroptosis in HepG2 cells.
Identification and validation of prognostic signature genes of bladder cancer by integrating methylation and transcriptomic analysis.
Curcumin induces ferroptosis and apoptosis in osteosarcoma cells by regulating Nrf2/GPX4 signaling pathway.
Danggui Buxue Tang improves therapeutic efficacy of doxorubicin in triple negative breast cancer via ferroptosis.
Sophocarpine alleviates doxorubicin-induced heart injury by suppressing oxidative stress and apoptosis.
NMNATs expression inhibition mediated NAD+ deficiency plays a critical role in doxorubicin-induced hepatotoxicity in mice.

Cell Rep. 2023 Dec 30. pii: S2211-1247(23)01640-6. [Epub ahead of print]43(1): 113629

Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.

Dimitris Karagiannis, Warren Wu, Albert Li, Makiko Hayashi, Xiao Chen, Michaela Yip, Vaibhav Mangipudy, Xinjing Xu, Francisco J Sánchez-Rivera, Yadira M Soto-Feliciano, Jiangbin Ye, Thales Papagiannakopoulos, Chao Lu.

  The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.

Keywords:  CP: Cancer; HDAC inhibitors; NRF2 pathway; cancer epigenetics; cancer metabolism; cancer targeted therapy; epigenetic reprogramming; lung cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.113629
Theranostics. 2024 ;14(2): 681-698

NRF2 promotes radiation resistance by cooperating with TOPBP1 to activate the ATR-CHK1 signaling pathway.

Xiaohui Sun, Mingxin Dong, Jiale Li, Yuxiao Sun, Yu Gao, Yan Wang, Liqing Du, Yang Liu, Kaihua Ji, Ningning He, Jinhan Wang, Manman Zhang, Huijuan Song, Chang Xu, Qiang Liu.

  Background: Radiation resistance is the main limitation of the application of radiotherapy. Ionizing radiation (IR) kills cancer cells mainly by causing DNA damage, particularly double-strand breaks (DSBs). Radioresistant cancer cells have developed the robust capability of DNA damage repair to survive IR. Nuclear factor erythroid 2-related factor 2 (NRF2) has been correlated with radiation resistance. We previously reported a novel function of NRF2 as an ATR activator in response to DSBs. However, little is known about the mechanism that how NRF2 regulates DNA damage repair and radiation resistance. Methods: The TCGA database and tissue microarray were used to analyze the correlation between NRF2 and the prognosis of lung cancer patients. The radioresistant lung cancer cells were constructed, and the role of NRF2 in radiation resistance was explored by in vivo and in vitro experiments. Immunoprecipitation, immunofluorescence and extraction of chromatin fractions were used to explore the underlying mechanisms. Results: In this study, the TCGA database and clinical lung cancer samples showed that high expression of NRF2 was associated with poor prognosis in lung cancer patients. We established radioresistant lung cancer cells expressing NRF2 at high levels, which showed increased antioxidant and DNA repair abilities. In addition, we found that NRF2 can be involved in the DNA damage response independently of its antioxidant function. Mechanistically, we demonstrated that NRF2 promoted the phosphorylation of replication protein A 32 (RPA32), and DNA topoisomerase 2-binding protein 1 (TOPBP1) was recruited to DSB sites in an NRF2-dependent manner. Conclusion: This study explored the novel role of NRF2 in promoting radiation resistance by cooperating with RPA32 and TOPBP1 to activate the ATR-CHK1 signaling pathway. In addition, the findings of this study not only provide novel insights into the molecular mechanisms underlying the radiation resistance of lung cancer cells but also validate NRF2 as a potential target for radiotherapy.

Keywords:  ATR; Ionizing radiation; NRF2; NSCLC; RPA32; TOPBP1

DOI:  https://doi.org/10.7150/thno.88899
bioRxiv. 2023 Dec 17. pii: 2023.12.16.572007. [Epub ahead of print]

Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.

