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A rare hereditary, metabolic disease characterized by serum levels of alpha-1-antitrypsin (AAT) that are well below the normal range. In the most severe form, the disease can clinically manifest with chronic liver disorders (cirrhosis, fibrosis), respiratory disorders (emphysema, bronchiectasis), and rarely panniculitis or vasculitis.
Low-dose metformin activates AMPK/ULK1 pathway while micro-dose rapamycin inhibits mTORC1, synergistically enhancing autophagosome formation and clearance of aggregated Z-variant SERPINA1 through LC3B-II and SQSTM1/p62-mediated selective autophagy
Evolocumab increases hepatic LDLR and LRP1 expression, enhancing cellular uptake of exogenous AAT therapy. Simultaneously reduces PCSK9-mediated degradation of SERPING1 and other serpins, creating synergistic anti-protease environment in lung tissue
Curcumin inhibits NF-κB p65 nuclear translocation and reduces CXCL8 (IL-8) secretion from lung epithelial cells. Piperine enhances bioavailability and independently reduces ADAM17-mediated shedding of TNFR1, breaking the inflammatory amplification loop that depletes functional AAT
Schisandrin B and schisandrol A activate SIRT1/FOXO3 pathway, reducing ER stress markers (GRP78, CHOP) and enhancing proper folding of mutant SERPINA1 protein through upregulation of protein disulfide isomerase (PDIA1) and calnexin (CANX)
Dasatinib + quercetin senolytic therapy eliminates p16INK4a+ senescent alveolar epithelial cells that secrete SASP factors (IL-6, TNF-α) promoting neutrophil elastase (ELANE) activity and reducing local SERPINA1 effectiveness through oxidative modifications at Met358 residue
Ashwagandha (Withania somnifera) withanolides and Brahmi (Bacopa monnieri) bacosides enhance mitochondrial biogenesis through PGC1α/TFAM pathway, increasing extrahepatic SERPINA1 expression in lung epithelial cells and macrophages via NRF2-mediated transcriptional activation