Limitations of Ferroptosis Inhibitors on the Doxorubicin-Induced Cardiotoxicity Yun-Ji Cha, Sae-Bom Jeon, Chan Joo Lee, Hyeong-Jin Kim, Sun-Ho Lee, Hyoeun Kim, So Hee Park, Elaine Zhelan Chen, Jong Woo Kim, Sahng Wook Park, Chulan Kwon, Boyoung Joung, Eun-Woo Lee, Seunghyun Lee Antioxidants, 2026 Doxorubicin is an anthracycline anticancer drug commonly used to treat lymphoma and breast cancer. Its major side effect is cardiotoxicity, which occurs by damaging cardiomyocytes. The mechanisms of doxorubicin-induced cardiotoxicity remain unclear; however, recent studies suggest that ferroptosis, an iron-dependent form of lipid peroxidation-mediated cell death, may play a key role. In this study, we investigated the role of ferroptosis in doxorubicin-induced cardiotoxicity using ferroptosis-specific inhibitors (ferrostatin-1 and liproxstatin-1). In both H9c2 cardiomyocyte cell lines and human induced pluripotent stem cell-derived cardiomyocytes, ferrostatin-1 and liproxstatin-1 rescued cell death induced by RSL3, a ferroptosis inducer, but failed to prevent doxorubicin-induced cell death. Additionally, the ferroptosis inhibitors did not restore the electrophysiological function of cardiomyocytes, measured using a multi-electrode array system, and instead slightly accelerated cardiomyocyte beating. Finally, doxorubicin-injected mice treated with ferroptosis inhibitors exhibited significantly reduced survival and increased levels of N-terminal pro B-type natriuretic peptide, a biomarker of heart failure. These findings suggest that inhibiting ferroptosis alone is insufficient to mitigate doxorubicin-induced cardiotoxicity.
Establishment of a homozygous LMNA knock-out human induced pluripotent stem cell line using CRISPR/Cas9 system So Hee Park, David Suh, Hyoeun Kim, Ru-Ri Lee, Isabella Leite Coscarella, Jaewon Oh, Sangwoo Kim, Hyoung-Pyo Kim, Chulan Kwon, Chan Joo Lee, Sahng Wook Park, Seunghyun Lee Stem Cell Research, 2025 The LMNA gene encodes lamin A/C, essential components of the nuclear envelope that play crucial roles in maintaining nuclear architecture, mechanotransduction, and gene regulation. LMNA mutations are linked to laminopathies, affecting multiple organ systems, including muscle, adipose tissue, and the cardiovascular system. To investigate LMNA-related disorders, we generated a human-induced pluripotent stem cell (hiPSC) line with a homozygous LMNA frameshift mutation (c.351_352insA) using CRISPR/Cas9 genome editing. The edited hiPSCs retained normal colony morphology and expressed key pluripotency markers. This LMNA knockout hiPSC line provides a valuable model for studying lamin A/C functions in nuclear integrity, cellular homeostasis, and disease pathogenesis.
Generation of an induced pluripotent stem cell line from a patient with arrhythmogenic right ventricular cardiomyopathy harboring a TMEM43 splice-site variant Sun-Ho Lee, Gibbeum Lim, Hyoeun Kim, David Suh, Hyo-Kyoung Choi, Hyoung-Pyo Kim, Ho-Geun Yoon, Sahng Wook Park, Seok-Min Kang, Chulan Kwon, Jaewon Oh, Seung-Hyun Lee Stem Cell Research, 2024 Arrhythmogenic cardiomyopathy (ACM) is a cardiomyopathy that is predominantly inherited and characterized by cardiac arrhythmias and structural abnormalities. TMEM43 (transmembrane protein 43) is one of the well-known genetic culprits behind ACM. In this study, we successfully generated an induced pluripotent stem cell (iPSC) line, YCMi010-A, derived from a male patient diagnosed with ACM. Although these iPSCs harbored a heterozygous intronic splice variant, TMEM43 c.443-2A > G, they still displayed normal cellular morphology and were confirmed to express pluripotency markers. YCMi010-A iPSC line is a promising model for investigating the pathomechanisms associated with ACM and exploring potential therapeutic strategies.
Inhibition of TBL1 cleavage alleviates doxorubicin-induced cardiomyocytes death by regulating the Wnt/β-catenin signal pathway Sun-Ho Lee, Jangho Lee, Jaewon Oh, Jin-Taek Hwang, Hae-Jeung Lee, Hwa Kyung Byun, Hyeong-Jin Kim, David Suh, Ho-Geun Yoon, Sahng Wook Park, Seok-Min Kang, Chulan Kwon, Seung-Hyun Lee, Hyo-Kyoung Choi Cardiovascular Research, 2024 Aims Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. Methods and results We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites—D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with β-catenin. As a result, Wnt reporter activity and Wnt target gene expression collectively indicate a decrease in Wnt/β-catenin signalling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. Conclusion Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.
