Hemin-induced transient senescence via DNA damage response: a neuroprotective mechanism against ferroptosis in intracerebral hemorrhage
Open accessPublished version of a preprint
Abstract
Intracerebral hemorrhage (ICH) poses acute fatality and long-term neurological risks due to hemin and iron accumulation from hemoglobin breakdown. Our observation that hemin induces DNA double-strand breaks (DSBs), prompting a senescence-like phenotype in neurons, necessitating deeper exploration of cellular responses. Using experimental ICH models and human ICH patient tissue, we elucidate hemin-mediated DNA damage response (DDR) inducing transient senescence and delayed expression of heme oxygenase (HO-1). HO-1 co-localizes with senescence-associated β-Galactosidase (SA-β-Gal) in ICH patient tissues, emphasizing clinical relevance of inducible HO-1 expression in senescent cells. We reveal a reversible senescence state protective against acute cell death by hemin, while repeat exposure leads to long-lasting senescence. Inhibiting early senescence expression increases cell death, supporting the protective role of senescence against hemin toxicity. Hemin-induced senescence is attenuated by a pleiotropic carbon nanoparticle that is a catalytic mimic of superoxide dismutase, but this treatment increased lipid peroxidation, consistent with ferroptosis from hemin breakdown released iron. When coupled with iron chelator deferoxamine (DEF), the nanoparticle reduces hemin-induced senescence and upregulates factors protecting against ferroptosis. Our study suggests transient senescence induced by DDR as an early potential neuroprotective mechanism in ICH, but the risk or iron-related toxicity supports a multi-pronged therapeutic approach.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691 · see citing works
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · see citing works
Geroscience: Linking Aging to Chronic Disease
Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., Franceschi, C., Lithgow, G. J., Morimoto, R. I., Pessin, J. E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.039 · Cited by 2,764 · see citing works
van Asch, C. J. J., Luitse, M. J. A., Rinkel, G. J. E., van der Tweel, I., Algra, A., & Klijn, C. J. M. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70340-0 · Cited by 2,676 · see citing works
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · cited 1× · see citing works
“The progression to long-lasting senescencecancreateapro-in fl ammatoryenvironmentthatnotonlycauses damage to neighboring cells through paracrine senescence, but also drives chronic low-grade in fl ammation within the brain 41 – 43 .”
Gene regulation and DNA damage in the ageing human brain
Lu, T., Pan, Y., Kao, S.-Y., Li, C., Kohane, I., Chan, J., & Yankner, B. A. (2004) · Nature · doi:10.1038/nature02661 · Cited by 1,874 · see citing works
The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase.
Tenhunen, R., Marver, H. S., & Schmid, R. (1968) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.61.2.748 · Cited by 1,803 · see citing works
Qureshi, A. I., Mendelow, A. D., & Hanley, D. F. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60371-8 · Cited by 1,526 · see citing works
Reversal of human cellular senescence: roles of the p53 and p16 pathways
Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg417 · Cited by 1,457 · see citing works
Senescent intimal foam cells are deleterious at all stages of atherosclerosis
Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016) · Science · doi:10.1126/science.aaf6659 · Cited by 1,195 · see citing works
Cellular senescence: the good, the bad and the unknown
Huang, W., Hickson, L. J., Eirin, A., Kirkland, J. L., & Lerman, L. O. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00601-z · Cited by 1,150 · see citing works
Epidemiology, Risk Factors, and Clinical Features of Intracerebral Hemorrhage: An Update
An, S. J., Kim, T. J., & Yoon, B. W. (2017) · Journal of Stroke · doi:10.5853/jos.2016.00864 · Cited by 1,020 · see citing works
Stein, G. H., Drullinger, L. F., Soulard, A., & Dulić, V. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.2109 · Cited by 868 · see citing works
Krishnamurthi, R., Ikeda, T., & Feigin, V. L. (2020) · Neuroepidemiology · doi:10.1159/000506396 · Cited by 757 · see citing works
Cerebral Hemorrhage: Pathophysiology, Treatment, and Future Directions
Magid-Bernstein, J. R., Girard, R., Polster, S. P., Srinath, A., Romanos, S. G., Awad, I. A., & Sansing, L. H. (2022) · Circulation Research · doi:10.1161/circresaha.121.319949 · Cited by 707 · see citing works
RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer
