Sodium butyrate alleviates neuronal ferroptosis after gas explosion-induced traumatic brain injury via regulation of JNK/P38 MAPK signaling pathway.

This study investigated the neuroprotective effects of sodium butyrate (NaB) against gas explosion (GE)-induced traumatic brain injury (TBI), with particular emphasis on its modulation of ferroptosis. GE exposure was simulated using a shock tube in vivo and a shockwave therapy instrument in vitro. A comprehensive assessment was performed, including behavioral tests, histopathological examination, molecular analyses (c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4), and interleukin-6 (IL-6)/interleukin-10 (IL-10)/tumor necrosis factor-α (TNF-α)), and in vitro validation using a CTX TNA2 rat astrocyte/H19-7 rat hippocampal neuron/GMI-R1 rat microglia (CTX/H19-7/GMI-R) tri-culture system. Pharmacological inhibition with SP600125 (a JNK inhibitor), SB203580 (a p38 MAPK inhibitor), and ferrostatin-1 (Fer-1, a ferroptosis inhibitor) was employed to confirm pathway involvement. GE exposure induced profound neuropathological changes, characterized by mitochondrial cristae disruption, inflammatory cell infiltration, and locomotor deficits. At the molecular level, GE exposure activated the JNK/p38 MAPK pathway (as evidenced by increased JNK and p38 phosphorylation), triggered ferroptosis (elevated Fe2+ and malondialdehyde levels, with reduced GPX4 and SLC7A11 expression), and elicited a pro-inflammatory response (increased IL-6 and TNF-α, decreased IL-10). NaB administration effectively counteracted these deleterious effects by restoring redox homeostasis, suppressing JNK/p38 MAPK activation, and rebalancing inflammatory cytokine profiles. Notably, co-administration of pathway inhibitors potentiated the protective effects of NaB, further corroborating the involvement of JNK/p38 MAPK-mediated ferroptosis in GE-induced TBI. Collectively, these findings indicate that NaB attenuates GE-induced TBI and ferroptosis, likely through inhibition of the JNK/p38 MAPK signaling pathway.