Nadhan Revathy, Nath Karthik, Basu Sneha, Isidoro Ciro, Song Yong Sang, Dhanasekaran Danny N
Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Nvidia Corporation, 2788 San Tomas Expressway, Santa Clara, CA, USA.
Signal Transduct Target Ther. 2025 Oct 10;10(1):337. doi: 10.1038/s41392-025-02423-4.
Lysophosphatidic acid (LPA) signaling has emerged as a central regulatory axis in both normal physiology and disease, orchestrating diverse cellular processes such as proliferation, survival, migration, immune modulation, and tissue remodeling. Originally identified as a bioactive lipid that regulates smooth muscle contraction and vascular tone, LPA has since emerged as a pleiotropic signaling molecule implicated in multiple physiological systems and a wide spectrum of pathological states. These include cancer, neurodegenerative disorders, cardiovascular and metabolic syndromes, inflammatory conditions, and fibrotic diseases. Elevated LPA levels, overexpression of autotaxin (ATX), and aberrant activation of LPA receptors (LPARs) contribute to disease initiation and progression, positioning the LPA axis as both a diagnostic biomarker and a promising therapeutic target. This review describes the multimodal and multinodal organization of the LPA signaling network, detailing upstream biosynthesis, receptor diversity, and downstream effectors across diverse organ systems. Therapeutic strategies targeting ATX, LPARs, and intracellular mediators are critically assessed, along with a review of ongoing and emerging clinical trials. Furthermore, we introduce a context-aware AI-based neural network model to simulate LPA signaling dynamics, providing a framework for predictive modeling and personalized therapeutic interventions. By integrating mechanistic insights with adaptive computational frameworks, this review positions the LPA axis as a powerful and versatile target for systems biology-guided precision medicine strategies in both health and disease.
溶血磷脂酸（LPA）信号传导已成为正常生理学和疾病中的核心调节轴，协调着多种细胞过程，如增殖、存活、迁移、免疫调节和组织重塑。LPA最初被鉴定为一种调节平滑肌收缩和血管张力的生物活性脂质，此后已成为一种多效性信号分子，涉及多个生理系统和广泛的病理状态。这些包括癌症、神经退行性疾病、心血管和代谢综合征、炎症性疾病以及纤维化疾病。LPA水平升高、自分泌运动因子（ATX）过表达以及LPA受体（LPARs）的异常激活促进疾病的发生和发展，使LPA轴成为一种诊断生物标志物和有前景的治疗靶点。本综述描述了LPA信号网络的多模式和多节点组织，详细介绍了不同器官系统中的上游生物合成、受体多样性和下游效应器。对靶向ATX、LPARs和细胞内介质的治疗策略进行了严格评估，并回顾了正在进行和新兴的临床试验。此外，我们引入了一种基于上下文感知人工智能的神经网络模型来模拟LPA信号动态，为预测建模和个性化治疗干预提供了一个框架。通过将机制性见解与适应性计算框架相结合，本综述将LPA轴定位为健康和疾病中系统生物学导向的精准医学策略的强大且通用的靶点。
