Ferroptosis plays a role in several diseases such as iron overload-induced liver diseases. Manipulation of ferroptosis has been explored as a potential therapeutic strategy to treat related diseases. Numerous antioxidants have been identified to control ferroptosis but the cell-autonomous mechanisms responsible for regulating ferroptosis remain elusive. In the present study, we found that iron overload promoted ferroptosis in hepatocytes by excessively inducing HO-1 expression, which contributed to the progression of liver injury and fibrosis, accompanied by the upregulation of the FGF21 protein level in vitro and in vivo. Interestingly, both recombinant FGF21 and Fgf21 overexpression significantly protected against iron overload-induced hepatocytes mitochondria damage, liver injury and fibrosis by inhibiting ferroptosis. In contrast, the loss of FGF21 aggravated iron overload-induced ferroptosis. Notably, FGF21-induced HO-1 inhibition (via the promotion of HO-1 ubiquitination and degradation) and NRF2 activation provide a mechanistic explanation for this phenomenon. Taken together, we identified FGF21 as a novel ferroptosis suppressor. Thus, FGF21 activation may provide an effective strategy for the potential treatment of iron overload-induced ferroptosis-related diseases, such as hereditary haemochromatosis (HH).

铁死亡在多种疾病中起作用，例如铁超载引起的肝脏疾病。已经探索了对铁死亡的操纵作为治疗相关疾病的潜在治疗策略。已经确定了许多抗氧化剂来控制铁死亡，但负责调节铁死亡的细胞自主机制仍然难以捉摸。在本研究中，我们发现铁超载通过过度诱导 HO-1 表达促进肝细胞铁死亡，这有助于肝损伤和纤维化的进展，并伴随着体外和体内 FGF21 蛋白水平的上调。有趣的是，重组 FGF21 和Fgf21过表达通过抑制铁死亡显着防止铁过载诱导的肝细胞线粒体损伤、肝损伤和纤维化。相比之下，FGF21 的缺失加剧了铁过载诱导的铁死亡。值得注意的是，FGF21 诱导的 HO-1 抑制（通过促进 HO-1 泛素化和降解）和 NRF2 激活为这种现象提供了机械解释。总之，我们将 FGF21 鉴定为一种新型的铁死亡抑制因子。因此，FGF21 激活可能为铁过载诱导的铁死亡相关疾病（如遗传性血色病（HH））的潜在治疗提供有效策略。