β-aminoisobutyric Acid, a Metabolite of BCAA, Activates the AMPK/Nrf-2 Pathway to Prevent Ferroptosis and Ameliorates Lung Ischemia-Reperfusion Injury

Abstract Background: Lung ischemia-reperfusion injury is a serious clinical problem and there is no effective treatment. Ischemia-reperfusion (I/R) injury is always accompanied with changed branched chain amino acid (BCAA) metabolism. Enhancing BCAA metabolism can protect against ischemia-reperfusion injury. We believe that this phenomenon is related to bioactive molecules produced by BCAA metabolism. And, L-β-aminoisobutyric acid (L-BAIBA) is a metabolite of valine, a member of BCAA. Methods: Adult C57BL/6 mouse were treated with L-BAIBA (150mg/kg/day) in the drinking water for 10 consecutive days before lung L/R injury. Then, lung function indexes including pathology and respiratory function were detected. Potential mechanisms were delineated by molecular biology experiment analysis in A549 cells, including western blot or immunofluorescence staining or biochemical detection and so on. Results:We find that L-BAIBA can protects lung during I/R injury. Further studies show that L-BAIBA can up-regulate the expression of GPX4 and SLC7A11, thereby inhibit ferroptosis. The regulation of L-BAIBA on the expression of GPX4 and SLC7A11 depends on the Nrf-2 signaling pathway. Interfering Nrf-2 eliminates the protective effect of L-BAIBA. We further find that L-BAIBA regulates Nrf-2 by activating AMPK signaling pathway. Meanwhile, in the presence of compound c, the protective effects of L-BAIBA on lung I/R injury are blocked. Conclusion:Our study reveals that L-BAIBA can alleviate lung I/R injury by inhibiting ferroptosis, which is an promising therapeutic target candidate.