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Abbreviations BMP: bone morphogenetic protein CMap: Connectivity Map COPD: chronic obstructive pulmonary disease CT: computed tomography DLCO: diffusing capacity of carbon monoxide DMEM: Dulbecco's modified Eagle's medium ECM: extracellular matrix FBS: fetal bovine serum FDR: false discovery rate FEV 1 : forced expiratory volume in 1 second FVC: forced vital capacity GOLD: Global Initiative for Chronic Obstructive Lung Disease GSEA: Gene Set Enrichment Analysis Lm: mean linear intercept PBS: phosphate-buffered saline TGF: transforming growth factor Vv: volume fraction

When metabolic stress occurs, MOTS-c in cells can be transferred to the nucleus in an AMPK-dependent manner and bind to transcription factors regulated by ARE, thus improving the stress resistance of cells (16, 24)

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By employing a combination of spectrometric, biochemical, and morphological approaches, this study clearly demonstrated that ALA effectively stabilizes hepatic Fe 2+ expression (Figure 1), alleviates ferroptotic changes (Figure 2), reduces oxidative stress by enhancing phosphorylated Nrf-2 activation-mediated downstream anti-oxidative enzymes expressions (Figure 3), decreases the production of NF-B-mediated inflammatory factors (Figure 4), depresses the activation of ER stress signaling (Figure 5), as well as counteracts the imbalance of pro- and anti-apoptotic proteins following CSD (Figure 6)