Tacrolimus Inhibits Hepatic Ferroptosis Through Modulating SIRT7-Dependent NRF2 Activation in Diabetes

Wang, Siqi; Liu, Wenbin; Cui, Feng; Guo, Xiangji; Li, Jun

doi:10.3390/antiox15050589

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Open AccessArticle

Tacrolimus Inhibits Hepatic Ferroptosis Through Modulating SIRT7-Dependent NRF2 Activation in Diabetes

by

Siqi Wang

,

Wenbin Liu

,

Feng Cui

,

Xiangji Guo

and

Jun Li

^*

State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China

^*

Author to whom correspondence should be addressed.

Antioxidants 2026, 15(5), 589; https://doi.org/10.3390/antiox15050589

Submission received: 18 March 2026 / Revised: 24 April 2026 / Accepted: 3 May 2026 / Published: 6 May 2026

(This article belongs to the Special Issue Oxidative Stress and NRF2 in Diabetes)

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Abstract

Hepatic lipotoxicity in type 2 diabetes promotes oxidative stress and ferroptosis, driving progressive liver injury, for which effective targeted therapies remain lacking. Here, we identify tacrolimus (TAC), a clinically established immunosuppressant, as an unexpected suppressor of hepatic ferroptosis in db/db diabetic mice. TAC administration markedly alleviated liver injury, fibrosis, and inflammation, accompanied by reduced oxidative stress and ferroptosis signatures. Transcriptomic profiling revealed enrichment of glutathione metabolism pathways in livers of TAC-treated db/db diabetic mice. Mechanistically, TAC inhibited ferroptosis in primary hepatocytes by activating the NRF2 pathway, increasing NRF2 protein abundance and its nuclear translocation in an SIRT7 deacetylase activity-dependent manner. Together, these findings uncover a previously unrecognized role of TAC in repressing ferroptosis through the SIRT7–NRF2 axis, highlighting ferroptosis modulation by TAC as a potential therapeutic strategy for diabetic liver diseases.

Keywords: ferroptosis; tacrolimus; NRF2; SIRT7; diabetes

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MDPI and ACS Style

Wang, S.; Liu, W.; Cui, F.; Guo, X.; Li, J. Tacrolimus Inhibits Hepatic Ferroptosis Through Modulating SIRT7-Dependent NRF2 Activation in Diabetes. Antioxidants 2026, 15, 589. https://doi.org/10.3390/antiox15050589

AMA Style

Wang S, Liu W, Cui F, Guo X, Li J. Tacrolimus Inhibits Hepatic Ferroptosis Through Modulating SIRT7-Dependent NRF2 Activation in Diabetes. Antioxidants. 2026; 15(5):589. https://doi.org/10.3390/antiox15050589

Chicago/Turabian Style

Wang, Siqi, Wenbin Liu, Feng Cui, Xiangji Guo, and Jun Li. 2026. "Tacrolimus Inhibits Hepatic Ferroptosis Through Modulating SIRT7-Dependent NRF2 Activation in Diabetes" Antioxidants 15, no. 5: 589. https://doi.org/10.3390/antiox15050589

APA Style

Wang, S., Liu, W., Cui, F., Guo, X., & Li, J. (2026). Tacrolimus Inhibits Hepatic Ferroptosis Through Modulating SIRT7-Dependent NRF2 Activation in Diabetes. Antioxidants, 15(5), 589. https://doi.org/10.3390/antiox15050589

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Tacrolimus Inhibits Hepatic Ferroptosis Through Modulating SIRT7-Dependent NRF2 Activation in Diabetes

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