Spinal cord injury (SCI), a severe central nervous system disorder, often results in motor and sensory dysfunction, causing significant psychological and economic burdens globally. Annually, 250,000 to 500,000 individuals worldwide suffer from SCI [1]. Current treatments, including high-dose methylprednisolone, gangliosides, immunoglobulin G, and exogenous basic fibroblast growth factor, offer limited clinical benefits due to SCI's complex pathophysiology [[2], [3], [4]]. SCI involves two pathological phases: primary injury from direct mechanical damage and secondary injury triggered by processes like hypoxia, ischemia, inflammation, oxidative stress, pyroptosis, and mitochondrial dysfunction [5,6]. Microglia-driven neuroinflammation plays a pivotal role in the secondary injury phase following SCI. During this process, activated M1 microglia exacerbate neural damage through the release of detrimental proinflammatory mediators, including IL-1β and TNF-α. Conversely, the M2 phenotype exerts neuroprotective effects by promoting tissue repair and anti-inflammatory responses via the secretion of factors such as IL-4 and IL-10 [7]. Therefore, regulating microglial polarization has become a crucial strategy for treating SCI.

Autophagy, a crucial self-protection mechanism in eukaryotic cells, eliminates cellular waste and damaged organelles, playing a pivotal role in the pathophysiology of neurological disorders [8]. Mitophagy, a selective form of autophagy, specifically targets and removes damaged or dysfunctional mitochondria to maintain cellular homeostasis and energy balance. Its activation exerts neuroprotective effects in SCI by reducing ROS levels and mitigating pyroptosis [9,10]. Enhancing mitophagy to alleviate inflammation and improve functional outcomes may thus represent a promising therapeutic strategy for SCI.

Na+/K+-ATPase (NKA), a ubiquitously expressed membrane protein in mammalian cells, hydrolyzes ATP to transport Na + and K+, maintaining ion balance [11,12]. Its dysfunction is closely linked to psychiatric and neurodegenerative disorders [[13], [14], [15]]. A previous study suggest a correlation between NKA and autophagy, with autophagy activation regulating NKA activity to influence disease progression [15]. Additionally, NKA activity is significantly reduced in the injured spinal cord tissues of SCI model animals [16].

Lupeol, a natural triterpenoid present in vegetables, fruits, and Chinese herbal medicine, exhibits potent antioxidant and anti-inflammatory properties and has demonstrated anticancer effects by inducing apoptosis and regulating the cell cycle [[17], [18], [19]]. Additionally, Lupeol has been shown to reverse NKA activity decline induced by hypercholesterolemia, prevent cardiac tissue hypertrophy, and restore normal ultrastructure [20]. However, its potential in treating SCI and addressing SCI-induced inflammation remains largely unexplored.

In this study, we evaluated the role of Lupeol in LPS-induced cellular pyroptosis in BV2 cells in vitro and the role of Lupeol in SCI progression in mice. Our data may provide a theoretical basis for Lupeol in the treatment of SCI.