Affinage

SERPINA1

Alpha-1-antitrypsin · UniProt P01009

Length
418 aa
Mass
46.7 kDa
Annotated
2026-06-10
100 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SERPINA1 (A1AT) is a secreted serine protease inhibitor whose canonical function is the neutralization of neutrophil elastase through a reactive-center loop centered on Met358 displayed on an external stressed loop, with two salt bridges (Glu342-Lys290; Glu263-Lys387) stabilizing the native fold (PMID:3289385). Disruption of these stabilizing interactions by natural missense variants causes intracellular polymerization and secretion failure: numerous variants form ER polymers and fail to secrete, while the Z (Glu342Lys) substitution drives polymer assembly that can incorporate wild-type M subunits into heteropolymers in vivo (PMID:29232161, PMID:32699193). This toxic hepatocyte polymer burden is cleared through autophagy/lysosomal degradation, and forced TFEB expression promotes autolysosomal polymer clearance while lowering monomer expression (PMID:23584152). Beyond protease inhibition, A1AT exerts elastase-inhibitory-independent activities: native and oxidized forms equally inhibit caspase-3/caspase-8 and reduce ADAM17/TACE activity to limit hepatocyte apoptosis (PMID:24449466), and it suppresses macrophage iNOS expression and NF-κB activation to dampen NO production (PMID:22975343). A1AT also acts as a hepatocyte-derived signaling ligand, complexing with the EphB2 receptor to drive preadipocyte proliferation, adipose browning, and UCP1-dependent thermogenesis (PMID:39532838), inhibiting RANKL-induced osteoclastogenesis by suppressing RANK and DC-STAMP (PMID:28332697), and promoting chondrogenic differentiation through PKA/CREB and Wnt/β-catenin signaling (PMID:33788977). Circulating A1AT reaches the lung epithelium by active transcytosis across pulmonary endothelium, with SR-BI serving as a key endocytic receptor via clathrin- and caveolae-mediated uptake (PMID:24743137, PMID:26092999). Its expression is tuned at multiple levels, including NQO1 binding to the SERPINA1 3'UTR to promote translation (PMID:27515817), a defined multi-helix 5'-UTR structure that optimizes translation initiation (PMID:36107773), and transcriptional repression by IL-1β via HNF4α in metabolic liver disease, where loss of A1AT disinhibits proteinase-3-mediated cleavage of IL-32γ to drive inflammation and fibrosis (PMID:39939782).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1988 High

    Established the molecular basis of protease inhibition and protein stability, defining the active-site residue and the salt bridges whose disruption causes disease variants.

    Evidence Structural and biochemical characterization of natural protein variants

    PMID:3289385

    Open questions at the time
    • Does not address non-canonical (elastase-independent) functions
    • Mechanism of polymer assembly not resolved at this stage
  2. 1987 Medium

    Determined that A1AT is N-glycosylated on three asparagines during secretion, clarifying post-translational processing in the secretory pathway.

    Evidence Recombinant expression in yeast with endoglycosidase H treatment

    PMID:3315863

    Open questions at the time
    • Yeast glycosylation differs from human; in vivo human glycan structure not defined here
    • Functional consequence of glycosylation not tested
  3. 1993 High

    Extended A1AT expression beyond hepatocytes to intestinal enterocytes and Paneth cells, indicating local production at mucosal surfaces.

    Evidence In situ hybridization and double-label immunohistochemistry of human gut

    PMID:8408656

    Open questions at the time
    • Functional role of intestinal A1AT not established
    • Relative contribution to systemic A1AT pool unknown
  4. 2002 Medium

    Identified mammary gland expression and milk A1AT, with a protease-protective role suggesting a function in protecting milk proteins during digestion.

    Evidence RT-PCR, milk ELISA, in vitro pepsin/pancreatin digestion assays

    PMID:12324297

    Open questions at the time
    • In vivo relevance to infant nutrition not demonstrated
    • Single lab
  5. 2012 Medium

    Revealed an elastase-independent anti-inflammatory mechanism whereby A1AT suppresses macrophage NO production through iNOS and NF-κB inhibition.

