bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2024–04–21
twelve papers selected by
Caner Geyik, Istinye University
  1. Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer.
  2. Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.
  3. Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2-related factor 2 (Nrf2).
  4. Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors.
  5. Prevalence and Associations of Co-occurrence of NFE2L2 Mutations and Chromosome 3q26 Amplification in Lung Cancer.
  6. Therapeutic Targeting of Thioredoxin Reductase 1 Causes Ferroptosis while Potentiating Anti-PD-1 Efficacy in Head and Neck Cancer.
  7. Machine Learning of Three-Dimensional Protein Structures to Predict the Functional Impacts of Genome Variation.
  8. The crosstalk between oncogenic signaling and ferroptosis in cancer.
  9. Icariin‑curcumol promotes ferroptosis in prostate cancer cells through Nrf2/HO‑1 signaling.
  10. Hesperidin activates Nrf2 to protect cochlear hair cells from cisplatin-induced damage.
  11. Human mesenchymal stem cells derived exosomes improve ovarian function in chemotherapy-induced premature ovarian insufficiency mice by inhibiting ferroptosis through Nrf2/GPX4 pathway.
  12. Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection.
  1. Front Oncol. 2024 ;14 1381467
    Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer.
    Feilong Chen, Mei Xiao, Shaofan Hu, Meng Wang.
      The Keap1-Nrf2 signaling pathway is a major regulator of the cytoprotective response, participating in endogenous and exogenous stress caused by ROS (reactive oxygen species). Nrf2 is the core of this pathway. We summarized the literature on Keap1-Nrf2 signaling pathway and summarized the following three aspects: structure, function pathway, and cancer and clinical application status. This signaling pathway is similar to a double-edged sword: on the one hand, Nrf2 activity can protect cells from oxidative and electrophilic stress; on the other hand, increasing Nrf2 activity can enhance the survival and proliferation of cancer cells. Notably, oxidative stress is also considered a marker of cancer in humans. Keap1-Nrf2 signaling pathway, as a typical antioxidant stress pathway, is abnormal in a variety of human malignant tumor diseases (such as lung cancer, liver cancer, and thyroid cancer). In recent years, research on the Keap1-Nrf2 signaling pathway has become increasingly in-depth and detailed. Therefore, it is of great significance for cancer prevention and treatment to explore the molecular mechanism of the occurrence and development of this pathway.
    Keywords:  Keap1; Nrf2; cancer; clinical; function; prevention; structure; transcriptional regulation
    DOI:  https://doi.org/10.3389/fonc.2024.1381467
  2. Ann Hematol. 2024 Apr 17.
    Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia.
    Daniel Zechariah Paul Jebanesan, Raveen Stephen Stallon Illangeswaran, Bharathi M Rajamani, Rakhi Thalayattu Vidhyadharan, Saswati Das, Nayanthara K Bijukumar, Balaji Balakrishnan, Vikram Mathews, Shaji R Velayudhan, Poonkuzhali Balasubramanian.
      De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide (ATO) used in the treatment of acute promyelocytic leukemia (APL) has been reported to be effective in degrading the FLT3 protein in AML cell lines and sensitizing non-APL AML patient samples in-vitro. We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples. We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2 expression, nuclear localization, and upregulation of bonafide NRF2 targets. Molecular inhibition of NRF2 in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.
    Keywords:  AML; Acquired chemoresistance; Arsenic trioxide; Digoxin; FLT3-ITD; NRF2
    DOI:  https://doi.org/10.1007/s00277-024-05742-8
  3. J Biochem Mol Toxicol. 2024 Apr;38(4): e23689
    Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2-related factor 2 (Nrf2).
    Xingyuan Wang, Jing Yang, Dechao Li, Lichen Teng, Yongsheng Chen, Jie Meng, Chen Yang, Zhihao Yin, Changfu Li.
      Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20 μM Pazopanib, respectively. Cellular senescence was measured using senescence-associated β-galactosidase (SA-β-Gal) staining. Western blot analysis and real-time polymerase chain reaction were used to measure the mRNA and protein expression of nuclear factor E2-related factor 2 (Nrf2), γH2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress  by increasing the production of reactive oxygen species, reducing the levels of glutathione peroxidase, and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of γH2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad- Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2.
    Keywords:  DNA damage; Nrf2; Pazopanib; cellular senescence; p53; renal cell carcinoma
    DOI:  https://doi.org/10.1002/jbt.23689
  4. Acta Neuropathol Commun. 2024 Apr 18. 12(1): 61
    Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors.
    Yijun Cheng, Yuting Dai, Hao Tang, Xingyu Lu, Jing Xie, Wanqun Xie, Qianqian Zhang, Yanting Liu, Shaojian Lin, Hong Yao, Hanbing Shang, Kun Yang, Hongyi Liu, Xuefeng Wu, Jianming Zhang, Xun Zhang, Li Xue, Zhe Bao Wu.
      We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.
    Keywords:  HDACIs; High-throughput screening; Nrf2; Panobinostat; PitNETs
    DOI:  https://doi.org/10.1186/s40478-024-01775-2
  5. Glob Med Genet. 2024 Jun;11(2): 150-158
    Prevalence and Associations of Co-occurrence of NFE2L2 Mutations and Chromosome 3q26 Amplification in Lung Cancer.
    Jinfeng Liu, Sijie Liu, Dan Li, Hongbin Li, Fan Zhang.
      Background   NFE2L2 (nuclear factor erythroid-2-related factor-2) encodes a basic leucine zipper (bZIP) transcription factor and exhibits variations in various tumor types, including lung cancer. In this study, we comprehensively investigated the impact of simultaneous mutations on the survival of NFE2L2 -mutant lung cancer patients within specific subgroups. Methods  A cohort of 1,103 lung cancer patients was analyzed using hybridization capture-based next-generation sequencing. Results  The NFE2L2 gene had alterations in 3.0% (33/1,103) of lung cancer samples, including 1.5% (15/992) in adenocarcinoma and 16.2% (18/111) in squamous cell carcinoma. Thirty-four variations were found, mainly in exons 2 (27/34). New variations in exon 2 (p.D21H, p.V36_E45del, p.F37_E45del, p.R42P, p.E67Q, and p.L76_E78delinsQ) were identified. Some patients had copy number amplifications. Co-occurrence with TP53 (84.8%), CDKN2A (33.3%), KMT2B (33.3%), LRP1B (33.3%), and PIK3CA (27.3%) mutations was common. Variations of NFE2L2 displayed the tightest co-occurrence with IRF2 , TERC , ATR , ZMAT3 , and SOX2 ( p  < 0.001). In The Cancer Genome Atlas Pulmonary Squamous Carcinoma project, patients with NFE2L2 variations and 3q26 amplification had longer median survival (63.59 vs. 32.04 months, p  = 0.0459) and better overall survival. Conclusions   NFE2L2 mutations display notable heterogeneity in lung cancer. The coexistence of NFE2L2 mutations and 3q26 amplification warrants in-depth exploration of their potential clinical implications and treatment approaches for affected patients.
    Keywords:  3q36 amplification; NFE2L2; co-occurrence mutations; lung cancer; next-generation sequencing
    DOI:  https://doi.org/10.1055/s-0044-1786004
  6. Chem Biol Interact. 2024 Apr 16. pii: S0009-2797(24)00150-9. [Epub ahead of print] 111004
    Therapeutic Targeting of Thioredoxin Reductase 1 Causes Ferroptosis while Potentiating Anti-PD-1 Efficacy in Head and Neck Cancer.
    Ming-Shou Hsieh, Hang Huong Ling, Syahru Agung Setiawan, Mardiah Suci Hardianti, Iat-Hang Fong, Chi-Tai Yeh, Jia-Hong Chen.
      Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin, which inhibits thioredoxin reductase (TrxR) through its gold-based composition, has shown potential in cancer treatment. It targets the TrxR system, essential for safeguarding cells from oxidative stress. The overproduction of TrxR in cancerous cells supports their proliferation. However, auranofin's interference with this system can upset the cellular redox equilibrium, boost levels of reactive oxygen species, and trigger the death of cancer cells. This study is the first to highlight TXNRD1 as a crucial factor contributing to resistance to anti-PD-1 treatment in HNSCC. In this study, we identified targetable regulators of resistance to immunotherapy-induced ferroptosis in HNSCC. We observed a link of thioredoxin reductase 1 (TXNRD1) with tumoral PD-L1 expression and ferroptosis suppression in HNSCC. Moreover, HNSCC tumors with aberrant TXNRD1 expression exhibited a lack of PD-1 response, NRF2 overexpression, and PD-L1 upregulation. TXNRD1 inhibition promoted ferroptosis in HNSCC cells with NRF2 activation and in organoid tumors derived from patients lacking a PD-1 response. Mechanistically, TXNRD1 regulated PD-L1 transcription and maintained the redox balance by binding to ribonucleotide reductase regulatory subunit M2 (RRM2). TXNRD1 expression disruption sensitized HNSCC cells to anti-PD-1-mediated Jurkat T-cell activation, promoting tumor killing through ferroptosis. Moreover, TXNRD1 inhibition through auranofin cotreatment synergized with anti-PD-1 therapy to potentiate immunotherapy-mediated ferroptosis by mediating CD8+ T-cell infiltration and downregulating PD-L1 expression. Our findings indicate that targeting TXNRD1 is a promising therapeutic strategy for improving immunotherapy outcomes in patients with HNSCC.
    Keywords:  Ferroptosis; HNSCC; Immunotherapy; NRF2; Pembrolizumab; TXNRD1
    DOI:  https://doi.org/10.1016/j.cbi.2024.111004
  7. J Chem Inf Model. 2024 Apr 18.
    Machine Learning of Three-Dimensional Protein Structures to Predict the Functional Impacts of Genome Variation.
    Kriti Shukla, Kelvin Idanwekhai, Martin Naradikian, Stephanie Ting, Stephen P Schoenberger, Elizabeth Brunk.
      Research in the human genome sciences generates a substantial amount of genetic data for hundreds of thousands of individuals, which concomitantly increases the number of variants of unknown significance (VUS). Bioinformatic analyses can successfully reveal rare variants and variants with clear associations with disease-related phenotypes. These studies have had a significant impact on how clinical genetic screens are interpreted and how patients are stratified for treatment. There are few, if any, computational methods for variants comparable to biological activity predictions. To address this gap, we developed a machine learning method that uses protein three-dimensional structures from AlphaFold to predict how a variant will influence changes to a gene's downstream biological pathways. We trained state-of-the-art machine learning classifiers to predict which protein regions will most likely impact transcriptional activities of two proto-oncogenes, nuclear factor erythroid 2 (NFE2L2)-related factor 2 (NRF2) and c-Myc. We have identified classifiers that attain accuracies higher than 80%, which have allowed us to identify a set of key protein regions that lead to significant perturbations in c-Myc or NRF2 transcriptional pathway activities.
    DOI:  https://doi.org/10.1021/acs.jcim.3c01967
  8. Crit Rev Oncol Hematol. 2024 Apr 16. pii: S1040-8428(24)00092-1. [Epub ahead of print]197 104349
    The crosstalk between oncogenic signaling and ferroptosis in cancer.
    Qianghu Pang, Zhirou Tang, Lianxiang Luo.
