Linking tetrahydrobiopterin depletion to ferroptosis: A novel mechanism of neurological injury in Hyperphenylalaninemia.
10.3760/cma.j.cn511374-20250923-00563
- Author:
Huizhong LI
1
,
2
;
Yanli SHEN
;
Zhou WEI
Author Information
1. Department of Medical Genetics and Prenatal Diagnosis, Xuzhou Maternity and Child Heath Care Hospital, Xuzhou, Jiangsu 221700, China. wei0743916@
2. com.
- Publication Type:English Abstract
- MeSH:
Ferroptosis;
Humans;
Biopterins/deficiency*;
Phenylketonurias/pathology*;
Animals
- From:
Chinese Journal of Medical Genetics
2025;42(12):1518-1522
- CountryChina
- Language:Chinese
-
Abstract:
Hyperphenylalaninemia (HPA) is an inherited metabolic disorder caused by deficiency of phenylalanine hydroxylase, characterized by significantly elevated phenylalanine levels. Conventional mechanisms, such as neurotransmitter deficiency and dysmyelination, fail to fully explain the progressive neurological damages associated with HPA. Meanwhile, ferroptosis, an emerging form of iron-dependent regulated cell death, has proven to play an important role in neurodegenerative diseases. We hereby propose a hypothesis that tetrahydrobiopterin (BH4) depletion in HPA may lead to the collapse of intracellular antioxidant defenses. This process could induce ferroptosis, thereby serving as a pivotal mechanism underlying HPA-related neurological injury. This review has systematically summarized the pathological mechanisms of HPA, the biological features of ferroptosis, and the bridging role of BH4 between them, thereby establishing a novel "HPA-BH4-ferroptosis" theoretical framework and providing a rationale for developing new therapeutic strategies targeting ferroptosis.