Sui, X., Zhang, R., Liu, S., Duan, T., Zhai, L., Zhang, M., Han, X., Xiang, Y., Huang, X., Lin, H., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01371 · Cited by 703 · see citing works
Doré, S., Takahashi, M., Ferris, C. D., Hester, L. D., Guastella, D. B., & Snyder, S. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.5.2445 · Cited by 699 · see citing works
Stroke injury, cognitive impairment and vascular dementia
Kalaria, R. N., Akinyemi, R., & Ihara, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.01.015 · Cited by 647 · see citing works
Impaired immune surveillance accelerates accumulation of senescent cells and aging
Ovadya, Y., Landsberger, T., Leins, H., Vadai, E., Gal, H., Biran, A., Yosef, R., Sagiv, A., Agrawal, A., Shapira, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07825-3 · Cited by 578 · see citing works
Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives
Baker, D. J., & Petersen, R. C. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95145 · Cited by 514 · see citing works
Chen, L., Hambright, W. S., Na, R., & Ran, Q. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.680090 · Cited by 498 · see citing works
Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage
Pradilla, G., Ratcliff, J. J., Hall, A. J., Saville, B. R., Allen, J. W., Paulon, G., McGlothlin, A. E., Lewis, R. J., Fitzgerald, M., Caveney, A. F., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2308440 · Cited by 465 · see citing works
Masaldan, S., Clatworthy, S. A. S., Gamell, C., Meggyesy, P. M., Rigopoulos, A.-T., Haupt, S., Haupt, Y., Denoyer, D., Adlard, P. A., Bush, A. I., et al. (2018) · Redox Biology · doi:10.1016/j.redox.2017.08.015 · Cited by 452 · see citing works
Ma, L., Hu, X., Song, L., Chen, X., Ouyang, M., Billot, L., Li, Q., Malavera, A., Li, X., Venturelli, P. M., et al. (2023) · The Lancet · doi:10.1016/s0140-6736(23)00806-1 · Cited by 418 · see citing works
Targeting secondary injury in intracerebral haemorrhage—perihaematomal oedema
Urday, S., Kimberly, W. T., Beslow, L. A., Vortmeyer, A. O., Selim, M. H., Rosand, J. M., Simard, J. M., & Sheth, K. N. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.264 · Cited by 277 · see citing works
Role of Inflammatory Processes in Hemorrhagic Stroke
Ohashi, S. N., DeLong, J. H., Kozberg, M. G., Mazur-Hart, D. J., van Veluw, S. J., Alkayed, N. J., & Sansing, L. H. (2023) · Stroke · doi:10.1161/strokeaha.122.037155 · Cited by 217 · see citing works
Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype
Maus, M., López-Polo, V., Mateo, L., Lafarga, M., Aguilera, M., De Lama, E., Meyer, K., Sola, A., Lopez-Martinez, C., López-Alonso, I., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00928-2 · Cited by 215 · see citing works
Highly efficient conversion of superoxide to oxygen using hydrophilic carbon clusters
Samuel, E. L. G., Marcano, D. C., Berka, V., Bitner, B. R., Wu, G., Potter, A., Fabian, R. H., Pautler, R. G., Kent, T. A., Tsai, A.-L., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417047112 · Cited by 214 · see citing works
Self-citationHemoglobin-Induced Cytotoxicity in Rat Cerebral Cortical Neurons
Wang, X., Mori, T., Sumii, T., & Lo, E. H. (2002) · Stroke · doi:10.1161/01.str.0000020121.41527.5d · Cited by 202 · see citing works
Hemin toxicity: a preventable source of brain damage following hemorrhagic stroke
Robinson, S. R., Dang, T. N. T., Dringen, R., & Bishop, G. M. (2009) · Redox Report · doi:10.1179/135100009x12525712409931 · Cited by 193 · see citing works
Babu, R., Bagley, J. H., Di, C., Friedman, A. H., & Adamson, C. (2012) · Neurosurgical FOCUS · doi:10.3171/2012.1.focus11366 · Cited by 193 · see citing works
Astrocyte senescence promotes glutamate toxicity in cortical neurons
Limbad, C., Oron, T. R., Alimirah, F., Davalos, A. R., Tracy, T. E., Gan, L., Desprez, P.-Y., & Campisi, J. (2020) · PLOS ONE · doi:10.1371/journal.pone.0227887 · Cited by 183 · see citing works
Qureshi, A. I., Mohammad, Y. M., Yahia, A. M., Suárez, J. I., Siddiqui, A. M., Kirmani, J. F., Suri, M. F. K., Kolb, J. C., & Zaidat, O. O. (2005) · Journal of Intensive Care Medicine · doi:10.1177/0885066604271619 · Cited by 157 · see citing works
Brain heme oxygenase isoenzymes and nitric oxide synthase are co-localized in select neurons
Vincent, S. R., Das, S., & Maines, M. D. (1994) · Neuroscience · doi:10.1016/0306-4522(94)90018-3 · Cited by 149 · see citing works
Brain iron overload following intracranial haemorrhage
Garton, T. P., Keep, R. F., Hua, Y., & Xi, G. (2016) · Stroke and Vascular Neurology · doi:10.1136/svn-2016-000042 · Cited by 131 · see citing works
Are there roles for brain cell senescence in aging and neurodegenerative disorders?
