Temporal Dynamics of Haptoglobin in Acute Ischemic Stroke and HMGB1-Mediated Neuroinflammation

Takafumi Nakano^1,*, Mayuka Morimoto-Arimatsu^2,3, Kenichi Mishima²
1 Department of Oncology and Infectious Disease Pharmacy, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, Japan
2 Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, Japan
3 Department of Pharmacy, Almeida Memorial Hospital, 1509-2, Oaza Miyazaki, Oita, Japan
* Corresponding Author: Takafumi Nakano. Email: email
(This article belongs to the Special Issue: Cellular and Molecular Insights into Brain Ischemic Insults)

BIOCELL https://doi.org/10.32604/biocell.2026.085207

Received 07 May 2026; Accepted 15 July 2026; Published online 30 July 2026

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Abstract

Haptoglobin (Hp) is an acute-phase protein that binds free hemoglobin and limits hemoglobin-mediated oxidative injury. In addition to this established function, Hp modulates inflammatory responses and interacts with high-mobility group box 1 (HMGB1), a major damage-associated molecular pattern, suggesting a multifunctional role. Hp is primarily produced by the liver, although local expression in brain-resident cells has also been reported, potentially contributing to tissue-specific protection. This review summarizes the biological properties of Hp, including hemoglobin clearance, immune modulation, and HMGB1 scavenging, and discusses experimental and clinical evidence linking Hp to ischemic stroke. In acute ischemic stroke, secondary brain injury is mainly driven by sterile inflammation and oxidative stress. Hemoglobin-mediated toxicity appears context-dependent, particularly in cases with blood–brain barrier disruption or hemorrhagic transformation, whereas HMGB1-mediated inflammatory signaling is more consistently implicated. However, the role of endogenous Hp in regulating these processes remains incompletely understood, particularly regarding its temporal dynamics after stroke. Accumulated evidence suggests that Hp undergoes dynamic temporal changes after stroke and may contribute to the regulation of post-ischemic inflammatory and oxidative pathways. A better understanding of its multifunctional roles and temporal regulation may provide new insights into ischemic stroke mechanisms and future therapeutic strategies.