The human ribonuclease A (hRNase A) superfamily is comprised of 13 members of secretory RNases, most of which are recognized as catabolic enzymes for their ribonucleolytic activity to degrade ribonucleic acids (RNAs) in the extracellular space, where they play a role in innate host defense and physiological homeostasis. Interestingly, human RNases 9–13, which belong to a non-canonical subgroup of the hRNase A superfamily, are ribonucleolytic activity-deficient proteins with unclear biological functions. Moreover, accumulating evidence indicates that secretory RNases, such as human RNase 5, can be internalized into cells facilitated by membrane receptors like the epidermal growth factor receptor to regulate intracellular RNA species, in particular non-coding RNAs, and signaling pathways by either a ribonucleolytic activity-dependent or -independent manner. In this review, we summarize the classical role of hRNase A superfamily in the metabolism of extracellular and intracellular RNAs and update its non-classical function as a cognate ligand of membrane receptors. We further discuss the biological significance and translational potential of using secretory RNases as predictive biomarkers or therapeutic agents in certain human diseases and the pathological settings for future investigations.

人类核糖核酸酶A（hRNase A）超家族由13种分泌性RNase组成，其中大多数被认为是分解代谢酶，因为它们具有核糖核酸分解活性，可降解细胞外空间中的核糖核酸（RNA），并在先天宿主中发挥作用防御和生理稳态。有趣的是，属于hRNase A超家族非典型亚组的人RNase 9-13是核糖核酸水解活性不足的蛋白，其生物学功能尚不清楚。此外，越来越多的证据表明，分泌型RNase（例如人RNase 5）可以通过膜受体（例如表皮生长因子受体）促进进入细胞内，从而调节细胞内RNA种类，尤其是非编码RNA，和核糖核酸分解活性依赖性或非依赖性方式的信号传导途径。在这篇综述中，我们总结了hRNase A超家族在细胞外和细胞内RNA代谢中的经典作用，并更新了其作为膜受体同源配体的非经典功能。我们进一步讨论了在某些人类疾病中使用分泌性RNase作为预测性生物标志物或治疗剂的生物学意义和翻译潜力，以及未来研究的病理背景。