Hannah E Greenwood, Richard S Edwards, Will E Tyrrell, Abigail R Barber, Friedrich Baark, Muhammet Tanc, Eman Khalil, Aimee Falzone, Nathan P Ward, Janine M DeBlasi, Laura Torrente, David R Pearce, George Firth, Lydia M Smith, Oskar Vilhelmsson Timmermand, Ariana Huebner, Madeleine E George, Charles Swanton, Robert E Hynds, Gina M DeNicola, Timothy H Witney.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system x c - , is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by ( S )-4-(3- 18 F-fluoropropyl)-ʟ-glutamate ([ 18 F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [ 18 F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC. We validate imaging readouts with metabolomic measurements of system x c - activity and their coupling to intracellular glutathione concentration. A redox gene signature was measured in patients from the TRACERx 421 cohort, suggesting an opportunity for patient stratification prior to imaging. Furthermore, we reveal that system x c - is a metabolic vulnerability that can be therapeutically targeted for sustained tumour growth suppression in aggressive NSCLC. Our results establish [ 18 F]FSPG as predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

DOI: https://doi.org/10.1101/2023.12.16.572007
Cell Commun Signal. 2024 Jan 02. 22(1): 7

Interplay of oxidative stress, cellular communication and signaling pathways in cancer.

Muhammad Javed Iqbal, Ayesha Kabeer, Zaighum Abbas, Hamid Anees Siddiqui, Daniela Calina, Javad Sharifi-Rad, William C Cho.

  Cancer remains a significant global public health concern, with increasing incidence and mortality rates worldwide. Oxidative stress, characterized by the production of reactive oxygen species (ROS) within cells, plays a critical role in the development of cancer by affecting genomic stability and signaling pathways within the cellular microenvironment. Elevated levels of ROS disrupt cellular homeostasis and contribute to the loss of normal cellular functions, which are associated with the initiation and progression of various types of cancer. In this review, we have focused on elucidating the downstream signaling pathways that are influenced by oxidative stress and contribute to carcinogenesis. These pathways include p53, Keap1-NRF2, RB1, p21, APC, tumor suppressor genes, and cell type transitions. Dysregulation of these pathways can lead to uncontrolled cell growth, impaired DNA repair mechanisms, and evasion of cell death, all of which are hallmark features of cancer development. Therapeutic strategies aimed at targeting oxidative stress have emerged as a critical area of investigation for molecular biologists. The objective is to limit the response time of various types of cancer, including liver, breast, prostate, ovarian, and lung cancers. By modulating the redox balance and restoring cellular homeostasis, it may be possible to mitigate the damaging effects of oxidative stress and enhance the efficacy of cancer treatments. The development of targeted therapies and interventions that specifically address the impact of oxidative stress on cancer initiation and progression holds great promise in improving patient outcomes. These approaches may include antioxidant-based treatments, redox-modulating agents, and interventions that restore normal cellular function and signaling pathways affected by oxidative stress. In summary, understanding the role of oxidative stress in carcinogenesis and targeting this process through therapeutic interventions are of utmost importance in combating various types of cancer. Further research is needed to unravel the complex mechanisms underlying oxidative stress-related pathways and to develop effective strategies that can be translated into clinical applications for the management and treatment of cancer. Video Abstract.

Keywords:  Cancer; Carcinogenesis mechanisms; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12964-023-01398-5
Autophagy. 2024 Jan 03. 1-17

DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.

Gamze Bildik, Joshua P Gray, Weiqun Mao, Hailing Yang, Rumeysa Ozyurt, Vivian R Orellana, Olivier De Wever, Mark S Carey, Robert C Bast, Zhen Lu.

  Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC.Abbreviations: AFR: autophagic flux reporter; ATG: autophagy related; CQ: chloroquine; DCFDA: 2'-7'-dichlorodihydrofluorescein diacetate; DIRAS3: DIRAS family GTPase 3; DOX: doxycycline; KRAS: KRAS proto-oncogene, LGSOC: low-grade serous ovarian cancer; MiT/TFE: microphthalmia family of transcription factors; NAC: N-acetylcysteine; PDAC: pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; TFEB: transcription factor EB.

Keywords:  Autophagy; DIRAS3; KRAS; LGSOC; PDAC; chloroquine

DOI:  https://doi.org/10.1080/15548627.2023.2299516
Naunyn Schmiedebergs Arch Pharmacol. 2024 Jan 02.

Arenobufagin regulates the p62-Keap1-Nrf2 pathway to induce autophagy-dependent ferroptosis in HepG2 cells.

YuTing Yang, Chun Liu, Meng Wang, Hui Cheng, Huan Wu, ShengYong Luo, Mei Zhang, XianChun Duan, Qinglin Li.

  Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer, accounting for the overwhelming majority of malignant liver tumors. Therefore, how to effectively prevent and cure HCC has become a research hotspot. Many studies have shown that arenobufagin can induce apoptosis, ferroptosis, and autophagy of tumor cells. An increasing number of studies have shown that autophagy is closely linked to ferroptosis. In this study, HepG2 cells and BALB/c nude mice were used as research objects to explore the effect and preliminary mechanism of hepatoma cell autophagy and ferroptosis induced by arenobufagin. We found that arenobufagin can significantly inhibit tumor growth in vivo, and interestingly, we found that arenobufagin inhibited ferroptosis-related proteins Nrf2 and COX-2 in a dose-dependent manner and decreased the levels of reduced glutathione (GSH) and superoxide dismutase (T-SOD) in tissues, while increased the level of reduced malondialdehyde (MDA). In addition, we found that arenobufagin increased the levels of COX-2 and MDA in cells, decreased the levels of Nrf2, GSH, and T-SOD, increased the levels of tissue reactive oxygen species (ROS) and lipid ROS in a dose-dependent manner, and promoted ferroptosis in HepG2 cells. HepG2 cells were preprotected by autophagy inhibitor chloroquine (CQ) and ferroptosis inhibitor deferoxamine (DFO), and then treated with arenobufagin. It was found that CQ partially reversed the changes of COX-2 and Nrf2 expression and lipid peroxidation induced by arenobufagin-induced autophagy and HepG2 cells. Interestingly, CQ partially reversed the inhibition of arenobufagin on cytoplasmic junction protein (Keap1) and heme oxygenase-1 (HO-1) in p62-Keap1-Nrf2 pathway. At the same time, we found that the effect of arenobufagin on oxidative stress of HepG2 cells overexpressed by Nrf2 was significantly less than that of the control group. To sum up, arenobufagin promotes autophagy-dependent ferroptosis of HepG2 cells by inducing autophagy and regulating p62-Keap1-Nrf2 pathway. It is suggested that arenobufagin can be used as a potential intervention therapy.

Keywords:  Arenobufagin; Autophagy; Ferroptosis; Liver cancer; Nrf2

DOI:  https://doi.org/10.1007/s00210-023-02916-5
Sci Rep. 2024 Jan 03. 14(1): 368

Identification and validation of prognostic signature genes of bladder cancer by integrating methylation and transcriptomic analysis.

Dipankor Chatterjee, Sadia Islam Mou, Tamanna Sultana, Md Ismail Hosen, Md Omar Faruk.

Being a frequent malignant tumor of the genitourinary system, Bladder Urothelial Carcinoma (BLCA) has a poor prognosis. This study focused on identifying and validating prognostic biomarkers utilizing methylation, transcriptomics, and clinical data from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA BLCA) cohort. The impact of altered differentially methylated hallmark pathway genes was subjected to clustering analysis to observe changes in the transcriptional landscape on BLCA patients and identify two subtypes of patients from the TCGA BLCA population where Subtype 2 was associated with the worst prognosis with a p-value of 0.00032. Differential expression and enrichment analysis showed that subtype 2 was enriched in immune-responsive and cancer-progressive pathways, whereas subtype 1 was enriched in biosynthetic pathways. Following, regression and network analyses revealed Epidermal Growth Factor Receptor (EGFR), Fos-related antigen 1 (FOSL1), Nuclear Factor Erythroid 2 (NFE2), ADP-ribosylation factor-like protein 4D (ARL4D), SH3 domain containing ring finger 2 (SH3RF2), and Cadherin 3 (CDH3) genes to be the most significant prognostic gene markers. These genes were used to construct a risk model that separated the BLCA patients into high and low-risk groups. The risk model was also validated in an external dataset by performing survival analysis between high and low-risk groups with a p-value < 0.001 and the result showed the high group was significantly associated with poor prognosis compared to the low group. Single-cell analyses revealed the elevated level of these genes in the tumor microenvironment and associated with immune response. High-grade patients also tend to have a high expression of these genes compared to low-grade patients. In conclusion, this research developed a six-gene signature that is pertinent to the prediction of overall survival (OS) and might contribute to the advancement of precision medicine in the management of bladder cancer.

