Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis

Abstract

Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to develop ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either high dietary iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation compared to healthy controls. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.

Iron Metabolism in Ferroptosis

“…The loss of SLC39A14 in mice also markedly reduces the liver's absorption of NTBI and prevents hepatic iron overload in mouse models of hemochromatosis (Jenkitkasemwong et al, 2015). As expected, the conditional knockout of hepatic SLC39A14 reduces iron accumulation in liver and ferroptosis-mediated liver fibrosis, indicating that SLC39A14-mediated iron uptake promotes ferroptotic liver injury and disease (Yu et al, 2020). Whether SLC39A8 plays a role similar to that of SLC39A14 in promoting ferroptosis in vivo remains to be further studied.…”

The interaction between ferroptosis and lipid metabolism in cancer

“…Excessive iron is stored in ferritin, an iron storage protein complex including ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). [14][15][16] It has been reported that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptosis as it inhibits the accumulation and absorption of intracellular iron by inhibiting TFR1 expression. [17][18][19][20] Silencing of iron-responsive element binding protein 2 (IREB2), a master transcription factor of iron metabolism, significantly limits erastin-induced ferroptosis.…”

Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms

“…15 Interestingly, we previously reported that mouse models of iron overload develop ferroptosis-related liver damage. 18,19 Ferroptosis is characterized as a lipid peroxidation-induced, iron-dependent form of cell death and has been attributed to pathological tissue damage induced by ischemia/reperfusion and chemotherapeutic drugs. [20][21][22][23] The antioxidant glutathione (GSH) is a robust scavenger of lipid peroxidation products, and impaired GSH metabolism is one of the major mechanisms underlying ferroptosis, 21,24 including GSH deficiency (i.e., cystine/glutamate antiporter xc − dysfunction) 25 and impaired GSH utilization (i.e., by inhibiting glutathione peroxidase 4).…”

“… 15 Interestingly, we previously reported that mouse models of iron overload develop ferroptosis-related liver damage. 18 , 19 …”