Fibrosis regardless of aetiology is characterised by persistently activated myofibroblasts that are contractile and secrete excessive amounts of extracellular matrix molecules that leads to loss of organ function. Damage-Associated Molecular Patterns (DAMPs) are endogenous host-derived molecules that are released from cells dying or under stress that can be triggered by a variety of insults, either chemical or physical, leading to an inflammatory response. Among these DAMPs is S100A4, part of the S100 family of calcium binding proteins that participate in a variety of cellular processes. S100A4 was first described in context of cancer as a pro-metastatic factor. It is now appreciated that aside from its role in cancer promotion, S100A4 is intimately involved in tissue fibrosis. The extracellular form of S100A4 exerts its effects through multiple receptors including Toll-Like Receptor 4 and RAGE to evoke signalling cascades involving downstream mediators facilitating extracellular matrix deposition and myofibroblast generation and can play a role in persistent activation of myofibroblasts. S100A4 may be best understood as an amplifier of inflammatory and fibrotic processes. S100A4 appears critical in systemic sclerosis pathogenesis and blocking the extracellular form of S100A4 in vivo in various animal models of disease mitigates fibrosis and may even reverse established disease. This review appraises S100A4’s position as a DAMP and its role in fibrotic conditions and highlight therapeutically targeting this protein to halt fibrosis, suggesting that it is a tractable target.

无论病因如何，纤维化的特征是肌成纤维细胞持续活化，其收缩并分泌过量的细胞外基质分子，导致器官功能丧失。损伤相关分子模式 (DAMP) 是内源性宿主衍生分子，它们从死亡或处于应激状态的细胞中释放出来，可以由各种化学或物理损伤触发，从而导致炎症反应。这些 DAMP 中包括 S100A4，它是参与多种细胞过程的钙结合蛋白 S100 家族的一部分。 S100A4 首次在癌症背景下被描述为促转移因子。现在人们认识到，除了促进癌症的作用之外，S100A4 还与组织纤维化密切相关。 S100A4 的细胞外形式通过 Toll 样受体 4 和 RAGE 等多种受体发挥作用，引发涉及下游介质的信号级联，促进细胞外基质沉积和肌成纤维细胞生成，并在肌成纤维细胞的持续激活中发挥作用。 S100A4 最好被理解为炎症和纤维化过程的放大器。 S100A4 在系统性硬化症发病机制中显得至关重要，在各种疾病动物模型中阻断体内 S100A4 的细胞外形式可以减轻纤维化，甚至可能逆转已确定的疾病。这篇综述评估了 S100A4 作为 DAMP 的地位及其在纤维化病症中的作用，并强调了以这种蛋白质为靶点来阻止纤维化的治疗方法，表明它是一个易于处理的靶点。