    Evidence Macrophage stimulation assays plus exhaled NO in AAT-deficient subjects

    PMID:22975343

    Open questions at the time
    • Direct molecular target upstream of NF-κB not identified
    • Receptor mediating macrophage uptake not defined here
  6. 2013 Medium

    Showed that boosting autophagy/lysosomal biogenesis via TFEB clears toxic Z polymer, defining a degradation route for misfolded intracellular A1AT.

    Evidence Liver-directed TFEB gene transfer in a SERPINA1 deficiency mouse model

    PMID:23584152

    Open questions at the time
    • Selectivity of polymer vs monomer clearance not fully dissected
    • Long-term efficacy and safety not established
  7. 2014 High

    Demonstrated that A1AT inhibits caspase-3/8 and ADAM17 independently of elastase inhibition, establishing a cytoprotective antiapoptotic role.

    Evidence Cell-free caspase assays and mouse acute liver failure models with native vs oxidized A1AT

    PMID:24449466

    Open questions at the time
    • Mode of caspase inhibition (direct vs indirect) not structurally resolved
    • Intracellular access of extracellular A1AT to caspases not fully explained
  8. 2014 Medium

    Established that A1AT is actively transcytosed across pulmonary endothelium, explaining how circulating A1AT reaches lung epithelium.

    Evidence Confocal time-lapse, transwell co-culture, and intravital microscopy with tunicamycin

    PMID:24743137

    Open questions at the time
    • Receptor not yet identified at this stage
    • Quantitative contribution to alveolar A1AT unknown
  9. 2015 High

    Identified SR-BI as a key endocytic receptor mediating A1AT uptake by pulmonary endothelium via clathrin- and caveolae-dependent routes.

    Evidence EM of gold-labeled A1AT, SR-BI Co-IP, siRNA, neutralizing antibody, Scarb1 KO mice

    PMID:26092999

    Open questions at the time
    • Residual 50-70% uptake implies additional receptors
    • Single lab
  10. 2016 High

    Uncovered translational control of A1AT by NQO1 binding the SERPINA1 3'UTR, linking redox status to A1AT protein output.

    Evidence RIP-microarray, biotin pulldown, polysome profiling, luciferase reporter, NQO1-KO mice

    PMID:27515817

    Open questions at the time
    • Precise NQO1 binding element not mapped
    • Mechanistic coupling to ribosome loading not structurally defined
  11. 2017 Medium

    Characterized A1AT as an inhibitor of RANKL-driven osteoclastogenesis through suppression of RANK and DC-STAMP, expanding its role to bone remodeling.

    Evidence In vitro osteoclast differentiation, receptor and gene expression, resorption assays

    PMID:28332697

    Open questions at the time
    • Receptor mediating A1AT effect on osteoclast precursors unknown
    • No in vivo bone phenotype shown
  12. 2017 Medium

    Identified a negative feedback loop in which exogenous A1AT lowers its own SERPINA1 mRNA in hepatocytes and PBMCs.

    Evidence Dose-response treatment of primary human hepatocytes and PBMCs with qRT-PCR

    PMID:28486562

    Open questions at the time
    • Signaling pathway mediating autoregulation not defined
    • Relevance to augmentation therapy dosing unclear
  13. 2017 Medium

    Showed that carbamylated A1AT is an autoantigen recognized by anti-CarP antibodies in rheumatoid arthritis, linking A1AT modification to autoimmunity.

    Evidence Ion exchange fractionation, mass spectrometry, ELISA, synovial fluid detection

    PMID:28291659

    Open questions at the time
    • Pathogenic role of anti-Ca-A1AT antibodies not established
    • Carbamylation site stoichiometry in vivo unknown
  14. 2018 Medium

    Functionally classified novel missense variants by polymerization and secretion behavior, refining genotype-to-pathology relationships.

    Evidence HEK293T overexpression with PAS staining, pulse-chase, elastase assays

    PMID:29232161

    Open questions at the time
    • Overexpression system may not reflect endogenous folding kinetics
    • Clinical penetrance of variants not addressed
  15. 2020 High

    Provided direct structural evidence that wild-type M A1AT is incorporated into Z polymers in vivo, demonstrating heteropolymerization.

