Bilirubin Alleviates Spinal Cord Injury by Enhancing SOCS3‐Mediated Anti‐Inflammatory Effects via Gas6‐Axl Signaling

ABSTRACT Background Many studies have emphasized the role of microglia‐mediated neuroinflammation in spinal cord injury (SCI); however, effective clinical targets remain elusive. The growth arrest‐specific 6 (Gas6)/Axl receptor tyrosine kinase (Axl) signaling pathway has been implicated in reducing inflammation, promoting tissue repair, and functional recovery. Here, we elucidate the importance of the Gas6‐Axl signaling pathway in SCI repair and evaluate the role of bilirubin in modulating Gas6‐Axl signaling after SCI. Methods SCI mice model was used to investigate the effects of bilirubin treatment on inflammation and motor function recovery. Additionally, Gas6‐deficient ( Gas6 − / − ) mice and wild‐type (WT) mice were employed to examine the role of Gas6‐Axl signaling in SCI recovery. Microglial cells were cultured to assess the effects of bilirubin on the activation of the Gas6‐Axl‐SOCS3 signaling pathway. Results Gas6 − / − mice exhibited increased mortality, severe locomotor deficits, and impaired neuromuscular activity compared to WT mice. Bilirubin treatment in SCI models facilitated recovery by upregulating Gas6‐Axl signaling, which in turn enhanced SOCS3 expression and suppressed the expression of pro‐inflammatory mediators such as IL‐1β and MMP‐9. Furthermore, bilirubin treatment reduced microglial activation, highlighting its neuroprotective and anti‐inflammatory properties. Conclusions This study underscores the importance of the Gas6‐Axl‐SOCS3 axis in regulating functional recovery and inflammation after SCI. Activation of the Gas6‐Axl pathway, particularly when combined with bilirubin treatment, represents a promising therapeutic strategy for mitigating SCI‐induced damage and improving functional outcomes. Given their central role in both the pathogenesis and resolution of SCI, bilirubin treatment emerges as a promising clinical therapeutic drug for SCI.