      Ferroptosis, a novel form of cell death regulation, was identified in 2012. It is characterized by unique features that differentiate it from other types of cell death, including necrosis, apoptosis, autophagy, and pyroptosis. Ferroptosis is defined by an abundance of iron ions and lipid peroxidation, resulting in alterations in subcellular structures, an elevation in reactive oxygen species (ROS), a reduction in glutathione (GSH) levels, and an augmentation in Fe (II) cytokines. Ferroptosis, a regulated process, is controlled by an intricate network of signaling pathways, where multiple stimuli can either enhance or hinder the process. This review primarily examines the defensive mechanisms of ferroptosis and its interaction with the tumor microenvironment. The analysis focuses on the pathways that involve AMPK, p53, NF2, mTOR, System Xc-, Wnt, Hippo, Nrf2, and cGAS-STING. The text discusses the possibilities of employing a combination therapy that targets several pathways for the treatment of cancer. It emphasizes the necessity for additional study in this field.
    Keywords:  ferroptosis; oncogenic signaling; oxidative stress; redox homeostasis; tumor
    DOI:  https://doi.org/10.1016/j.critrevonc.2024.104349
  9. Exp Ther Med. 2024 May;27(5): 232
    Icariin‑curcumol promotes ferroptosis in prostate cancer cells through Nrf2/HO‑1 signaling.
    Wen Sheng, Bonan Li, Tiansong Sun, Congxu Zhu, Yingqiu Li, Wenjing Xu.
      Ferroptosis is a form of regulatory cell death that relies on iron and reactive oxygen species (ROS) to inhibit tumors. The present study aimed to investigate whether icariin-curcumol could be a novel ferroptosis inducer in tumor inhibition. Various concentrations of icariin-curcumol were used to stimulate prostate cell lines (RWPE-2, PC-3, VCAP and DU145). Small interfering negative control (si-NC) and si-nuclear factor erythroid 2-related factor 2 (Nrf2) were used to transfect DU145 cells. Cell viability was determined by using cell counting kit-8. Ferroptosis-related factor levels were analyzed using western blotting and reverse transcription-quantitative PCR. Enzyme-linked immunosorbent assays were used to assess the ferrous (Fe2+), glutathione and malondialdehyde (MDA) content. The ROS fluorescence intensity was assessed using flow cytometry. DU145 cells were most sensitive to icariin-curcumol concentration. The Fe2+ content, ROS fluorescence intensity and MDA level gradually increased, while solute carrier family 7 member 11 (SLC7A11) level, glutathione peroxidase 4 (GPX4) level, GSH content, Nrf2 and heme oxygenase-1 (HO-1) decreased with icariin-curcumol in a dose-dependent manner. After si-Nrf2 was transfected, the cell proliferation ability, SLC7A11 and GPX4 levels declined compared with the si-NC group. In contrast to the control group, the icariin + curcumol group showed reductions in Nrf2 and HO-1 levels, cell proliferation, SLC7A11 and GPX4 levels, with an increase in Fe2+ content and ROS fluorescence intensity. Overexpression of Nrf2 reversed the regulation observed in the icariin + curcumol group. Icariin-curcumol induced ferroptosis in PCa cells, mechanistically by inhibiting the Nrf2/HO-1 signaling pathway. Icariin-curcumol could be used as a new type of ferroptosis inducer to treat PCa effectively.
    Keywords:  ferroptosis; icariin-curcumol; nuclear factor erythroid 2-related factor 2/heme oxygenase-1; prostate cancer
    DOI:  https://doi.org/10.3892/etm.2024.12519
  10. Redox Rep. 2024 Dec;29(1): 2341470
    Hesperidin activates Nrf2 to protect cochlear hair cells from cisplatin-induced damage.
    Jintao Lou, Fan Wu, Wuhui He, Rui Hu, Ziyi Cai, Guisheng Chen, Wenji Zhao, Zhigang Zhang, Yu Si.
