Senp1 knockdown alleviates neuronal pyroptosis after subarachnoid hemorrhage by enhancing PINK1-mediated mitophagy

Subarachnoid hemorrhage (SAH) is a critical condition in neurosurgery, and the severity of early brain injury (EBI) plays a pivotal role in determining patient outcomes. Recent studies have demonstrated that neuronal pyroptosis occurs following SAH, aggravating neuroinflammatory damage and severely affecting prognosis. Small ubiquitin-like modifier (SUMO)-specific protease 1 (Senp1), a member of the SUMO protease family, is known to be involved in the regulation of neuroinflammation. However, whether Senp1 also modulates neuronal pyroptosis to influence neuroinflammation after SAH remains unclear.

A total of 284 male C57BL/6J mice were used to establish the SAH model via endovascular perforation. Fourteen days prior to modeling, an adeno-associated virus carrying Senp1 shRNA was injected into the lateral ventricles of the mice for gene knockdown. Additionally, primary neurons were treated with oxyhemoglobin to simulate the in vitro SAH environment. CCCP and PINK1 siRNA were applied to enhance and inhibit mitophagy, respectively.

Senp1 primarily localized in cortical neurons, with its expression being significantly upregulated following SAH and peaking at 24 h. Its knockdown markedly alleviated brain edema and improved neurological function 24 h after SAH. Moreover, its downregulation reduced the neuronal expression of NLRP3 and cleaved GSDMD, as well as the production of IL-1β and IL-18, thereby attenuating neuroinflammation. Mechanistically, Senp1 knockdown enhanced PINK1-mediated mitophagy, reducing reactive oxygen species accumulation.

Our findings suggest that Senp1 knockdown enhances mitophagy, thereby inhibiting NLRP3 inflammasome-mediated neuronal pyroptosis following SAH and improving EBI and neurological prognosis.