Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China; National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, Hunan, PR China.
Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, 410013, PR China.
Biomed Pharmacother. 2020 Nov;131:110791. doi: 10.1016/j.biopha.2020.110791. Epub 2020 Sep 23.
Therapeutic targeting of extracellular proteins has attracted huge attention in treating human diseases. The lysyl oxidases (LOXs) are a family of secreted copper-dependent enzymes which initiate the covalent crosslinking of collagen and elastin fibers in the extracellular microenvironment, thereby facilitating extracellular matrix (ECM) remodeling and ECM homeostasis. Apart from ECM-dependent roles, LOXs are also involved in other biological processes such as epithelial-to-mesenchymal transition (EMT) and transcriptional regulation, especially following hypoxic stress. Dysregulation of LOXs is found to underlie the onset and progression of multiple pathologies, such as carcinogenesis and cancer metastasis, fibrotic diseases, neurodegeneration and cardiovascular diseases. In this review, we make a comprehensive summarization of clinical and experimental evidences that support roles of for LOXs in disease pathology and points out LOXs as promising therapeutic targets for improving prognosis. Additionally, we also propose that LOXs reshape cell-ECM interaction or cell-cell interaction due to ECM-dependent and ECM-independent roles for LOXs. Therapeutic intervention of LOXs may have advantages in the maintenance of communication between ECM and cell or intercellular signaling, finally recovering organ function.
治疗细胞外蛋白已成为治疗人类疾病的研究热点。赖氨酰氧化酶（LOXs）是一族分泌型铜依赖性酶，能够启动细胞外基质（ECM）中胶原蛋白和弹性蛋白纤维的共价交联，从而促进细胞外基质重塑和 ECM 稳态。除了依赖 ECM 的作用外，LOXs 还参与其他生物学过程，如上皮间质转化（EMT）和转录调控，尤其是在缺氧应激下。LOXs 的失调被发现与多种病理学的发生和发展有关，如癌发生和癌症转移、纤维化疾病、神经退行性疾病和心血管疾病。在这篇综述中，我们全面总结了支持 LOXs 在疾病病理学中作用的临床和实验证据，并指出 LOXs 是改善预后的有前途的治疗靶点。此外，我们还提出 LOXs 通过依赖 ECM 和非依赖 ECM 的作用重塑细胞-ECM 相互作用或细胞-细胞相互作用。LOXs 的治疗干预可能有利于维持 ECM 与细胞或细胞间信号之间的交流，最终恢复器官功能。