      Cisplatin is widely employed in clinical oncology as an anticancer chemotherapy drug in clinical practice and is known for its severe ototoxic side effects. Prior research indicates that the accumulation of reactive oxygen species (ROS) plays a pivotal role in cisplatin's inner ear toxicity. Hesperidin is a flavanone glycoside extracted from citrus fruits that has anti-inflammatory and antioxidant effects. Nonetheless, the specific pharmacological actions of hesperidin in alleviating cisplatin-induced ototoxicity remain elusive. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical mediator of the cellular oxidative stress response, is influenced by hesperidin. Activation of Nrf2 was shown to have a protective effect against cisplatin-induced ototoxicity. The potential of hesperidin to stimulate Nrf2 in attenuating cisplatin's adverse effects on the inner ear warrants further investigation. This study employs both in vivo and in vitro models of cisplatin ototoxicity to explore this possibility. Our results reveal that hesperidin mitigates cisplatin-induced ototoxicity by activating the Nrf2/NQO1 pathway in sensory hair cells, thereby reducing ROS accumulation, preventing hair cell apoptosis, and alleviating hearing loss.
    Keywords:  Cisplatin; Nrf2; ROS; apoptosis; hearing loss; hesperidin; ototoxicity; sensory hair cells
    DOI:  https://doi.org/10.1080/13510002.2024.2341470
  11. J Ovarian Res. 2024 Apr 15. 17(1): 80
    Human mesenchymal stem cells derived exosomes improve ovarian function in chemotherapy-induced premature ovarian insufficiency mice by inhibiting ferroptosis through Nrf2/GPX4 pathway.
    Yuan Zhou, Jinfa Huang, Lingling Zeng, Qian Yang, Fangjuan Bai, Qiqing Mai, Kaixian Deng.
       BACKGROUND: Chemotherapy exposure has become a main cause of premature ovarian insufficiency (POI). This study aimed to evaluate the role and molecular mechanism of human umbilical cord mesenchymal stem cell-derived exosomes (hUMSC-Exos) in ovarian function protection after chemotherapy.
    METHODS: hUMSC-Exos were applied to cyclophosphamide-induced premature ovarian insufficiency mice and human ovarian granulosa tumor cells (KGN) to determine their effects on follicular development and granulosa cell apoptosis. Evaluation was done for iron ion and reactive oxygen species (ROS) production, lipid peroxidation levels, and changes in iron death-related molecules (nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Glutathione Peroxidase enzyme 4 (GPX4), and Solute carrier family 7 member 11 cystine glutamate transporter (SLC7A11; xCT)). Furthermore, rescue experiments using an Nrf2 inhibitor were performed to assess the therapeutic effects of hUMSC-Exos on granulosa cells.
    RESULTS: hUMSC-Exos promoted ovarian hormone levels and primary follicle development in POI mice and reduced granulosa cell apoptosis. After hUMSC-Exos treatment, the ROS production, free iron ions and lipid peroxidation levels of granulosa cells decreased, and the iron death marker proteins Nrf2, xCT and GPX4 also decreased. Furthermore, the Nrf2 inhibitor ML385 significantly attenuated the effects of hUMSC-Exos on granulosa cells.
    CONCLUSION: hUMSC-Exos inhibit ferroptosis and protect against CTX-induced ovarian damage and granulosa cell apoptosis through the Nrf2/GPX4 signaling pathway, revealing a novel mechanism of hUMSC-Exos in POI therapy.
    Keywords:  Chemotherapy; Exosomes derived from stem cells; Ferroptosis; Nrf2/GPX4 pathway; Ovarian dysfunction
    DOI:  https://doi.org/10.1186/s13048-024-01403-6
  12. Phytomedicine. 2024 Apr 12. pii: S0944-7113(24)00292-7. [Epub ahead of print]129 155633
    Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection.
    Ji-Hye Song, Min-Sun Kim, Seung-Hyun Lee, Jin-Taek Hwang, Soo-Hyun Park, Sahng Wook Park, Sae-Bom Jeon, Ru-Ri Lee, Jangho Lee, Hyo-Kyoung Choi.
       BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity.
    PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT).
    METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death.
    RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs.
    CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.
    Keywords:  Cardiac functions; Cirsium setidens; Doxorubicin-induced cardiotoxicity; Human induced pluripotent stem cell; Oxidative stress
    DOI:  https://doi.org/10.1016/j.phymed.2024.155633
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