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

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.