Hemoglobin as a peroxidase and drug target for oxidative stress-related diseases

Summary paragraph Hemoglobin (Hb) is well-known for transporting oxygen in red blood cells within blood vessels 1 . Although Hb is also present in the brain 2 , its role remains poorly understood. Here, we show that Hb, found in astrocytes of neurodegenerative animal models and patients, displays significant antioxidant effects through its H 2 O 2 -decomposing peroxidase activity, and a small molecule enhancer boosts this activity, reducing aberrant H 2 O 2 and mitigating H 2 O 2 -induced neurodegeneration. To counteract the harmful effects of aberrant H 2 O 2 -production in Alzheimer’s disease (AD), we developed KDS12025, a blood-brain barrier (BBB)-permeable small molecule that effectively enhances the peroxidase activity of Hb by a hundredfold, especially at a low level of Hb. KDS12025 and its analogs achieve this enhancement through its electron-donating amine group. KDS12025 reduces H 2 O 2 levels in astrocytes, exhibits neuroprotective effects, and reverses memory impairment in AD models. Gene-silencing of Hbβ abrogates KDS12025’s impact in both culture and animal models of AD. Moreover, KDS12025 prevented the death of dopaminergic neurons in a Parkinson’s disease (PD) model without altering the oxygen-transporting function of Hb. KDS12025 extended survival and improved motor function even in the severe amyotrophic lateral sclerosis (ALS) mouse model. Our findings propose Hb as a new therapeutic target for neurodegenerative diseases, with KDS12025 emerging as a first-in-class drug candidate that enhances Hb’s peroxidase activity to reduce H 2 O 2 . Boosting Hb’s peroxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD, PD, and ALS with broad applicability for numerous oxidative-stress-driven diseases.