Semaphorin 7A Induces Liver Inflammation and Promotes Parenteral Nutrition-Associated Cholestasis via ITGβ1/NF-κB Pathway

Abstract Objective To investigate the mechanistic role of semaphorin 7A (Sema7A) in neonatal parenteral nutrition-associated cholestasis (PNAC). Methods Blood samples were collected from neonates, and an established animal model was used to evaluate inflammatory markers and liver pathology in PNAC. We quantified the expression of Sema7A, integrin β1 (ITGβ1), P65, and phosphorylated P65 (p-P65) in neonatal and rat samples, and investigated the NF-κB pathway involvement by manipulating Sema7A and ITGβ1 expression in vitro. The effects of the Sema7A/ITGβ1/NF-κB pathway were validated through targeted interventions in animal models. Results Neonates and rats with PNAC showed increased TNF-α and IL-1β levels, alongside decreased IL-4 and IL-10 levels. Correspondingly, Sema7A, ITGβ1, and P65/p-P65 mRNA and protein expressions were elevated. In vitro, Sema7A overexpression activated the NF-κB pathway, reversible by ITGβ1 inhibition; conversely, Sema7A knockdown attenuated NF-κB activation, partially reversible by ITGβ1 overexpression. In vivo, Sema7A overexpression worsened liver injury and cholestasis through NF-κB pathway activation, while its inhibition ameliorated these effects. Conclusions Sema7A activates the NF-κB signaling pathway in an ITGβ1-dependent manner, exacerbating PN-induced liver injury and cholestasis. Targeting Sema7A may offer a therapeutic strategy for alleviating neonatal PNAC.