Research Progress on the Target GDF15 Signaling Pathway and Related Drugs

Growth differentiation factor 15 (GDF15), identified and discovered from activated macrophage lineage clones, functions as an autocrine regulatory molecule in macrophages and serves as an endocrine hormone. It belongs to the transforming growth factor β (TGFβ) superfamily. The GDF15 molecule has been given various names based on the tissue source or function at the time of its discovery: macrophage inhibitory cytokine-1 (MIC-1), placental bone morphogenetic protein (PLAB), placental transforming growth factor-β (PTGF-β), nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), and prostate-derived factor (PDF).

GDF15 primarily participates in organ growth, differentiation, development, and cellular repair. Under physiological conditions, GDF15 expression is low in tissues other than the placenta. However, under pathological conditions such as inflammation or traumatic stress, where various stimuli including TGFβ, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) are present, GDF15 expression is upregulated. Endoplasmic reticulum stress induced by IL-1β or tunicamycin can stimulate GDF15 expression in hepatocytes. In non-alcoholic fatty liver disease (NAFLD), hepatic GDF15 expression is directly correlated with IL-1β levels and the severity of steatosis, indicating GDF15 serves as an inflammatory marker or stress response protein. Numerous studies have shown that elevated GDF15 levels are associated with cardiovascular diseases such as cardiac hypertrophy, heart failure, atherosclerosis, and endothelial dysfunction, as well as obesity, diabetes, cancer, and cachexia. GDF15 has been validated as a novel biomarker for the diagnosis, progression, or prognosis of these diseases. As a biomarker for obesity, diabetes, cancer, NAFLD, and ischemic diseases, GDF15 has emerged as a new target for new drug development.

Application of GDF15 Target in Diseases

1. GDF15 and Obesity and Related Metabolic Diseases

The GDF15 molecule plays a role in regulating food intake and energy metabolism, driving research into the potential functions of targeting GDF15 in pathological conditions of excess nutrition (obesity) and malnutrition (anorexia/cachexia). The GDNF family receptor alpha-like (GFRAL) is a receptor localized in the neurons of the area postrema, essential for GDF15-mediated anorexia. This ligand-receptor relationship has outlined a novel pathway for controlling energy homeostasis. While sharing some characteristics with other endocrine factors that regulate food intake, GDF15 remains unique in several aspects. For instance, the regulation of GDF15/GFRAL facilitates increased and maintained tissue expression levels across various conditions. Unlike transient postprandial anorectic signals, postprandial GDF15 levels do not increase.

GDF15 possesses dual functions of appetite suppression and increased peripheral energy expenditure, playing a crucial role in the prevention and treatment of obesity. The discovery of GDF15 has opened up new avenues for anti-obesity therapy. Studies have shown that anorexia in patients with advanced cancer is related to the TGFβ pathway, mediated by MIC-1 regulating the feeding center. Normal mice administered with systemic MIC-1 and transgenic mice overexpressing MIC-1 exhibit dysphagia and weight loss. Furthermore, metformin, a star molecule in anti-diabetic drugs, has also been proven to exert its anti-obesity effects through GDF15. It elevates serum GDF15 levels, reducing food intake and body weight by restricting the brainstem, independently of blood glucose reduction. GDF15 has been validated as a biomarker in patients with abnormal blood glucose taking metformin, with its concentration reflecting the metformin dose. Additionally, elevated serum GDF15 in type 2 diabetes patients treated with metformin is associated with weight loss. Therefore, developing drugs for obesity and cancer-induced cachexia based on the brain GDF15-GFRAL-RET receptor signaling complex becomes feasible. Beyond its central role in inhibiting food intake, GDF15 also exerts anti-obesity effects through peripheral mechanisms such as promoting thermogenesis and reducing adipogenesis. During cold exposure and adrenergic stimulation, brown and beige adipose tissues release GDF15, targeting macrophages to mediate local downregulation of inflammatory pathways, thereby exerting a thermogenic effect. This suggests that GDF15 may function as a brown adipose tissue cytokine.

2. GDF15 and Non-alcoholic Fatty Liver Disease (NAFLD)

Research has revealed that excess lipid accumulation and endoplasmic reticulum stress in the liver may potentiate the expression of GDF15 in mice. In animal models of non-alcoholic steatohepatitis (NASH) and in human subjects with NASH, increased expression of GDF15 is observed in the liver. Notably, liver-specific Gdf15 gene knockout mice exhibit exacerbated NASH phenotypes, including increased steatosis, inflammation, fibrosis, liver damage, and metabolic deterioration. In contrast, Gdf15 transgenic mice or ectopic expression of hepatic GDF15 enhance fatty acid β-oxidation in the liver of mice fed a high-fat diet, reducing hepatic lipid accumulation and thereby mitigating the progression and metabolic deterioration of NAFLD and NASH.

GDF15 emerges as a novel biomarker for advanced fibrosis in NAFLD. Among NAFLD patients, the highest quartile of GDF15 levels is significantly associated with an increased risk of advanced fibrosis. In LX-2 cells treated with GDF15, the phosphorylation of Smad2 and Smad3 leads to enhanced expression of α-smooth muscle actin and collagen I. On the other hand, improvements in metabolic inflammation and weight loss reduce hepatic GDF15 expression, suggesting that hepatic GDF15 may act as a negative feedback mechanism in controlling energy balance in NAFLD.

