AGAPIR: A Novel PIWI-Interacting RNA Enhancing Post-Decompression Angiogenesis in Degenerative Cervical Myelopathy

Degenerative cervical myelopathy (DCM) is the most common cause of spinal cord dysfunction worldwide. Although surgical decompression can halt disease progression and improve neurological function in most patients, there remains a subset for whom functional improvement is limited. Impaired spinal cord perfusion is a pathological hallmark of DCM, which highlights the importance of restoring blood flow to enhance neurological outcomes. Here, this work identifies a novel angiogenesis-associated PIWI-interacting RNA (AGAPIR) that enhances angiogenesis and motor function following spinal cord decompression. Using piRNA sequencing, this work identifies AGAPIR as a key regulator of DCM pathogenesis. This work observes significant upregulation of AGAPIR expression in the spinal cord following surgical decompression, which is correlated with enhanced angiogenesis. Overexpression of AGAPIR markedly improves blood vessel formation and promotes motor function in mice following spinal cord decompression. Using RNA sequencing and cellular validation, this work finds that AGAPIR directly interacts with USP18, leading to an increase in its protein expression level and stabilization of HIF-1α protein via its deubiquitinating activity. This data demonstrate that AGAPIR is a novel piRNA that further improves the functional status of DCM mice following surgical decompression. These results provide the pioneering evidence and novel insights into piRNA-directed therapeutic strategies for DCM.