Reprogramming lymphatic endothelial glucose metabolism for the treatment of lymphangiogenesis-related disease

Lymphangiogenesis plays important roles in the pathogenesis of several human diseases, including keratitis, transplant rejection, and cancers. Dysregulated glucose metabolism has emerged as a critical driver of pathological lymphangiogenesis. This study aimed to identify novel regulators of this process and elucidate their roles in the metabolic regulation of lymphatic endothelial cells (LECs). miR-484 was identified as a key regulator of LECs, with its expression down-regulated under inflammatory stress and in a suture-induced corneal lymphangiogenesis murine model. Overexpression of miR-484 inhibited the proliferation, migration, tube formation, and sprouting abilities of LECs and corneal lymphangiogenesis in vivo. Mechanistically, miR-484 directly targeted hexokinase 2 (HK2), a central enzyme in glycolysis, thereby modulating glucose metabolism and mitochondrial function to restrain lymphangiogenesis. Moreover, exosome-mediated delivery of miR-484 enhanced its anti-lymphangiogenic efficacy while exhibiting favorable biosafety. Collectively, these findings highlight the miR-484-HK2 axis as a potential therapeutic target and support the use of exosome-based strategies for safe and effective intervention in pathological lymphangiogenesis.