Tan, F. C. C., Hutchison, E. R., Eitan, E., & Mattson, M. P. (2014) · Biogerontology · doi:10.1007/s10522-014-9532-1 · Cited by 116 · see citing works
Mallah, K., Couch, C., Borucki, D. M., Toutonji, A., Alshareef, M., & Tomlinson, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02021 · Cited by 103 · see citing works
Zhang, Z., Song, Y., Zhang, Z., Li, D., Zhu, H., Liang, R., Gu, Y., Pang, Y., Qi, J., Wu, H., et al. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16655814 · Cited by 89 · see citing works
Vasquez, V., Mitra, J., Hegde, P. M., Pandey, A., Sengupta, S., Mitra, S., Rao, K. S., & Hegde, M. L. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-170342 · Cited by 88 · see citing works
Self-citationDharmalingam, P., Talakatta, G., Mitra, J., Wang, H., Derry, P. J., Nilewski, L. G., McHugh, E. A., Fabian, R. H., Mendoza, K., Vasquez, V., et al. (2020) · ACS Nano · doi:10.1021/acsnano.9b05821 · Cited by 83 · see citing works
Self-citationRoles of Heme Oxygenase-1 in Neuroinflammation and Brain Disorders
Wu, Y., & Hsieh, H. (2022) · Antioxidants · doi:10.3390/antiox11050923 · Cited by 83 · see citing works
Chan, L. L., Rice, W. L., & Qiu, J. (2020) · PLoS ONE · doi:10.1371/journal.pone.0227950 · Cited by 68 · see citing works
Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage
Chen‐Roetling, J., & Regan, R. F. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666161027150616 · Cited by 62 · see citing works
Derry, P. J., Vo, A. T. T., Gnanasekaran, A., Mitra, J., Liopo, A. V., Hegde, M. L., Tsai, A., Tour, J. M., & Kent, T. A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.603043 · Cited by 40 · see citing works
Self-citationKodavati, M. M., Wang, H., Guo, W., Mitra, J., Hegde, P. M., Provasek, V. E., Rao, V. H. M., Vedula, I., Zhang, A., MITRA, S. P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45978-6 · Cited by 39 · see citing works
Self-citationRossi, M., Piagnerelli, M., MEERHAEGHE, A. V., & Boudjeltia, K. Z. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110242 · Cited by 38 · see citing works
Carlsson, M., Wilsgaard, T., Johnsen, S. H., Johnsen, L.-H., Løchen, M.-L., Njølstad, I., & Mathiesen, E. B. (2021) · Stroke · doi:10.1161/strokeaha.120.032750 · Cited by 31 · see citing works
McHugh, E. A., Liopo, A. V., Mendoza, K., Robertson, C. S., Wu, G., Wang, Z., Chen, W., Beckham, J. L., Derry, P. J., Kent, T. A., et al. (2023) · Advanced Materials · doi:10.1002/adma.202211239 · Cited by 31 · see citing works
Self-citationHEMOGLOBIN POTENTIATES THE PRODUCTION OF REACTIVE OXYGEN SPECIES BY ALVEOLAR MACROPHAGES
Huffman, L. J. (2000) · Experimental Lung Research · doi:10.1080/019021400269871 · Cited by 27 · see citing works
Vasconcellos, L. R. C., Martimiano, L., Dantas, D. P., Fonseca, F. M., dos Santos, H. A. M., Travassos, L. H., Méndez‐Otero, R., Bozza, M. T., & Pimentel‐Coelho, P. M. (2021) · Stroke · doi:10.1161/strokeaha.120.031911 · Cited by 26 · see citing works
Heme oxygenase-2 (HO-2) binds and buffers labile ferric heme in human embryonic kidney cells
Hanna, D. A., Moore, C. M., Liu, L., Yuan, X., Dominic, I. M., Fleischhacker, A. S., Hamza, I., Ragsdale, S. W., & Reddi, A. R. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101549 · Cited by 26 · see citing works
Kodavati, M. M., Khandagale, P., Patel, S. K., Sahu, J. K., & Acharya, N. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101506 · Cited by 16 · see citing works
Self-citationCinti, A., Giorgi, M. D., Chisci, E., Arena, C., Galimberti, G., Farina, L., Bugarin, C., Rivolta, I., Gaipa, G., Smolenski, R. T., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141933 · Cited by 11 · see citing works