    Evidence Antibody epitope crystallography and negative-stain EM of Fab-labeled liver-explant polymers

    PMID:32699193

    Open questions at the time
    • Full polymer interface structure not solved
    • Functional consequence of M incorporation for MZ carriers not quantified
  16. 2020 Medium

    Defined how A1AT deficiency dysregulates neutrophil degranulation via Rac2/PAR2/ROS, and showed augmentation therapy normalizes the membrane proteome.

    Evidence Neutrophil membrane proteomics, FRET, ELISA, in vivo augmentation cohort

    PMID:32060059

    Open questions at the time
    • Direct A1AT target in the Rac2/PAR2 axis not identified
    • Single lab
  17. 2021 Medium

    Established A1AT as a promoter of chondrogenic differentiation acting through PKA/CREB activation and Wnt/β-catenin inhibition.

    Evidence SERPINA1 transfection and recombinant protein in human chondrocytes with pathway and gene analysis plus arthritis models

    PMID:33788977

    Open questions at the time
    • Receptor transducing the chondrocyte signal unknown
    • Direct vs indirect pathway engagement unresolved
  18. 2021 Medium

    Linked SERPINA1 to placental biology and preterm birth through cytoskeletal/Slit-Robo/ECM pathway regulation in trophoblasts and human genetic data.

    Evidence siRNA knockdown with pathway analysis, whole exome sequencing, placental proteomics

    PMID:35477570

    Open questions at the time
    • Mechanism connecting A1AT to actin/Slit-Robo regulation unclear
    • Causality of rare variants not functionally proven
  19. 2024 High

    Identified A1AT as a hepatocyte-derived EphB2 ligand controlling adipose browning and systemic metabolism, a receptor-mediated signaling role.

    Evidence Liver-specific transgenic and KO mice, EphB2 Co-IP, adipocyte assays, metabolic phenotyping

    PMID:39532838

    Open questions at the time
    • Structural basis of A1AT-EphB2 interaction not solved
    • Whether protease-inhibitory activity is required not determined
  20. 2025 High

    Positioned A1AT in a MASH circuit where IL-1β/HNF4α represses A1AT, disinhibiting PR3 cleavage of IL-32γ to drive liver inflammation and fibrosis.

    Evidence Quintuple Serpina1 KO mice, cleavage-resistant IL-32γ mutant, HNF4α analysis, in vivo A1AT restoration

    PMID:39939782

    Open questions at the time
    • Direct HNF4α binding at the SERPINA1 promoter not structurally mapped
    • Translation of PR3 inhibition to human MASH not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How A1AT's diverse receptor-mediated and protease-independent signaling functions are integrated, and which require versus do not require its protease-inhibitory activity, remains unresolved.
  • No unified structural model linking elastase inhibition, EphB2 binding, and caspase inhibition
  • Receptors for several non-canonical effects (chondrocyte, osteoclast) unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0048018 receptor ligand activity 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2 GO:0140096 catalytic activity, acting on a protein 1
Partners
EPHB2NQO1SCARB1