3. GDF15 and Cancer

GDF15 serves as a biomarker for cancer diagnosis, disease progression, and prognosis. Its levels are elevated in various solid tumor types, making it a diagnostic biomarker for pancreatic cancer, colorectal cancer, ovarian cancer, prostate cancer, primary liver cancer, and lung cancer. Furthermore, GDF15 correlates with disease progression, prognosis, and overall survival in multiple cancer types, including colorectal cancer, gastric cancer, hepatocellular carcinoma, non-small cell lung cancer, urothelial/renal cell carcinoma, ovarian cancer, and breast cancer. However, no correlation has been found between GDF15 and hematological malignancies.

GDF15 can also serve as a biomarker for predicting the efficacy of chemotherapy drugs and drug resistance responses. Studies have shown that serum GDF15 levels are significantly higher in patients with epithelial ovarian cancer who are resistant to platinum-based first-line chemotherapy (carboplatin or cisplatin) compared to chemotherapy-sensitive patients, and patients with high GDF15 expression have a shorter progression-free survival. Additionally, GDF15 plays a crucial role in the diagnosis of primary liver cancer and the evaluation of chemotherapy efficacy. As an immune checkpoint, GDF-15 represents a novel target for cancer immunotherapy. Cancer is characterized by tumor cells evading immune surveillance, and given GDF15's role as an inflammatory marker, it is expected that GDF15 can influence tumor immunity. Depletion of glioma-derived GDF15 enhances the sensitivity of mouse glioma cells to syngeneic natural killer cells and spleen cells, leading to reduced tumorigenicity, increased T-cell infiltration, improved immune response, and prolonged survival. Therefore, endogenous GDF15 contributes to the proliferation and immune escape of malignant gliomas. Dendritic cells (DCs) play a pivotal role in initiating antigen-specific immune responses. Research indicates that GDF15 is an effective inhibitor of DC maturation and function, potentially suppressing the formation of surface protrusions during DC maturation, promoting TGFβ1 secretion, inhibiting T-cell stimulation and CD8+ T-lymphocyte activation, thereby suppressing tumor-specific immune responses and facilitating tumor cell immune escape. As a well-established biomarker for cancer diagnosis, prognosis, and chemotherapy resistance, as well as an immune checkpoint, GDF15 represents a novel target for cancer immunotherapy, providing new avenues for anti-tumor drug development.

4. GDF15 and Cardiovascular Diseases

GDF15 is involved in the development of various cardiovascular diseases, with its elevated levels being associated with myocardial hypertrophy, heart failure, atherosclerosis, and endothelial dysfunction. During myocardial ischemia-reperfusion injury, stress in cardiomyocytes, macrophages, endothelial cells, vascular smooth muscle cells, and adipocytes can induce increased expression of GDF15. Endothelial dysfunction represents the initial step in the progression of cardiovascular diseases, and GDF15 levels increase both during endothelial dysfunction and in cardiovascular diseases. Studies have shown that GDF15 produced by senescent endothelial colony-forming cells may act in a paracrine manner on non-senescent cells, exerting a beneficial effect in vascular dysfunction by limiting endothelial dysfunction related to vascular stress. Therefore, based on current research findings, GDF15 is considered a novel cardiogenic cytokine. However, its role in cardiovascular diseases and its potential as a therapeutic target for cardiovascular drug development require further experimental data for confirmation.

GDF15 is a pleiotropic protein that plays a crucial role in various complex diseases and has emerged as a novel biomarker for disease diagnosis, progression, or prognosis, as well as a new therapeutic target. Currently, the indications for drug development targeting GDF15 encompass diverse therapeutic areas such as obesity, diabetes, cancer, and anorexia, with various drugs being in different stages of preclinical or Phase I clinical trials. Regarding its precise anorectic and immune checkpoint functions, anti-obesity drugs have been developed by leveraging its activating effects, such as GDF15 analogues and GFRAL receptor agonists. Conversely, anorexic syndromes and anti-cancer drugs have been developed by exploiting its antagonistic effects, including GDF15 monoclonal antibodies and GFRAL antagonist monoclonal antibodies.

References:

[1] Zheng Lei, Feng Yingming, Song Yang, Li Hong, Nie Na, Su Haichuan. Preparation, Identification, and Preliminary Exploration of Medicinal Value of Monoclonal Antibody against Human Growth Differentiation Factor 15. Progress in Modern Biomedicine, 2015, 15(24): 4601-4604. DOI: 10.13241/j.cnki.pmb.2015.24.001.

[2] Xu Chuanyang, Wang Zhaowei, He Lei, Pang Zhijun, Zhu Yichao, Li Weina, Li Zhengmin. Research Progress of the New Therapeutic Target GDF15/GFRAL Signaling Pathway in Obesity and Metabolism-Related Diseases. China Medical Herald, 2019, 16(18): 25-29.

[3] Qiang Hao, Sun Mingxia, Wang Hongjian, Zhu Tingting, Ji Tengfei. The Mechanism of Action of the Novel Target GDF15 and the Current Status of Related Drug Research and Development. Acta Pharmaceutica Sinica, 2021, 56(10): 2728-2734. DOI: 10.16438/j.0513-4870.2021-0675.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.