DOI: https://doi.org/10.1038/s41598-023-50740-x
Exp Biol Med (Maywood). 2024 Jan 03. 15353702231220670

Curcumin induces ferroptosis and apoptosis in osteosarcoma cells by regulating Nrf2/GPX4 signaling pathway.

Chuanjian Yuan, Rong Fan, Kai Zhu, Yutong Wang, Wenpeng Xie, Yanchen Liang.

  Curcumin, an antitumor agent, has been shown to inhibit cell growth and metastasis in osteosarcoma. However, there is no evidence of curcumin and its regulation of cell ferroptosis and nuclear factor E2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathways in osteosarcoma. This study aimed to investigate the effects of curcumin on osteosarcoma both in vitro and in vivo. To explore the effects and mechanisms of curcumin on osteosarcoma, cells (MNNG/HOS and MG-63) and xenograft mice models were established. Cell viability, cell apoptosis rate, cycle distribution, cell migration, cell invasion, reactive oxygen species, malonaldehyde and glutathione abilities, and protein levels were detected by cell counting kit-8, flow cytometry, wound healing, transwell assay, respectively. Nrf2 and GPX4 expressions were detected using an immunofluorescence assay. Nrf2/GPX4-related protein levels were detected using western blotting. The results showed that curcumin effectively decreased cell viability and increased apoptosis rate. Meanwhile, curcumin inhibited tumor volume in the xenograft model, and Nrf2/GPX4-related protein levels were also altered. Interestingly, the effects of curcumin were reversed by liproxstatin-1 (an effective inhibitor of ferroptosis) and bardoxolone-methyl (an effective activator of Nrf2). Our results indicate that curcumin has therapeutic effects on osteosarcoma cells and a xenograft model by regulating the expression of the Nrf2/GPX4 signaling pathway.

Keywords:  GSH; Nrf2/GPX4; Osteosarcoma; ROS; ferroptosis

DOI:  https://doi.org/10.1177/15353702231220670
J Ethnopharmacol. 2023 Dec 27. pii: S0378-8741(23)01525-8. [Epub ahead of print] 117655

Danggui Buxue Tang improves therapeutic efficacy of doxorubicin in triple negative breast cancer via ferroptosis.

Guowei Gong, Kumar Ganesan, Yaqun Liu, Yongping Huang, Yuting Luo, XueXu Wang, Zhenxia Zhang, Yuzhong Zheng.

  ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue Tang (DBT) has been used for over 800 years to enhance Qi and nourish Blood, and it is particularly beneficial for cancer patients. Recent research has shown that combining DBT with chemotherapy agents leads to superior anti-cancer effects, thereby enhancing therapeutic efficacy.AIM OF THE STUDY: The aim of this study was to evaluate the effectiveness of a combination therapy involving doxorubicin (DOX) and Danggui Buxue Tang (DBT) in the treatment of triple-negative breast cancer (TNBC) and to elucidate the underlying mechanisms of action.
MATERIALS AND METHODS: In vitro experiments were performed using MDA-MB-231 and 4T1 cells, while in vivo experiments were carried out using MDA-MB-231 xenograft mice. The therapeutic effects of the combination therapy were evaluated using various techniques, including MTT assay, colony formation assay, flow cytometry, transwell assay, immunofluorescence, transmission electron microscopy (TEM), histological analysis, western blotting, and bioluminescence assay.
RESULTS: DBT was found to enhance DOX's anti-TNBC activity in vitro by promoting ferroptosis, as evidenced by the observed mitochondrial morphological changes using TEM. The combination therapy was also found to reduce the expression of Nrf2, HO-1, and GPX4, which are all targets for ferroptosis induction, while simultaneously increasing ROS production. Additionally, the combination therapy reduced nuclear accumulation and constitutive activation of Nrf2, which is a significant cause of chemotherapy resistance and promotes cancer growth. In vivo experiments using an MDA-MB-231 xenograft animal model revealed that the combination therapy significantly reduced tumor cell proliferation and accelerated TNBC deaths by modulating the Nrf2/HO-1/GPX4 axis, with no evidence of tissue abnormalities. Moreover, the combination therapy exhibited a liver protective effect, and administration of Fer-1 was able to reduce the ROS formation produced by the DBT + DOX combination therapy.
CONCLUSION: This study provides evidence that the combination therapy of DOX and DBT has the potential to treat TNBC by promoting ferroptosis through the Nrf2/HO-1/GPX4 axis.