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 SERPINA1/A1AT inhibits neutrophil elastase through an active site centered around Met358 contained within an external stressed loop on the surface of the molecule. Two salt bridges (Glu342-Lys290; Glu263-Lys387) are critical for protein stability; disruption of either causes distinct molecular pathology resulting in reduced serum A1AT levels. Molecular characterization of protein variants, structural analysis, active-site mutagenesis inference from natural variants The American journal of medicine High 3289385
1993 The SERPINA1 gene is expressed in human intestinal enterocytes (villous and crypt) in vivo, and also in Paneth cells where it co-localizes with lysozyme, as demonstrated by in situ hybridization and double-label immunohistochemistry of human jejunum and ileum. In situ hybridization, double-label immunohistochemistry The Journal of clinical investigation High 8408656
1987 Human A1AT is glycosylated on three asparagine residues during secretion. When expressed in yeast, the protein receives core carbohydrate on two or three asparagine residues; the secreted yeast form additionally acquires outer mannose chains (yeast-type), all removable by endoglycosidase H treatment. Recombinant expression in Saccharomyces cerevisiae, endoglycosidase H treatment, analysis of mnn9 mutant Gene Medium 3315863
2002 Alpha-1-antitrypsin is produced by the mammary gland (mRNA detected by PCR) and is present in human milk at high concentrations early in lactation. A1AT resists in vitro proteolysis by pepsin and pancreatin and, when present, protects lactoferrin from pancreatin-mediated digestion. RT-PCR of mammary gland cDNA, ELISA measurement in milk samples, in vitro digestion assay with pepsin/pancreatin The American journal of clinical nutrition Medium 12324297
2014 A1AT is actively transcytosed across pulmonary endothelial cells to lung epithelial cells. Uptake involves the classical secretory/Golgi pathway; inhibition of Golgi secretion with tunicamycin increased intracellular A1AT retention but promoted non-classical secretion via microparticles. Polymerized A1AT or cigarette smoke exposure decreased transcytosis. Confocal time-lapse microscopy, transwell co-culture assays, two-photon intravital microscopy in mice, tunicamycin inhibition PloS one Medium 24743137
2015 A1AT uptake by pulmonary endothelial cells is mediated primarily by clathrin-coated vesicles and caveolae, and scavenger receptor class B type I (SR-BI) serves as a key receptor for A1AT endocytosis. SR-BI knockdown, neutralizing antibodies, or ligand competition reduced A1AT uptake by 30–50%. SR-BI null mice showed decreased lung A1AT after systemic administration. Transmission electron microscopy of gold-labeled A1AT, SR-BI immunoprecipitation, SCARB1 siRNA knockdown, neutralizing antibodies, Scarb1 knockout mice American journal of physiology. Lung cellular and molecular physiology High 26092999
2014 A1AT inhibits active caspase-3 and caspase-8 directly in liver homogenates and in a cell-free system in vitro. Both native and oxidized (elastase-inhibitory-activity-deficient) forms of A1AT were equally effective, indicating that the antiapoptotic effect is independent of elastase inhibitory activity. AAT treatment also reduced ADAM17 (TACE) activity and TNF-α levels in vivo. Cell-free in vitro caspase activity assays, liver homogenate assays, mouse models of acute liver failure (Jo2, acetaminophen, α-amanitin), native vs. oxidized A1AT comparison Hepatology (Baltimore, Md.) High 24449466
2013 TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, when delivered by liver-directed gene transfer, reduces toxic Z-SERPINA1 polymer accumulation in hepatocytes. The mechanism involves increased degradation of SERPINA1 polymer in autolysosomes and decreased SERPINA1 monomer expression. Liver-directed TFEB gene transfer in mouse model of SERPINA1 deficiency, histological and biochemical analysis of polymer levels, apoptosis and fibrosis markers Autophagy Medium 23584152