Human induced pluripotent stem cell line YCMi007-A generated from a dilated cardiomyopathy patient with a heterozygous dominant c.613C > T (p. Arg205Trp) variant of the TNNT2 gene Sae-Bom Jeon, Hyoeun Kim, Kyeong-Hyeon Chun, Jaewon Oh, Chulan Kwon, Hyo-Kyoung Choi, Sangwoo Kim, Hyoung-Pyo Kim, In-Cheol Kim, Jung-Yoon Yoo, Sahng Wook Park, Seok-Min Kang, Seung-Hyun Lee Stem Cell Research, 2023 Cardiac muscle troponin T protein binds to tropomyosin and regulates the calcium-dependent actin-myosin interaction on thin filaments in cardiomyocytes. Recent genetic studies have revealed that TNNT2 mutations are strongly linked to dilated cardiomyopathy (DCM). In this study, we generated YCMi007-A, a human induced pluripotent stem cell (hiPSC) line from a DCM patient with a p. Arg205Trp mutation in the TNNT2 gene. The YCMi007-A cells show high expression of pluripotent markers, normal karyotype, and differentiation into three germ layers. Thus, YCMi007-A-an established iPSC-could be useful for the investigation of DCM.
An induced pluripotent stem cell line (YCMi006-A) generated from a patient with hypertrophic cardiomyopathy who carries the ACTA1 mutation p.Ile343Met Hyoeun Kim, Hyeong-Jin Kim, Jaewon Oh, Seung-Tae Lee, Dongju Won, Hyo-Kyoung Choi, Jong Rak Choi, Sangwoo Kim, Hyoung-Pyo Kim, Seok-Jun Kim, Sahng Wook Park, Seok-Min Kang, Seung-Hyun Lee Stem Cell Research, 2022 Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease and is characterized by hypertrophy of the left ventricle. We reprogrammed peripheral blood mononuclear cells (PBMCs) from a HCM patient into pluripotent stem cells (iPSC) (YCMi006-A) carrying a heterozygous c.1029C > G mutation in ACTA1. The YCMi006-A cells expressed high levels of pluripotent markers, had a normal 46XX karyotype and demonstrated the capacity to differentiate into derivatives of all three germ layers. This cell line can be a valuable tool for investigating the pathogenesis of HCM.
Derivation of YCMi005-A, a human-induced pluripotent stem cell line, from a patient with dilated cardiomyopathy carrying missense variant in TPM1 (p. Glu192Lys) Yun-Ji Cha, Sae-Bom Jeon, Jaewon Oh, Seung-Tae Lee, Sangwoo Kim, Hyoeun Kim, Jungyoon Choi, Hyo-Kyoung Choi, Dongju Won, Jong Rak Choi, Seok-Jun Kim, Sahng Wook Park, Seok-Min Kang, Seung-Hyun Lee Stem Cell Research, 2022 Dilated cardiomyopathy (DCM) is one of the leading causes of heart transplantation. The clinical feature of DCM is characterized by enlarged heart and impaired function of the left or both ventricles, while its etiology is varied. In this study, we generated YCMi005-A, a human-induced pluripotent stem cell (hiPSC) line from a patient with DCM carrying the missense mutation of p.Glu192Lys in the TPM1 genes. YCMi005-A, an established hiPSC, showed the normal karyotype (46, XX) and high expression of pluripotency markers. In addition, it was confirmed that YCMi005-A has the differentiation potential assessed by staining of three germ layer markers.
Generation of a human induced pluripotent stem cell line YCMi004-A from a patient with dilated cardiomyopathy carrying a protein-truncating mutation of the Titin gene and its differentiation towards cardiomyocytes Sun-Ho Lee, Jaewon Oh, Seung-Tae Lee, Dongju Won, Sangwoo Kim, Hyo-Kyoung Choi, Seok-Jun Kim, Hyunho Han, Minjae Yoon, Jong Rak Choi, Ho-Geun Yoon, Sahng Wook Park, Seok-Min Kang, Seung-Hyun Lee Stem Cell Research, 2022 Dilated cardiomyopathy (DCM) is a heart muscle disease that causes heart failure and is the leading cause for heart transplantation. It is a heart muscle disease resulted from a variety of genetics, toxic, metabolic, and infectious causes. One of the most prevalent genetic causes of DCM is a protein-truncating variant in the Titin gene (TTNtv). We have generated a human-induced pluripotent stem cell (hiPSC) line from patients who underwent heart transplantation due to DCM carrying a TTNtv mutation (c.70051C > T, p.Arg23351Ter) at the age of 20. The generated hiPSCs showed normal karyotype (46, XY) and expression of pluripotency markers, and were differentiated towards cardiomyocytes successfully.
Inhibition of STAT5A promotes osteogenesis by DLX5 regulation Kyoung-Mi Lee, Kwang Hwan Park, Ji Suk Hwang, Moses Lee, Dong Suk Yoon, Hyun Aae Ryu, Ho Sun Jung, Ki Won Park, Jihyun Kim, Sahng Wook Park, Sung-Hwan Kim, Yong-Min Chun, Woo Jin Choi, Jin Woo Lee Cell Death and Disease, 2018
Lipin1 regulates PPARγ transcriptional activity Hee Eun Kim, Eunju Bae, Deok-yoon Jeong, Min-Ji Kim, Won-Ji Jin, Sahng-Wook Park, Gil-Soo Han, George M. Carman, Eunjin Koh, Kyung-Sup Kim Biochemical Journal, 2013
Resveratrol downregulates acetyl-CoA carboxylase α and fatty acid synthase by AMPK-mediated downregulation of mTOR in breast cancer cells Food Science and Biotechnology, 2008
