MRPL35 Attenuates Neonatal Parenteral Nutrition-Associated Cholestasis by Modulating the ROS/JNK/NF-κB Pathway

This study aimed to elucidate the role of the MRPL35/ROS/JNK/NF-κB signaling pathway in the pathogenesis of neonatal parenteral nutrition-associated cholestasis (PNAC) to identify underlying mechanisms and potential therapeutic targets.

The study employed both human and animal models. Neonates receiving parenteral nutrition for at least 2 weeks were divided into PNAC (n=10) and control groups (n=13). A PNAC model was established in male Sprague-Dawley rats (parenteral nutrition for 14 days, n=6/group), with interventions including adenovirus-mediated MRPL35 overexpression and N-acetylcysteine (NAC) treatment. Inflammatory markers, oxidative stress indicators, and signaling pathway activation were assessed using ELISA, immunohistochemistry, qRT-PCR, and Western blotting.

Clinically, neonates with PNAC exhibited elevated serum levels of AST, DBil, TBA, TNF-α, and IL-1β, along with reduced levels of anti-inflammatory cytokines (IL-4, IL-10), increased ROS, and higher apoptosis in peripheral blood mononuclear cells (PBMCs). MRPL35 expression was significantly downregulated and JNK and NF-κB pathways were activated. In the animal model, PNAC rats showed severe liver injury, elevated TNF-α, IL-1β and ROS in hepatocytes, and higher hepatocyte apoptosis; the expression of MRPL35 mRNA was significantly downregulated. Overexpression of MRPL35 reduced JNK/NF-κB activation, inflammatory cytokines, oxidative stress and liver injury, effects that were enhanced by co-treatment with N-acetylcysteine (NAC).

The MRPL35/ROS/JNK/NF-κB signaling pathway plays a critical role in the pathogenesis of PNAC. Targeting MRPL35 is expected to alleviate liver injury by blocking mitochondrial ROS signaling, offering a novel precision treatment model targeting the mitochondrial-inflammation axis for PNAC.