2016 NQO1 (NAD(P)H:quinone oxidoreductase 1) binds SERPINA1 mRNA at its 3'UTR and coding region, and promotes translation of A1AT without affecting mRNA levels. NQO1 silencing decreased polysome loading on SERPINA1 mRNA and reduced A1AT protein levels. NQO1-KO mice had reduced hepatic and serum A1AT and increased neutrophil elastase activity. Ribonucleoprotein immunoprecipitation (RIP) + microarray, biotin pulldown assay, polysome profiling, luciferase reporter assay, NQO1 siRNA knockdown, NQO1-KO mice Free radical biology & medicine High 27515817
2022 The 5'-UTR of the NM_000295.4 SERPINA1 transcript folds into a well-defined multi-helix structural domain that optimizes translation by maintaining accessibility at the translation initiation site. Mutations that disrupted the anchor helix of this domain led to non-native structures that created a stable helix near the initiation site, thereby decreasing translation. SHAPE (Selective 2'-Hydroxyl Acylation analyzed by Primer Extension) RNA structure probing, systematic mutagenesis of the 5'-UTR, luciferase reporter translation assays Nucleic acids research High 36107773
2020 Z A1AT can form heteropolymers with wild-type M A1AT in vivo. A monoclonal antibody (mAb2H2) was developed that preferentially binds M over Z A1AT; its epitope was localized by crystallography to a region perturbed by the Z (Glu342Lys) substitution. Negative-stain electron microscopy of Fab-labeled polymers from an MZ heterozygote liver explant revealed that M A1AT comprises approximately 6% of polymer subunits in vivo. Monoclonal antibody epitope mapping by crystallography, negative-stain electron microscopy of Fab-labeled polymers from human liver explant JCI insight High 32699193
2018 Seven novel SERPINA1 missense variants were functionally characterized in HEK293T cells. Variants S+S14F, I50N, A58D, F227C, and T249A formed intracellular polymers and failed to secrete AAT protein. Variant K328E showed intracellular retention and reduced antielastase activity. Variant E151K secreted normally without polymer formation. Overexpression in HEK293T cells, PAS staining, Western blotting, pulse-chase assay, elastase inhibition assay American journal of respiratory cell and molecular biology Medium 29232161
2017 Carbamylated alpha-1-antitrypsin (Ca-A1AT) is an antigenic target of anti-carbamylated protein (anti-CarP) antibodies in rheumatoid arthritis patients. A1AT contains surface-accessible lysines that can be carbamylated, and carbamylated A1AT peptides were identified in synovial fluid of an RA patient by mass spectrometry. Ion exchange chromatography fractionation of carbamylated FCS, mass spectrometry identification, ELISA with Ca-A1AT, mass spectrometry of synovial fluid Journal of autoimmunity Medium 28291659
2012 AAT inhibits NO production in macrophages by suppressing iNOS expression and NF-κB activation, independent of MAPK signaling. AAT reduced intracellular translocation of exogenous AAT in stimulated cells. In vivo, individuals with genetic AAT deficiency had significantly increased exhaled NO compared to healthy controls. RAW 264.7 cell stimulation assays, NO measurement, iNOS and NF-κB activation assays, MAPK phosphorylation assays, comparison with synthetic serine protease inhibitor CE-2072, exhaled NO measurement in AAT-deficient subjects Journal of leukocyte biology Medium 22975343
