Sawant Harshal, Borthakur Alip
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.
Int J Mol Sci. 2025 Jun 14;26(12):5713. doi: 10.3390/ijms26125713.
Growth Differentiation Factor 15 (GDF15), also known as non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) or macrophage inhibitory cytokine 1 (MIC-1), is a stress- and inflammation-induced cytokine distantly related to the TGF-β superfamily. Its highly elevated levels showed close association with various pathological conditions, making it an emerging biomarker of disease prognosis. However, most GDF15-mediated effects under normal physiology and various pathological conditions are poorly understood. This is partly because the only known GDF15 receptor is exclusively localized in the brain, and how GDF15 functions peripherally is currently unknown. Mounting recent evidence has shown GDF15's critical role in fibrosis in multiple organs, such as the liver, lung, and kidney. Evidence further suggests that it can either contribute to fibrosis by promoting inflammation and fibroblast activation or confer protective effects by modulating the immune response and mitigating fibrosis severity. Thus, the exact role of GDF15 in fibrosis can vary depending on the organ involved and the specific disease context. For example, increased GDF15 in idiopathic pulmonary fibrosis (IPF) promotes fibrosis via fibroblast activation and collagen deposition. Conversely, GDF15 might have a protective role in liver fibrosis, with decreased GDF15 levels causing increased fibrosis severity, while GDF15 treatment ameliorates fibrosis. Due to its close association with fibrosis, GDF15 is being investigated as a potential biomarker for disease severity and monitoring treatment response. However, further research unraveling its mechanisms of action is needed to explore the potential of GDF15 as a therapeutic target for treating fibrosis, either by modulating its expression or utilizing its immunomodulatory properties. This review marshals the limited studies addressing the recently appreciated differential role of GDF15 in regulating the fibrotic process in different organs. The review also discusses the aspects of further research needed to highlight GDF 15 as a novel predictor and therapeutic target for fibrosis in different organs.
生长分化因子15（GDF15），也被称为非甾体抗炎药激活基因-1（NAG-1）或巨噬细胞抑制细胞因子1（MIC-1），是一种由应激和炎症诱导产生的细胞因子，与转化生长因子-β（TGF-β）超家族有较远的亲缘关系。其水平的显著升高与多种病理状况密切相关，使其成为一种新兴的疾病预后生物标志物。然而，在正常生理和各种病理条件下，大多数GDF15介导的效应仍知之甚少。部分原因是已知的唯一GDF15受体仅定位于大脑，目前尚不清楚GDF15在周围组织中的作用机制。最近越来越多的证据表明，GDF15在肝脏、肺和肾脏等多个器官的纤维化过程中起关键作用。进一步的证据表明，它既可以通过促进炎症和成纤维细胞活化来促进纤维化，也可以通过调节免疫反应和减轻纤维化严重程度来发挥保护作用。因此，GDF15在纤维化中的具体作用可能因所涉及的器官和特定疾病背景而异。例如，特发性肺纤维化（IPF）中GDF15的增加通过成纤维细胞活化和胶原蛋白沉积促进纤维化。相反，GDF15可能在肝纤维化中具有保护作用，GDF15水平降低会导致纤维化严重程度增加，而GDF15治疗则可改善纤维化。由于其与纤维化密切相关，GDF15正在作为疾病严重程度和监测治疗反应的潜在生物标志物进行研究。然而，需要进一步研究揭示其作用机制，以探索通过调节其表达或利用其免疫调节特性将GDF15作为治疗纤维化的治疗靶点的潜力。这篇综述整理了有限的研究，这些研究探讨了最近认识到的GDF15在调节不同器官纤维化过程中的差异作用。该综述还讨论了进一步研究的方向，以突出GDF15作为不同器官纤维化的新型预测指标和治疗靶点。
