ArticleEuropean journal of medical research2026
HIF-1α/BNIP3-mediated mitophagy mitigates cerebral ischemia/reperfusion injury in rats by suppressing NLRP3 inflammasome activation.
Article in European journal of medical research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Targeting Peptidylarginine Deiminases in Neurons and Astrocytes in Central Nervous System Injury-Effects of Pan-PAD Inhibitor Cl-Amidine in an Oxygen-Glucose Deprivation Model of Ischaemia (OGD/R) and LPS Stimulation In Vitro.International journal of molecular sciences · 2026Article
- Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.Journal of physiology and biochemistry · 2026Review
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Abstract
backgroundThe hypoxia-inducible factor-1α (HIF-1α)/Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3) pathway, a key regulator of mitophagy, has demonstrated protective effects in renal and cardiac ischemia/reperfusion (I/R) injury. However, its specific role and mechanism in cerebral I/R injury (CIRI) are not fully understood.
methodsAn oxygen-glucose deprivation/reoxygenation (OGD/R) model in SH-SY5Y neuroblastoma cells and a transient middle cerebral artery occlusion (MCAO) model in rats were established to simulate CIRI. HIF-1α overexpression plasmids was then introduced into the two models. Mitophagic activity was assessed through immunoblotting of BNIP3, microtubule-associated protein 1 light chain 3B (LC3B), and p62 protein, quantification of LC3B-mitochondria colocalization, and transmission electron microscopic analysis of mitochondrial ultrastructure and autophagosomes. NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome activation was evaluated by measuring levels of NLRP3, cleaved caspase-1, interleukin (IL)-1β, and IL-18. The cell-type specificity of the HIF-1α/BNIP3/mitophagy pathway was evaluated by comparative analysis in SH-SY5Y neuronal cells and BV-2 microglia. Mechanistic dependency was tested NLRP3 agonist nigericin using the autophagy inhibitor 3-methyladenine (3-MA) and the specific NLRP3 inflammasome agonist nigericin in rescue experiments. In addition, cerebral infarction and neurological deficits were assessed in rats.
resultsHIF-1α transcriptionally upregulated BNIP3 in SH-SY5Y cells. HIF-1α overexpression increased BNIP3 and LC3B II levels, reduced p62 level, increased autophagosome accumulation, and enhanced mitophagy in SH-SY5Y cells. This enhanced mitophagy suppressed OGD/R-induced apoptosis and NLRP3 inflammasome activation, while these effects were abolished by 3-MA or nigericin. Comparative analysis revealed the HIF-1α/BNIP3/mitophagy pathway to be a predominant and potent mechanism in SH-SY5Y cells, rather than BV-2 microglia. In addition, HIF-1α overexpression enhanced mitophagy and attenuated NLRP3 inflammasome activation in brain tissues, thereby alleviating cerebral infarction and neurological deficits in MCAO rats.
conclusionsActivation of the HIF-1α/BNIP3 pathway drives protective mitophagy to suppress the NLRP3 inflammasome in neuronal cells, thereby conferring neuroprotection against CIRI. This study provides mechanistic insights into the protective role of HIF-1α/BNIP3-mediated mitophagy against CIRI, highlighting its potential as a therapeutic target for ischemic injury.
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