Dietary stearic acid aggravates acute graft-versus-host disease by promoting oxidative stress and pro-inflammatory...

Acute graft-versus-host disease (aGVHD) remains a major life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although immune activation and tissue inflammation are central to aGVHD pathogenesis, how dietary fatty acid exposure shapes inflammatory responses after transplantation remains insufficiently defined. Building on our previous finding that a high stearic acid diet (HSAD) alters the gut microbiota and aggravates aGVHD, we hypothesized that stearic acid (SA), a major saturated fatty acid, further exacerbates aGVHD by inducing oxidative stress and promoting pro-inflammatory macrophage polarization. Using a murine aGVHD model, we found that HSAD significantly increased serum SA levels and aggravated disease severity. Mechanistically, HSAD enhanced reactive oxygen species (ROS) production in splenocytes and disrupted glutathione redox homeostasis, indicating increased systemic oxidative stress. SA promoted M1-like macrophage polarization both in vivo and in vitro, without directly altering Th1 or Th17 differentiation. Pharmacological ROS scavenging with N-acetylcysteine (NAC) attenuated SA-induced ROS accumulation and M1 polarization. Additionally, SA activated mTOR signaling and promoted NLRP3 inflammasome activation in macrophages, as evidenced by increased NLRP3 expression, caspase-1 cleavage, and IL-1β maturation, which were attenuated by rapamycin. Collectively, these findings identify dietary SA as a modifiable factor that aggravates aGVHD by linking lipid metabolic stress to oxidative injury and M1 macrophage polarization. This work provides a rationale for targeting SA intake or its downstream signaling pathways as a strategy to mitigate aGVHD severity.