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.
Xiang et al. (2026) studied this question.