Seokhyeong Go1, Mikyung Kang1, Sung Pil Kwon2, Mungyo Jung2, Ok Hee Jeon3, Byung-Soo Kim4,5,6. 1. Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea. 2. School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea. 3. Department of Biomedical Sciences, BK21 Graduate Program, Korea University of College of Medicine, Seoul, 02841, Republic of Korea. ojeon@korea.ac.kr. 4. Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea. byungskim@snu.ac.kr. 5. School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea. byungskim@snu.ac.kr. 6. Institute of Chemical Processes, Institute of Engineering Research, and BioMAX, Seoul National University, Seoul, 08826, Republic of Korea. byungskim@snu.ac.kr.
Abstract
BACKGROUND: Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis. METHODS: Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining. RESULTS: At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells. CONCLUSION: The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.
BACKGROUND: Ferroptosis is an iron-dependent, non-apoptotic programmed cell death. Cellular senescence contributes to aging and various age-related diseases through the expression of a senescence-associated secretory phenotype (SASP). Senescent cells are often resistant to ferroptosis via increased ferritin and impaired ferritinophagy. In this study, we investigated whether treatment with JQ1 could remove senescent cells by inducing ferroptosis. METHODS: Senescence of human dermal fibroblasts was induced in vitro by treating the cells with bleomycin. The senolytic effects of JQ1 were evaluated using a SA-β gal assay, annexin V analysis, cell counting kit-8 assay, and qRT-PCR. Ferroptosis following JQ1 treatment was evaluated with qRT-PCR and BODIPY staining. RESULTS: At a certain range of JQ1 concentrations, JQ1 treatment reduced the viability of bleomycin-treated cells (senescent cells) but did not reduce that of untreated cells (non-senescent cells), indicating that JQ1 treatment can selectively eliminate senescent cells. JQ1 treatment also decreased SASP expression only in senescent cells. Subsequently, JQ1 treatment reduced the expression of ferroptosis-resistance genes in senescent cells. JQ1 treatment induced lipid peroxidation in senescent cells but not in non-senescent cells. CONCLUSION: The data indicate that JQ1 can eliminate senescent cells via ferroptosis. This study suggests ferroptosis as a new mechanism of senolytic therapy.
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