β-Hydroxy-β-methylbutyrate attenuates sepsis-associated lung injury by regulating NF-κB p65-mediated inflammation, ER stress and mitochondrial apoptosis in a rat model.

Sepsis-induced acute lung injury (ALI) is a leading cause of mortality in intensive care, driven by inflammatory, apoptotic, and oxidative stress pathways. β-Hydroxy-β-methylbutyrate (HMB), a leucine metabolite, exhibits anti-inflammatory and antioxidant effects, but its role in septic lung injury remains unclear. Thirty-two male Wistar rats were randomized into four groups (n = 8 each): Control, HMB (300 mg/kg), cecal ligation and puncture (CLP), and CLP + HMB. Lung tissues were analyzed histopathologically, nuclear factor kappa B p65 (NF-κB p65) and caspase 3 (Cas-3) expression was evaluated immunohistochemically, and mRNA expression of C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), caspase 12 (Cas-12), B-cell lymphoma 2 (BCL-2), BCL-2-associated X protein (BAX), cytochrome C (Cyt-C), nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) was measured at the molecular level. CLP induced upregulation of NF-κB p65, ER stress markers (CHOP, GRP78, Cas-12), and mitochondrial apoptotic proteins (BAX, Cyt-C, Cas-3), while downregulating BCL-2, NRF2, and GPX4 expression. HMB treatment reversed these expression changes and improved lung histopathology. HMB protects lungs in experimental sepsis by inhibiting NF-κB inflammation, reducing ER and mitochondrial apoptosis, and boosting antioxidant defenses via NRF2/GPX4. These findings support its potential as adjunct therapy for sepsis-induced ALI.