Yes-associated protein 1 (YAP1) is a critical regulator of BMP6 expression and iron homeostasis

The expression of hepatocellular hepcidin is critically dependent on bone morphogenetic protein 6 (BMP6) derived from liver sinusoidal endothelial cells (LSECs) during iron-loading. Our prior research demonstrated that tumor necrosis factor α (TNFα), originating from hepatocytes, is upregulated during iron-loading and can stimulate BMP6 expression in LSECs. Here, we explored the intracellular mechanisms by which TNFα, and more broadly, iron-loading, regulate BMP6 expression in LSECs. RNA sequencing revealed that the induction of BMP6 expression in LSECs by TNFα is mediated by Yes-associated protein 1 (YAP1), but is Hippo and its associated YAP1 phosphorylation independent. However, TNFα could specifically phosphorylate YAP1 at serine 367 (S367). In vivo knockdown of YAP1 via adeno-associated virus type 9 resulted in reduced BMP6 and hepcidin expression in both holo-transferrin injection and high iron diet-induced iron-loading mouse models, thereby disrupting iron homeostasis. Moreover, the small molecule compound Anisomycin, which could induce YAP1 phosphorylating at S367, was found to stimulate BMP6 expression and regulate iron metabolism in vivo . Finally, Anisomycin administration reduced the iron burden in Hfe knockout hemochromatosis mice. Our study identifies a novel function of YAP1 in the regulation of iron homeostasis, mediated through its phosphorylation at S367 and the regulation of BMP6 expression in LSECs. Therefore, YAP1 emerges as a potential therapeutic target for the treatment of iron-related disorders.