Wang Xiaojun, Chang Hung-Chen, Gu Xuchao, Zhang Yuxin, Bao Zhijun
Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, People's Republic of China.
Shanghai Institute of Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, People's Republic of China.
Clin Interv Aging. 2025 Jun 28;20:911-929. doi: 10.2147/CIA.S522049. eCollection 2025.
The angiopoietin-like protein 4 (ANGPTL4), also known as fasting-induced adipose factor, is a secreted glycoprotein that belongs to the ANGPTL protein family. Due to its expression in various cell types and tissues and its interactions with other proteins, ANGPTL4 plays diverse roles within its family, exhibiting a wider range of molecular functions. For instance, ANGPTL4 is intricately involved in modulating central energy metabolism and enhancing exercise endurance, while also acting as a pivotal mediator in the interaction between gut microbiota and host lipid metabolism. Moreover, the expression of ANGPTL4 is directly controlled by aging-related signaling pathways. Its excessive activation accelerates the aging process by triggering mechanisms like heightened oxidative stress, epithelial-mesenchymal transition (EMT) and fibrosis, abnormal lipid accumulation, and cellular arrest, thereby advancing the development of age-related diseases. Given the pivotal roles of ANGPTL4 and its associated molecules in organ fibrosis and cancer advancement, targeting ANGPTL4 emerges as a promising therapeutic approach. However, the intricate and sometimes conflicting functions of the two cleavage fragments of ANGPTL4, namely N-terminal fragment (nANGPTL4) and C-terminal fragment (cANGPTL4), in different chronic diseases-exerting inhibitory or stimulatory effects depending on the disease stage-have posed challenges to the progress of ANGPTL4 antibody therapy. This review provides an overview of the biological mechanisms of ANGPTL4, its dual impact on fibrosis and tumorigenesis, and highlights its recent advancements as a potential biomarker in age-related diseases and inflammation-related conditions. ANGPTL4 is a high-potential but complex target, requiring mechanism-driven strategies for safe clinical translation.
血管生成素样蛋白4（ANGPTL4），也被称为禁食诱导脂肪因子，是一种分泌型糖蛋白，属于ANGPTL蛋白家族。由于其在多种细胞类型和组织中的表达以及与其他蛋白质的相互作用，ANGPTL4在其家族中发挥着多种作用，展现出更广泛的分子功能。例如，ANGPTL4复杂地参与调节中枢能量代谢和增强运动耐力，同时还在肠道微生物群与宿主脂质代谢的相互作用中充当关键介质。此外，ANGPTL4的表达直接受衰老相关信号通路的控制。其过度激活通过引发如氧化应激增强、上皮-间质转化（EMT）和纤维化、异常脂质积累以及细胞停滞等机制加速衰老过程，从而推动与年龄相关疾病的发展。鉴于ANGPTL4及其相关分子在器官纤维化和癌症进展中的关键作用，靶向ANGPTL4成为一种有前景的治疗方法。然而，ANGPTL4的两个裂解片段，即N端片段（nANGPTL4）和C端片段（cANGPTL4），在不同慢性疾病中具有复杂且有时相互矛盾的功能，根据疾病阶段发挥抑制或刺激作用，这给ANGPTL4抗体治疗的进展带来了挑战。本综述概述了ANGPTL4的生物学机制、其对纤维化和肿瘤发生的双重影响，并强调了其作为与年龄相关疾病和炎症相关病症潜在生物标志物的最新进展。ANGPTL4是一个具有高潜力但复杂的靶点，需要基于机制的策略以实现安全的临床转化。
