Hemoglobin acts as a natural antioxidant defense for the brain

A paper by an international team of neuroscientists has been published in Signal Transduction and Targeted Therapy, which radically expands the role of hemoglobin (Hb) in the brain. In addition to its classic function of oxygen transport, hemoglobin in astrocytes and dopamine neurons behaves as a pseudoperoxidase - an enzyme-like "quencher" of hydrogen peroxide (H₂O₂), one of the key drivers of oxidative stress. The researchers showed that enhancing this latent activity with the KDS12025 molecule dramatically reduces H₂O₂ levels, weakens astrocytic reactivity and restrains neurodegeneration in models of Alzheimer's, Parkinson's and ALS, as well as in aging and even rheumatoid arthritis. This hints at a new drug target: enhancing the brain's antioxidant "self-help" without interfering with oxygen transport. The article was published on August 22, 2025.

Background of the study

Hemoglobin is traditionally considered as an "oxygen carrier" in erythrocytes, but in recent years it has also been found in brain cells - in particular, in astrocytes and dopaminergic neurons. Against this background, oxidative stress acquires special significance: hydrogen peroxide (H₂O₂) plays a dual role - as a universal signaling "second messenger" and, when in excess, as a toxic factor damaging proteins, nucleic acids and mitochondria. Excess H₂O₂ and associated reactive oxygen species are involved in the pathogenesis of neurodegenerative diseases (Alzheimer's, Parkinson's, ALS), as well as in age-associated dysfunction and a number of inflammatory conditions outside the central nervous system. Hence the logic of searching for "point" approaches to redox regulation that do not disrupt the physiological signaling of H₂O₂.

A key cellular actor in the brain are reactive astrocytes, which become a source of excess H₂O₂ (including via the monoamine oxidase B pathway) in disease and aging. Such astrocytic dysregulation fuels astrocytosis, neuroinflammation, and neuronal death, perpetuating a vicious cycle. However, “broad” antioxidants are often ineffective or non-selective: they can behave as pro-oxidants and show unstable clinical results. Therefore, solutions targeting specific cells and subcellular compartments are needed to dampen pathological excess H₂O₂ while preserving physiological redox signaling.

Against this background, interest arises in the unusual role of hemoglobin itself in the brain. On the one hand, its degradation and release of iron/heme increase oxidative stress; on the other hand, evidence has accumulated that Hb has pseudoperoxidase activity, i.e., is capable of decomposing H₂O₂ and thereby restraining damage. However, the effectiveness of this “self-protective” mechanism in neuronal and glial cells is normally low, and the molecular details have long remained unclear, which has limited the therapeutic use of this pathway.

The idea underlying the current work is not to "flood" the brain with external antioxidants, but to enhance the endogenous antioxidant micromachine: to increase the pseudoperoxidase function of hemoglobin exactly where it is needed - in astrocytes and vulnerable neurons. Such pharmacological tuning theoretically allows to reduce the excess of H₂O₂, remove the reactivity of astrocytes and break the vicious circle of neurodegeneration without interfering with the main - gas transport - function of Hb.

Key Findings

The authors found hemoglobin not only in the cytoplasm, but also in the mitochondria and nuclei of hippocampal astrocytes and the substance nigra, as well as in dopamine neurons. Normally, this Hb is able to decompose H₂O₂ and restrain damage caused by peroxide. But during neurodegeneration and aging, excess H₂O₂ "knocks out" astrocytic Hb, closing the vicious circle of oxidative stress. The team synthesized a small molecule KDS12025 that passes through the BBB, which enhances the pseudoperoxidase activity of Hb by about 100 times and thereby reverses the process: H₂O₂ falls, astrocytosis subsides, the Hb level normalizes, and neurons get a chance to survive - while the oxygen transfer by hemoglobin is not affected.

How it works at the chemical and cellular level

The initial clue came from H₂O₂ degradation tests: a series of derivatives with an electron-donating amino group enhanced the activity of a peroxidase-like reaction in which Hb, H₂O₂, and a “booster” molecule form a stable complex. Genetic “silencing” of Hb abolished the entire effect of KDS12025 in both culture and animal models – direct evidence that Hb is the target. Also notable is the “localization” finding: Hb enrichment in astrocyte nucleoli may protect the nucleus from oxidative damage – another potential layer of antioxidant defense for the brain.

What the disease models showed

The work combines biochemistry, cell experiments and in vivo approaches in several pathologies where H₂O₂ and reactive oxygen species play a leading role. In animal models, the authors observed:

• Neurodegeneration (AD/PD): decreased H₂O₂ in astrocytes, attenuated astrocytosis and preservation of neurons against the background of activation of Hb pseudoperoxidase KDS12025.
• ALS and Aging: Improved motor skills and even prolonged survival in severe ALS models; beneficial effects in brain aging.
• Outside the CNS: signs of effectiveness in rheumatoid arthritis, which emphasizes the commonality of the oxidative stress mechanism in different tissues.
  Key point: the effect is achieved without disrupting the gas transport function of Hb - a vulnerable spot for any "game" with hemoglobin.

Why the approach looks promising

Conventional antioxidants often "miss the mark": either they act too non-specifically, or they give unstable results in the clinic. Here the strategy is different - not to catch free radicals everywhere and at once, but to tweak the cell's own antioxidant micromachine in the right place (astrocyte) and in the right context (excess H₂O₂), and in such a way as not to affect the normal signaling roles of peroxide. This is a pinpoint intervention in redox homeostasis, and not a "total cleanse", so it is potentially compatible with physiology.

Details to look out for

• BBB Permeability: KDS12025 is designed to reach the brain and work where excess hydrogen peroxide is primarily produced - in reactive astrocytes (including via the MAO-B pathway).
• Structural motif: Efficacy is related to the electron-donating amino group stabilizing the Hb-H₂O₂-KDS12025 interaction.
• Proof of specificity: turning off Hb nullified the effect of the molecule - a strong argument in favor of the target's precision.
• Broad application: from AD/PD/ALS to aging and inflammatory diseases - where H₂O₂ dysregulation runs like a “red thread”.

Limitations and what's next

We have a preclinical story before us: yes, the range of models is impressive, but before human trials, we still need to go through toxicology, pharmacokinetics, long-term safety testing, and, most importantly, understand in whom and at what stage of the disease the enhancement of the pseudoperoxidase function of Hb will provide the maximum clinical benefit. In addition, oxidative stress is only one layer of pathogenesis in neurodegeneration; it is probably logical to consider KDS12025 in combinations (for example, with anti-amyloid/anti-synuclein or anti-MAO-B approaches). Finally, translating the “100x in vitro” effect into sustainable clinical benefit is a separate task of dosing, delivery, and response biomarkers (including MR spectroscopy, redox metabolites, etc.).

What can this change in the long run?

If the concept is confirmed in humans, a new class of redox modulators will emerge that do not “suppress” all radical chemistry, but delicately enhance the protective role of Hb in the right cells. This could expand the toolkit of therapy for Alzheimer’s and Parkinson’s diseases, slow the progression of ALS, and also provide options for age-associated and inflammatory conditions, where the role of H₂O₂ has long been discussed. In essence, the authors have proposed a new target and a new principle: “teach” a well-known protein to work a little differently - for the benefit of neurons.

Source: Woojin Won, Elijah Hwejin Lee, Lizaveta Gotina, et al. Hemoglobin as a pseudoperoxidase and drug target for oxidative stress-related diseases. Signal Transduction and Targeted Therapy (Nature Portfolio), published August 22, 2025. DOI: https://doi.org/10.1038/s41392-025-02366-w