Targeting glycolytic reprogramming by tsRNA-0032 for treating pathological lymphangiogenesis

Abstract

Lymphangiogenesis is vital for tissue fluid homeostasis, immune function, and lipid absorption. Disruption of this process is implicated in diseases such as cancer, inflammation, and autoimmune disorders. In this study, we elucidate the role of tsRNA-0032 in lymphangiogenesis and its molecular mechanisms. tsRNA-0032 expression is significantly diminished in corneal suture and LPS-induced human lymphatic endothelial cell (HLEC) models under inflammatory conditions. Overexpression of tsRNA-0032 suppresses lymphangiogenesis by inhibiting HLEC proliferation, migration, and tube formation. Moreover, overexpression of tsRNA-0032 inhibits suture-induced mouse corneal lymphangiogenesis in vivo. tsRNA-0032 is mainly found in the cytoplasm and interacts with Ago2 protein. Overexpression of tsRNA-0032 leads to a reduction in ATP production and lowers the levels of pyruvate and lactate by targeting PKM2, which is crucial for the final step of glycolysis. This regulation of glycolysis impacts the cellular energy and metabolic balance in HLECs, contributing to the inhibition of lymphangiogenesis. Clinical data show that tsRNA-0032 levels are markedly lower in corneal tissues from transplant recipients compared to donors, whereas PKM2 expression is elevated, underscoring the clinical significance of the tsRNA-0032/PKM2 axis in corneal lymphangiogenesis. This study provides novel insights into lymphangiogenesis regulation and offers potential therapeutic targets for lymphatic-related diseases.