2017 AAT dose-dependently inhibited RANKL-induced osteoclast formation from bone marrow macrophages and RAW264.7 cells. Mechanistically, AAT inhibited M-CSF-induced RANK surface expression on osteoclast precursors, suppressed RANKL-induced TNF-α production, and inhibited DC-STAMP gene expression and CD9 surface expression. AAT treatment significantly inhibited osteoclast-mediated mineral resorption. In vitro osteoclast differentiation assay, gene expression analysis, RANK surface expression assay, mineral resorption assay Molecular medicine (Cambridge, Mass.) Medium 28332697
2021 In human chondrocytes, SERPINA1 transfection and recombinant AAT protein promoted chondrogenic differentiation through activation of PKA-dependent CREB signaling and inhibition of Wnt/β-catenin pathways, upregulating col2a1, acan, and sox9 while downregulating mmp13 and adamts5. SERPINA1 transfection in human chondrocytes, signaling pathway analysis (PKA/CREB, Wnt/β-catenin), gene expression analysis, in vivo arthritis models (KBxN serum, neutrophil elastase) FASEB journal Medium 33788977
2020 In AATD neutrophils, increased degranulation involves Rac2 activation leading to PAR2 activation by serine proteinases, resulting in enhanced reactive oxygen species production. AAT reduced primary granule release; augmentation therapy in vivo resolved the elevated surface abundance of neutrophil elastase and altered the AATD neutrophil membrane proteome toward that of non-AATD COPD. Label-free tandem mass spectrometry of neutrophil membrane proteome, Western blot, ELISA, FRET analysis, in vivo augmentation therapy cohort comparison The European respiratory journal Medium 32060059
2024 Hepatocyte-derived SerpinA1/A1AT forms a complex with EphB2 receptor and regulates its downstream signaling in adipocytes, promoting preadipocyte proliferation and increasing UCP1 expression to activate mitochondrial thermogenesis. Liver-specific SerpinA1 transgenic mice showed increased adipose browning, reduced adiposity, and improved glucose tolerance; SerpinA1 KO mice had impaired thermogenesis, obesity, and insulin resistance. Liver-specific transgenic overexpression, SerpinA1 knockout mice, co-immunoprecipitation (EphB2 complex), gene expression and protein assays in adipocytes, metabolic phenotyping Nature communications High 39532838
2025 In MASH, hepatic IL-1β produced by Kupffer cells transcriptionally inhibits A1AT expression via HNF4α. Loss of A1AT increases activity of proteinase 3 (PR3), which cleaves IL-32γ and converts it from an anti-inflammatory/antifibrogenic cytokine into a KC activator, thereby promoting MASH and fibrosis progression. A1AT restoration or PR3 inhibition mitigated MASH in vivo. Quintuple Serpina1a-e knockout mice on fast-food diet, IL-1β stimulation, PR3 activity assays, IL-32γ V104A cleavage-resistant mutant, cytokine arrays, in vivo A1AT restoration, transcription factor (HNF4α) analysis Experimental & molecular medicine High 39939782
2021 siRNA knockdown of SERPINA1 in trophoblast-derived HTR8/SVneo cells markedly affected actin cytoskeleton pathway regulation, Slit-Robo signaling, and extracellular matrix organization. Rare damaging SERPINA1 variants were identified in families with recurrent spontaneous preterm deliveries, and A1AT protein levels were downregulated in placental tissue from spontaneous preterm births. siRNA knockdown with pathway analysis, whole exome sequencing, placental proteomics and mRNA quantification, immunoelectron microscopy BMC medicine Medium 35477570
2017 Exogenous A1AT dose-dependently reduced SERPINA1 mRNA expression in primary human hepatocytes (including AAT-deficient patient hepatocytes), an effect potentiated by Oncostatin M. Exogenous A1AT also reduced SERPINA1 expression in human peripheral blood mononuclear cells, suggesting a negative feedback mechanism on its own expression. Treatment of primary human hepatocytes and PBMCs with purified A1AT, qRT-PCR for SERPINA1 mRNA, dose-response analysis, OSM co-stimulation, analysis of lung tissue from patients on augmentation therapy PloS one Medium 28486562

