CD44 is a transmembrane glycoprotein linked to various biological processes reliant on epigenetic plasticity, which include development, inflammation, immune responses, wound healing and cancer progression. Although it is often referred to as a cell surface marker, the functional regulatory roles of CD44 remain elusive. Here we report the discovery that CD44 mediates the endocytosis of iron-bound hyaluronates in tumorigenic cell lines, primary cancer cells and tumours. This glycan-mediated iron endocytosis mechanism is enhanced during epithelial–mesenchymal transitions, in which iron operates as a metal catalyst to demethylate repressive histone marks that govern the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron through a positive feedback loop, which is in contrast to the negative regulation of the transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This study reveals an alternative iron-uptake mechanism that prevails in the mesenchymal state of cells, which illuminates a central role of iron as a rate-limiting regulator of epigenetic plasticity.

CD44 是一种跨膜糖蛋白，与依赖表观遗传可塑性的各种生物过程相关，包括发育、炎症、免疫反应、伤口愈合和癌症进展。虽然它通常被称为细胞表面标记，但 CD44 的功能调节作用仍然难以捉摸。在这里，我们报告了 CD44 在致瘤细胞系、原发性癌细胞和肿瘤中介导铁结合透明质酸盐的内吞作用的发现。这种聚糖介导的铁内吞机制在上皮-间质转化过程中得到增强，其中铁作为金属催化剂发挥作用，使控制间充质基因表达的抑制性组蛋白标记去甲基化。CD44 本身由核铁通过正反馈环进行转录调节，这与过量铁对转铁蛋白受体的负调节相反。最后，我们表明可以通过使用小分子干扰铁稳态来改变表观遗传可塑性。这项研究揭示了一种在细胞间充质状态中普遍存在的替代铁摄取机制，它阐明了铁作为表观遗传可塑性的限速调节剂的核心作用。