Protective effect of tokinolide B against renal ischemia-reperfusion injury in mice and its anti-ferroptosis mechanism
10.12464/j.issn.1674-7445.2026148
- VernacularTitle:东当归内酯B减轻小鼠肾缺血-再灌注损伤的作用及其抗铁死亡机制
- Author:
Jinlong GONG
1
;
Huaiyin HUANG
1
;
Xiao WANG
2
;
Yi LI
2
;
Wanping CHEN
1
;
Xianbo SHEN
1
;
Chuang PENG
1
Author Information
1. Department of Hepatobiliary Surgery, Organ Transplantation Center, Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Changsha 410000, China.
2. null.
- Publication Type:OriginalArticle
- Keywords:
Kidney transplantation;
Ischemia-reperfusion injury;
Tokinolide B;
Nuclear factor E2-related factor 2;
Glutathione peroxidase 4;
Solute carrier family 7 member 11;
Ferroptosis;
Acyl-CoA synthetase long-chain family 4
- From:
Organ Transplantation
2026;17(6):953-962
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the therapeutic effect of tokinolide B (TB) on renal ischemia-reperfusion injury (IRI) in mice and its underlying molecular mechanism. Methods Male C57BL/6J mice were randomly assigned into six groups with 10 animals per group: sham operation group (Sham group), sham operation + TB treatment group (Sham+TB group), renal IRI model group (IRI group), TB intervention group (IRI+TB group), ML385 pretreatment group (IRI+TB+ML385 group) and sham + ML385 control group (Sham+ML385 group). Serum samples and renal tissues were harvested 24 hours after renal IRI surgery. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured to evaluate renal function. The levels of interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α in renal tissue homogenate were detected to assess inflammatory response, and hematoxylin-eosin (HE) staining was performed to observe pathological lesions in renal tissues. Transcriptomic analysis was conducted on renal tissues from the IRI group and IRI+TB group to screen relevant biological processes and signaling pathways. Malondialdehyde (MDA), glutathione (GSH) and ferrous ion (Fe2+) contents in kidney tissues were quantified. Real-time fluorescence quantitative polymerase chain reaction was used to detect the messenger RNA (mRNA) expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Western blot was adopted to determine the protein levels of nuclear factor E 2-related factor 2 (Nrf2), GPX4 and SLC7A11. Results Compared with the IRI group, the IRI+TB group exhibited decreased serum Scr and BUN concentrations, suppressed expression of renal IL-6, IL-1β and TNF-α, as well as alleviated renal pathological damage. Enrichment analysis demonstrated that DEGs induced by TB intervention were predominantly enriched in ferroptosis, oxidative stress and Nrf2-associated signaling pathways. Detection of ferroptosis-related biomarkers revealed that relative to the Sham group, the IRI group presented elevated MDA and Fe2+ levels, reduced GSH content, downregulated mRNA expression of GPX4 and SLC7A11, and upregulated ACSL4 mRNA expression. In contrast with the IRI group, the IRI+TB group showed lowered MDA and Fe2+ concentrations, elevated GSH level, upregulated GPX4 and SLC7A11 mRNA levels, and downregulated ACSL4 mRNA level (all P<0.05). Molecular docking verified that TB could bind stably to Nrf2 with a binding free energy of −32.6 kJ/mol. Western blot results indicated that the protein abundances of Nrf2, GPX4 and SLC7A11 in renal tissues were markedly higher in the IRI+TB group than those in the IRI group. ML385 pretreatment abrogated the renoprotective effect of TB against renal IRI (all P<0.05). Conclusions TB exerts protective effects against renal IRI in mice possibly by binding to Nrf2 to facilitate its nuclear translocation, subsequently activating the downstream Nrf2/GPX4/SLC7A11 signaling cascade to suppress ferroptosis.