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 Molecular basis of alpha-1-antitrypsin deficiency. The American journal of medicine 429 3289385
1997 Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bulletin of the World Health Organization 170 9447774
1989 The alpha 1-antitrypsin gene and its deficiency states. Trends in genetics : TIG 148 2696185
2012 Expanding the clinical indications for α(1)-antitrypsin therapy. Molecular medicine (Cambridge, Mass.) 128 22634722
1993 Cell-specific expression of alpha 1-antitrypsin in human intestinal epithelium. The Journal of clinical investigation 113 8408656
2009 Protein-cofactor interactions in bioenergetic complexes: the role of the A1A and A1B phylloquinones in Photosystem I. Biochimica et biophysica acta 103 19409369
2014 Immune-modulating effects of alpha-1 antitrypsin. Biological chemistry 93 24854541
2022 Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency. The New England journal of medicine 89 35748699
2021 Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum. The application of clinical genetics 84 33790624
2008 Alpha-1 antitrypsin Null mutations and severity of emphysema. Respiratory medicine 79 18353624
2008 SERPINA1 gene variants in individuals from the general population with reduced alpha1-antitrypsin concentrations. Clinical chemistry 64 18515255
2021 Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder. Journal of hepatology 63 34848258
1989 The alpha 1-antitrypsin gene and emphysema. The American journal of physiology 60 2679136
2021 Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency. Gut 59 33632708
2002 Alpha(1)-antitrypsin and antichymotrypsin in human milk: origin, concentrations, and stability. The American journal of clinical nutrition 59 12324297
2020 α1-Antitrypsin deficiency and chronic respiratory disorders. European respiratory review : an official journal of the European Respiratory Society 58 32051168
2019 Clinical Significance of SERPINA1 Gene and Its Encoded Alpha1-antitrypsin Protein in NSCLC. Cancers 55 31487965
2014 α-1-antitrypsin inhibits acute liver failure in mice. Hepatology (Baltimore, Md.) 54 24449466
2014 Identification and characterisation of eight novel SERPINA1 Null mutations. Orphanet journal of rare diseases 54 25425243
1987 Glycosylation and secretion of human alpha-1-antitrypsin by yeast. Gene 54 3315863
2016 Alpha-1-antitrypsin (SERPINA1) mutation spectrum: Three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal. Respiratory medicine 52 27296815
2020 Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease. JCI insight 49 32379724
2005 A review of alpha-1 antitrypsin deficiency. Seminars in respiratory and critical care medicine 49 16088434
2014 α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics. Blood 46 25224412
2013 Autophagy master regulator TFEB induces clearance of toxic SERPINA1/α-1-antitrypsin polymers. Autophagy 46 23584152
1982 Alpha-1-antitrypsin: an ignored protein in understanding liver disease. Seminars in liver disease 45 6763344
2003 Gene therapy progress and prospects: alpha-1 antitrypsin. Gene therapy 44 12571637
2018 SERPINA1 mRNA as a Treatment for Alpha-1 Antitrypsin Deficiency. Journal of nucleic acids 43 30009048
1997 alpha 1-Antitrypsin (AAT) deficiency and ANCA-positive systemic vasculitis: genetic and clinical implications. European journal of clinical investigation 43 9279535
2014 Active trafficking of alpha 1 antitrypsin across the lung endothelium. PloS one 42 24743137
1992 Molecular biology and genetics of alpha 1-antitrypsin deficiency. Seminars in liver disease 41 1439881
2017 Identification of carbamylated alpha 1 anti-trypsin (A1AT) as an antigenic target of anti-CarP antibodies in patients with rheumatoid arthritis. Journal of autoimmunity 40 28291659
2021 Variants of SERPINA1 and the increasing complexity of testing for alpha-1 antitrypsin deficiency. Therapeutic advances in chronic disease 38 34408833
2004 Alpha-1-antitrypsin associated panniculitis: the MS variant. Journal of the American Academy of Dermatology 38 15389208
2019 Emphysema: looking beyond alpha-1 antitrypsin deficiency. Expert review of respiratory medicine 37 30761929
2013 Gene-based therapy for alpha-1 antitrypsin deficiency. COPD 37 23527792
2014 Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions. Expert review of gastroenterology & hepatology 36 25066184
2010 Alpha-1-antitrypsin deficiency. Best practice & research. Clinical gastroenterology 36 20955965
2004 Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. European journal of human genetics : EJHG 35 14694355
2016 Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease. Annals of the American Thoracic Society 34 27564673
2015 Alternative transcripts of the SERPINA1 gene in alpha-1 antitrypsin deficiency. Journal of translational medicine 34 26141700
2021 Alpha-1-antitrypsin reduces inflammation and exerts chondroprotection in arthritis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 33788977
2018 Alpha-1 Antitrypsin Therapy for Autoimmune Disorders. Chronic obstructive pulmonary diseases (Miami, Fla.) 32 30723786
2016 Alpha-1 Antitrypsin and Lung Cell Apoptosis. Annals of the American Thoracic Society 31 27115949
2012 A review of augmentation therapy for alpha-1 antitrypsin deficiency. Expert opinion on biological therapy 30 22500781
2011 Gene therapy for alpha-1 antitrypsin deficiency. Human molecular genetics 30 21498872
2007 Alpha-1-antitrypsin deficiency: current concepts. Lung 30 17562108
