Multi‐Omics Profiling Reveals PDK4 as a Key Regulator of Acute Lung Injury in Glufosinate‐Ammonium Poisoning

Glufosinate-ammonium (GA) is a widely utilised herbicide. With the gradual phase-out of highly toxic herbicides, the usage rate of GA as an alternative herbicide has significantly increased, which has led to a rise in GA poisoning incidents. In this study, an acute GA poisoning mouse model was constructed and integrated transcriptomic, proteomic and functional experiments to systematically elucidate the molecular mechanisms underlying GA-induced acute lung injury. For the first time, pyruvate dehydrogenase kinase 4 (PDK4) was identified as a potential therapeutic target. Our findings demonstrated that GA poisoning significantly impaired lung tissue structure and inflammatory balance in mice, characterised by alveolar damage, increased neutrophil infiltration, elevated levels of pro-inflammatory factors (TNF-α, IL-1β, IL-6) and reduced levels of anti-inflammatory factors (IL-10). Transcriptomic and proteomic analyses revealed significant upregulation of PDK4 at both gene and protein levels, indicating its pivotal role in GA-induced lung injury. Further experimentation showed that the PDK4 inhibitor (PDK4-IN-1) could markedly reduce neutrophil infiltration, restore the balance of pro-inflammatory and anti-inflammatory factors and mitigate pathological lung tissue damage. In conclusion, this study revealed the core position of PDK4 in GA-induced lung injury, providing a theoretical basis for the treatment of GA-induced lung injury. Given the safety of PDK4 inhibitors in preclinical tumour models, the potential for further study is noteworthy.