Keywords:  Combination therapy; Danggui Buxue Tang; Doxorubicin; Ferroptosis; Nrf2/HO-1/GPX4 axis; TNBC

DOI:  https://doi.org/10.1016/j.jep.2023.117655
Sci Rep. 2024 Jan 03. 14(1): 428

Sophocarpine alleviates doxorubicin-induced heart injury by suppressing oxidative stress and apoptosis.

Hong-Jin Zhang, Yang Fu, Huang Zhang, Ze-Qun Lai, Yi-Fei Dong.

Doxorubicin (DOX) is an effective anti-tumor drug accompanied with many side effects, especially heart injury. To explore what effects of sophocarpine (SOP) on DOX-induced heart injury, this study conducted in vivo experiment and in vitro experiment, and the C57BL/6J mice and the H9C2 cells were used. The experimental methods used included echocardiography, enzyme-linked immunosorbent assay (ELISA), dihydroethidium (DHE) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, western blotting and so on. Echocardiography showed that SOP alleviated DOX-induced cardiac dysfunction, as evidenced by the improvements of left ventricle ejection fraction and left ventricle fractional shortening. DOX caused upregulations of creatine kinase (CK), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), while SOP reduced these indices. The relevant stainings showed that SOP reversed the increases of total superoxide level induced by DOX. DOX also contribute to a higher level of MDA and lower levels of SOD and GSH, but these changes were suppressed by SOP. DOX increased the pro-oxidative protein level of NOX-4 while decreased the anti-oxidative protein level of SOD-2, but SOP reversed these effects. In addition, this study further discovered that SOP inhibited the decreases of Nrf2 and HO-1 levels induced by DOX. The TUNEL staining revealed that SOP reduced the high degree of apoptosis induced by DOX. Besides, pro-apoptosis proteins like Bax, cleaved-caspase-3 and cytochrome-c upregulated while anti-apoptosis protein like Bcl-2 downregulated when challenged by DOX, but them were suppressed by SOP. These findings suggested that SOP could alleviate DOX-induced heart injury by suppressing oxidative stress and apoptosis, with molecular mechanism activating of the Nrf2/HO-1 signaling pathway.

DOI: https://doi.org/10.1038/s41598-023-51083-3
Toxicol Appl Pharmacol. 2023 Dec 30. pii: S0041-008X(23)00438-6. [Epub ahead of print]482 116799

NMNATs expression inhibition mediated NAD+ deficiency plays a critical role in doxorubicin-induced hepatotoxicity in mice.

Fang Cheng, Yongtai Zhang, Hongli Xiong, Minzhu Zhao, Qi Wang, Ying Zhu, Yongguo Li, Renkuan Tang, Jianbo Li.

  Doxorubicin (DOX) is one of the most widely used antineoplastic drugs with known cardiotoxicity while other organ toxicity, such as hepatotoxicity is not well defined. This study was to explore the role of nicotinamide adenine dinucleotide (NAD+) in DOX-induced hepatotoxicity. DOX (20 mg/kg) induced acute liver injury and oxidative stress in C57BL/6 J mice at 48 h. Notably, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H dehydrogenase quinone 1 (NQO1) were downregulated. NAD+ deficiency was confirmed due to DOX exposure. Mechanistically, the downregulation of nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1), NMNAT2 and NMNAT3, while no alteration of nicotinamide phosphoribosyl transferase was proved. As a consequence of NAD+ deficiency, the expression of poly-ADP-ribose polymerase1 (PARP1), CD38 and Sirtuin1 (SIRT1) were reduced. Furthermore, supplementation of NAD+ (200 mg/kg/day) or its precursor nicotinamide mononucleotide (NMN) (500 mg/kg/day) alleviated liver injury, attenuated oxidative stress, and elevated the downregulation of Nrf2 and NQO1. More importantly, compromised expression of NMNAT1-3, PARP1, CD38 and SIRT1 were improved by NAD+ and NMN. In conclusion, NAD+ deficiency due to NMNATs expression inhibition may attribute to the pathogenesis of DOX-induced hepatotoxicity, thus providing new insights for mitigating DOX side effects.

Keywords:  Doxorubicin; Hepatotoxicity; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide adenylyl transferase; Oxidative stress

DOI:  https://doi.org/10.1016/j.taap.2023.116799