ABSTRACT Liver fibrosis, driven by excessive collagen synthesis following hepatic injury, poses a significant health challenge. SLC39A13/ZIP13, a recently characterized intracellular iron transporter, is shown to provide iron to the ER/Golgi to help catalyze procollagen hydroxylation during collagen maturation. Here, we investigate whether ZIP13 plays a role during hepatic fibrogenesis modeled by CCl 4 stress or other inducers. ZIP13 expression is induced during liver fibrosis. Germline disruption of Zip13 dramatically reduces fibrosis. Surprisingly, these mice do not benefit from ZIP13 loss after CCl 4 challenge; instead, they are more susceptible to CCl 4 toxicity even with substantially less fibrosis development. This elevated vulnerability turns out to be a consequence of ferroptosis in the hepatocyte due to increased cytosolic iron after ZIP13 loss. Tissue‐specific knockout (KO) reveals that hepatic stellate cell (HSC) KO of Zip13 attenuates liver fibrosis progression without adverse effects. Leveraging these findings, HSC‐targeted delivery of Zip13 ‐siRNA demonstrates robust efficacy and safety in preclinical fibrosis models. These results provide critical insights into the complex role of iron in liver fibrosis, and indicate that targeting iron homeostasis via ZIP13 in the HSC may be effective to mitigate fibrogenesis by simultaneously suppressing the synthesis of multiple kinds of collagen while minimizing possible side effects.
Yu et al. (Wed,) studied this question.