Emerging Roles of De Novo Proline Biosynthesis in Human Diseases

De novo proline synthesis is a highly conserved and essential biochemical pathway in mammals. Beyond serving as a fundamental building block for proteins, proline also plays key roles in diverse cellular functions and maintaining tissue homeostasis. Over the past decade, accumulating evidence has underscored the significance of this pathway in regulating critical cellular processes, including redox balance, cell growth, signal transduction, and the synthesis of nucleotides and proteins, as well as overall cellular metabolism. The biosynthesis of proline is tightly controlled by multiple evolutionarily conserved mechanisms to ensure proper cellular function. Importantly, disruptions in proline metabolism-particularly changes in the activity or expression of enzymes involved in its synthesis and degradation-have been implicated in the onset and progression of several diseases, notably cancer and fibrosis. In this review, we highlight recent advances in understanding the regulation of de novo proline synthesis. We also examine how dysregulation of this pathway contributes to disease development and influences therapeutic outcomes. Finally, we explore the therapeutic potential of targeting proline metabolism in disease treatment.