Aging-associated GSK3β overexpression exacerbates hepatic ischemia-reperfusion injury through Nrf2 deficiency-induced hepatocyte ferroptosis

IF 6.4 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2026-03-01 Epub Date: 2026-01-16 DOI:10.1016/j.lfs.2026.124214

You Wu , Yan Zhang , Shiwei Zhang , Huahong Yang , Xinxin Ci

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引用次数: 0

Abstract

Background and aims

Aging can exacerbate hepatic ischemia-reperfusion injury (HIRI), but the underlying mechanisms remain uncertain. In this study, the mechanisms through which age-related dysregulation of the GSK3β-Nrf2 axis promotes hepatocyte ferroptosis and exacerbates HIRI were investigated.

Methods

We used a comparative approach to analyze the following: 1) human liver specimens from young (25–35 years) and elderly (65–75 years) donors; 2) young and aged C57BL/6 mice and Nrf2-knockout (Nrf2-KO) mouse models subjected to HIRI; and 3) radiation-induced senescent L02 hepatocytes. Key interventions included the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the GSK3β inhibitor lithium (LiCl).

Results

Our study revealed that aging leads to significant downregulation of Nrf2 in human livers, aged mice, and senescent hepatocytes. This suppression of age-related Nrf2 exacerbates HIRI, as reflected by impaired antioxidant defenses and increased ferroptosis (elevated lipid peroxidation, iron overload, malondialdehyde (MDA) accumulation, glutathione (GSH) depletion and TFR upregulation). Genetic Nrf2 deficiency exacerbates these pathological changes in both cellular and animal models. Notably, treatment with Fer-1 effectively reduced liver damage biomarkers (ALT/AST) and ferroptotic responses in Nrf2-knockout systems. Mechanistically, aging-induced GSK3β overexpression drives Nrf2 dysfunction, establishing a GSK3β-Nrf2-ferroptosis axis involved in IRI progression. Notably, therapeutic targeting of GSK3β by microdose lithium or ferroptosis inhibition by Fer-1 alleviated HIRI in aged mice.

Conclusions

Our study revealed a novel aging-related pathogenesis axis in which GSK3β upregulation drives Nrf2 deficiency-mediated ferroptosis in hepatocytes, thereby exacerbating HIRI. Pharmacological targeting of this pathway may be a promising therapeutic strategy for elderly patients undergoing liver surgery.

Abstract Image

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衰老相关的GSK3β过表达通过Nrf2缺乏诱导的肝细胞铁凋亡加剧肝缺血再灌注损伤。

背景与目的：衰老可加重肝缺血再灌注损伤（HIRI），但其机制尚不清楚。在本研究中，研究了GSK3β-Nrf2轴的年龄相关失调促进肝细胞铁凋亡和加重HIRI的机制。方法：采用比较方法分析：1)年轻（25-35 岁）和老年（65-75 岁）供者的肝脏标本；2) HIRI诱导的C57BL/6小鼠和nrf2敲除（Nrf2-KO）小鼠模型；3)辐射诱导的衰老L02肝细胞。主要干预措施包括给予铁下垂抑制剂铁抑素-1 （fer1）和GSK3β抑制剂锂（LiCl）。结果：我们的研究表明，衰老导致人类肝脏、老年小鼠和衰老肝细胞中Nrf2的显著下调。这种与年龄相关的Nrf2的抑制加剧了HIRI，反映在抗氧化防御受损和铁下沉增加（脂质过氧化升高、铁超载、丙二醛（MDA）积累、谷胱甘肽（GSH）消耗和TFR上调）。在细胞和动物模型中，遗传Nrf2缺乏加剧了这些病理变化。值得注意的是，在nrf2敲除系统中，用fe -1治疗可有效降低肝损伤生物标志物（ALT/AST）和铁致凋亡反应。从机制上讲，衰老诱导的GSK3β过表达驱动Nrf2功能障碍，建立参与IRI进展的GSK3β-Nrf2-铁下沉轴。值得注意的是，通过微剂量锂靶向GSK3β或fer1抑制铁下垂可减轻老年小鼠HIRI。结论：我们的研究揭示了一种新的与衰老相关的发病轴，其中GSK3β上调驱动Nrf2缺陷介导的肝细胞铁凋亡，从而加剧HIRI。这一途径的药理靶向可能是一种很有前途的治疗策略，用于老年肝脏手术患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.