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<p>Intracerebral hemorrhage (ICH) poses acute fatality and long-term neurological risks, in part due to hemin and iron accumulation from hemoglobin breakdown. We&#xa0;observed that hemin induces DNA double-strand breaks (DSBs), prompting a senescence-like phenotype in neurons, necessitating a&#xa0;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&#xa0;the 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 of iron-related toxicity supports a multi-pronged therapeutic approach.</p>

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Hemin-induced transient senescence via DNA damage response: a neuroprotective mechanism against ferroptosis in intracerebral hemorrhage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月17日

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  • Vikas H. Malojirao,
  • Velmarini Vasquez,
  • Manohar Kodavati,
  • Joy Mitra,
  • Vincent Provasek,
  • Anh Tran Tram Voh,
  • Anton V. Liopo,
  • Paul J. Derry,
  • Andrei M. Mikheev,
  • Robert C. Rostomily,
  • Philip J. Horner,
  • James M. Tour,
  • Gavin W. Britz,
  • Thomas A. Kent,
  • Muralidhar L. Hegde

摘要

Intracerebral hemorrhage (ICH) poses acute fatality and long-term neurological risks, in part due to hemin and iron accumulation from hemoglobin breakdown. We observed that hemin induces DNA double-strand breaks (DSBs), prompting a senescence-like phenotype in neurons, necessitating a 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 the 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 of iron-related toxicity supports a multi-pronged therapeutic approach.