Sodium butyrate protects against necrotizing enterocolitis through a mechanism involving YB-1-dependent regulation of intestinal epithelial apoptosis.

Due to a lack of complete mechanistic understanding, there are no specific therapeutics for necrotizing enterocolitis (NEC), a deadly gastrointestinal disease affecting premature newborns. While sodium butyrate offers intestinal protection, its efficacy is strictly dose-dependent, and the underlying mechanisms regulating intestinal epithelial cell (IEC) survival remain elusive. Here, using neonatal murine NEC models and human IECs, we demonstrate that moderate-dose butyrate (50 mg/kg) significantly attenuates mucosal injury and improves survival, whereas high-dose butyrate (250 mg/kg) exacerbates mortality by inducing complex cell death pathways including necroptosis and ferroptosis. Mechanistically, moderate butyrate suppresses glycolysis and intracellular lactate production, which restores expression of the translational regulator PABPC1; PABPC1 then binds to YB-1 mRNA to enhance YB-1 protein synthesis without altering transcription. Elevated YB-1 subsequently binds BCL-2 mRNA, increasing BCL-2 protein levels to inhibit intrinsic mitochondrial apoptosis. Functional validation shows that YB-1 knockdown abolishes butyrate-mediated protection and exacerbates TNF-α-induced apoptosis, while YB-1 overexpression rescues cell viability, and exogenous lactate supplementation reverses these effects by suppressing the PABPC1-YB-1 axis. These findings elucidate a novel Lactate-PABPC1-YB-1-BCL-2 signaling axis through which butyrate safeguards the intestinal epithelium, highlighting precise dosing and the modulation of epithelial translational control as promising therapeutic strategies for NEC.