Nrf2 regulates angiogenesis in spinal cystic echinococcosis via RTN4

Spinal cystic echinococcosis (CE) is a rare but serious zoonotic disease associated with significant morbidity, disability, and mortality in endemic regions. It has the potential to cause disability or death in more than half of those affected. Due to its complex pathological features, conventional drugs and surgical interventions are often ineffective, highlighting the pressing requirement for identifying novel therapeutic targets. This study aimed to clarify the function of Nrf2, which is highly expressed, in the neovascularization linked to cystic echinococcosis of the spinal cord and to investigate its potentially relevant molecular mechanisms. Establishing a co-culture system between protoscoleces (PSCs) and human umbilical vein endothelial cells (HUVECs) with high expression of Nrf2 significantly enhanced the proliferation, migration, and angiogenesis of HUVECs. Additionally, it exhibited significant anti-angiogenic effects in a cystic Echinococcus granulosus model of the spinal cord in Nrf2 knockout mice. Transcriptome Sequencing revealed a strong correlation between RTN4 and Nrf2, and the upregulation and inhibition of RTN4 via lentivirus confirmed its impact on angiogenesis. The results indicated that RTN4 negatively correlated with Nrf2, inhibiting lumen formation in HUVECs when influenced by PSCs. Furthermore, RTN4 was found to be negatively regulated by Nrf2. In conclusion, Nrf2 might promote angiogenesis by inhibiting RTN4, positioning it as a potential therapeutic target for spinal cystic echinococcosis treatment.

Importance: Spinal cystic echinococcosis represents a severe therapeutic challenge in endemic regions, characterized by progressive osseous destruction and high rates of recurrence following surgical intervention. The pathogenic mechanisms underpinning parasitic establishment and survival, particularly the role of host-derived angiogenesis, remain poorly elucidated, hindering the development of targeted therapies. This study identifies a critical host signaling axis, involving the transcription factor Nrf2 and its downstream target RTN4, which is exploited by Echinococcus granulosus to stimulate neovascularization. Elucidating this Nrf2/RTN4 regulatory pathway provides fundamental insights into host-parasite interactions and unveils a novel mechanistic basis for angiogenesis within the unique bony microenvironment. These findings position the Nrf2/RTN4 axis as a promising therapeutic target for anti-angiogenic strategies aimed at improving the management of this debilitating disease.