Derry, P. J., Liopo, A. V., Mouli, K., McHugh, E. A., Vo, A. T. T., McKelvey, A. M., Suva, L. J., Wu, G., Gao, Y., Olson, K. R., et al. (2024) · Advanced Materials · doi:10.1002/adma.202470076 · Cited by 2 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Ferro-aging: A novel paradigm linking iron overload, lipid peroxidation and cellular senescence
Gao, S., Qi, L., Bai, W., Zhang, J., Xu, Z. Y., Zhao, Z., Li, N., & Liu, W. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.06.012 · Cited by 7 · see citing works
Kodavati, M. M., Rao, V. H. M., Mitra, J., & Hegde, M. L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.25.625276 · Cited by 4 · see citing works
Self-citationCellular Senescence Triggered by Food and Environmental Genotoxins
Kaina, B., Tomicic, M. T., & Christmann, M. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052389 · Cited by 3 · see citing works
Wu, Y. J., Wei, C., Yang, Y., Yang, Y., Dou, S., Sun, F., Guo, N., & Fan, X. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.158569 · Cited by 3 · see citing works
Zhang, R.-C., Lu, H., Zhu, J., Liu, Y.-W., Wang, X.-Y., Shi, Y., Lan-lan, D., Zhu, S.-G., & Cheng, Y.-B. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.115691 · Cited by 1 · see citing works
An, J., Wang, T., Wang, Y., Sun, M., Meng, K., Wang, Y., Xu, H., Ye, D., Liu, Z., Li, M., et al. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.102671
Hematopoietic stem cell senescence and opportunities for intervention
Barve, A., Dabas, P., Cain, T. L., & McKinney‐Freeman, S. (2026) · Experimental Hematology · doi:10.1016/j.exphem.2026.105425 · Cited by 1 · see citing works
Research progress of peripheral inflammation in spontaneous cerebral hemorrhage
Chen, Y., Yu, T., kong, F., Xu, T., Xie, C., He, L., Bao, B., Chen, Z., & Yin, X. (2026) · Brain Hemorrhages · doi:10.1016/j.hest.2026.03.006
Closed-loop iron chelate recycling via molecularly imprinted hydrogels suppresses ferroptosis
Yao, Y., Ying, T., Zong, C., Ding, T., Li, Q., Han, Z., Wang, F., Cui, W., & Zhang, M. (2026) · Nature Communications · doi:10.1038/s41467-026-74330-3
Kang, D. S., Seok, S. H., Lee, S.-H., & Na, Y. R. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1888359
Wang, K., Liu, Y., Li, X., Li, L., & Zhou, R. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27188053
Yuan, Q., Tang, X., Yang, Z., Xiao, Y., Dong, J., Cai, X., Gao, W., Wang, Y., Zeng, W., 张才乔, et al. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104444
- Authors
- Malojirao, V. H., Vasquez, V., Kodavati, M., Mitra, J., Provasek, V., Voh, A. T. T., Liopo, A. V., Derry, P. J., Mikheev, A. M., Rostomily, R. C., Horner, P. J., Tour, J. M., Britz, G. W., Kent, T. A., & Hegde, M. L.
- Affiliations
- Houston Methodist (US)
- Houston Methodist Research Institute (US)
- Texas A&M Health Science Center (US)
- Rice University (US)
- Corresponding author
- Kent, Thomas A.
- Hegde, Muralidhar L.
- ORCID
- Venue
- Communications Biology
- Published
- 2025-04-17
- Volume
- 8
- Issue
- 1
- Pages
- 622-622
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC12006456
- OpenAlex
- W4409523066
- Cited by
- 13
- References
- 54
- Citations by year
- 2026: 10 · 2025: 2 · 2024: 1
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Communications Biology (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rice Research Repository (Rice University) (submittedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (RF1NS112719, R01NS094535)
- Topics
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- intracerebral hemorrhage, hemin, DNA damage response, DNA double-strand breaks, ferroptosis, heme oxygenase-1, senescence-associated β-galactosidase, iron accumulation, carbon nanoparticles, superoxide dismutase mimetic, deferoxamine, lipid peroxidation, neuroprotection, neuronal cell death
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