1991 Alpha 1-antitrypsin deficiency and liver disease. Journal of inherited metabolic disease 30 1749216
2018 Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency. American journal of respiratory cell and molecular biology 29 29232161
2016 Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation. Free radical biology & medicine 28 27515817
2013 Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection. BMC urology 28 24011266
2006 Alpha-1-antitrypsin deficiency: diagnosis, pathophysiology, and management. Current gastroenterology reports 28 16510030
2012 Alpha-1-antitrypsin inhibits nitric oxide production. Journal of leukocyte biology 27 22975343
2009 Promoter methylation of glutathione S-transferase pi1 and multidrug resistance gene 1 in bronchioloalveolar carcinoma and its correlation with DNA methyltransferase 1 expression. Cancer 26 19484794
2021 Alpha-1 antitrypsin deficiency liver disease. Translational gastroenterology and hepatology 24 33824927
2018 Alpha-1-antitrypsin in cell and organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 23 29607607
2014 Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option? Biological research 23 25723058
2022 Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth. BMC medicine 22 35477570
2020 Advances in Alpha-1 Antitrypsin Gene Therapy. American journal of respiratory cell and molecular biology 22 32668173
2020 Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin. JCI insight 22 32699193
2016 Neutrophil Fates in Bronchiectasis and Alpha-1 Antitrypsin Deficiency. Annals of the American Thoracic Society 22 27115946
1984 alpha-1-Antitrypsin deficiency. Hepatology (Baltimore, Md.) 22 6607204
2017 Liver Transplantation in Alpha-1 Antitrypsin Deficiency. Clinics in liver disease 21 28364818
2022 Global 5'-UTR RNA structure regulates translation of a SERPINA1 mRNA. Nucleic acids research 20 36107773
2020 α1 Antitrypsin therapy modulates the neutrophil membrane proteome and secretome. The European respiratory journal 20 32060059
2017 Alpha-1 antitrypsin inhibits RANKL-induced osteoclast formation and functions. Molecular medicine (Cambridge, Mass.) 20 28332697
2011 α(1)-antitrypsin deficiency and inflammation. Expert review of clinical immunology 20 21426261
2015 SERPINA1 Full-Gene Sequencing Identifies Rare Mutations Not Detected in Targeted Mutation Analysis. The Journal of molecular diagnostics : JMD 19 26321041
2000 Liver injury in alpha 1-antitrypsin deficiency. Clinics in liver disease 19 11232197
2020 CSF SerpinA1 in Creutzfeldt-Jakob disease and frontotemporal lobar degeneration. Annals of clinical and translational neurology 18 31957347
2015 Scavenger receptor class B, type I-mediated uptake of A1AT by pulmonary endothelial cells. American journal of physiology. Lung cellular and molecular physiology 18 26092999
1992 Genetic variants of alpha-1-antitrypsin (AAT). Liver 18 1447962
2023 Alpha-1 antitrypsin deficiency. Medicina clinica 17 37993348
2018 Update on α1-antitrypsin deficiency. Breathe (Sheffield, England) 17 30131830
2017 Pathophysiology of Alpha-1 Antitrypsin Lung Disease. Methods in molecular biology (Clifton, N.J.) 17 28752442
2023 Gene therapy for alpha-1 antitrypsin deficiency: an update. Expert opinion on biological therapy 16 36825473
2021 miR-320c Regulates SERPINA1 Expression and Is Induced in Patients With Pulmonary Disease. Archivos de bronconeumologia 16 35698951
2014 Molecular pathogenesis of alpha-1-antitrypsin deficiency. Revue des maladies respiratoires 16 25442121
2024 Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations. Pulmonology 15 37236906
2019 SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis. Journal of gastrointestinal and liver diseases : JGLD 15 31517326
2017 Exogenous alpha 1-antitrypsin down-regulates SERPINA1 expression. PloS one 15 28486562
2008 [Alpha-1 antitrypsin deficiency: diagnosis and treatment]. Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia 15 18695797
2004 What we owe to alpha(1)-antitrypsin and to Carl-Bertil Laurell. COPD 15 16997740
2002 Alpha-1-antitrypsin deficiency and nephropathy. Nephron 15 11744816
2000 Alpha-1-antitrypsin deficiency, the serpinopathies and conformational disease. Journal of the Royal College of Physicians of London 15 10904927
1991 Alpha 1-antitrypsin deficiency: pathogenesis and treatment. Hospital practice (Office ed.) 15 1899256
2024 Editing Approaches to Treat Alpha-1 Antitrypsin Deficiency. Chest 14 39401571
1991 The molecular genetics of alpha 1 antitrypsin deficiency. BioEssays : news and reviews in molecular, cellular and developmental biology 14 1859394
1990 Discovery of alpha 1-antitrypsin deficiency. Lung 14 2117160
2024 Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression. Nature communications 13 39532838
2023 Novel SERPINA1 Alleles Identified through a Large Alpha-1 Antitrypsin Deficiency Screening Program and Review of Known Variants. Chronic obstructive pulmonary diseases (Miami, Fla.) 13 36367950
2023 Soybean transporter AAT Rhg1 abundance increases along the nematode migration path and impacts vesiculation and ROS. Plant physiology 13 36805759
2023 Plasma exosomal protein PLG and SERPINA1 in colorectal cancer diagnosis and coagulation abnormalities. Journal of cancer research and clinical oncology 13 37093347
2022 Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice. Molecular therapy. Methods & clinical development 13 35592360
2022 Alpha-1 Antitrypsin Deficiency Liver Disease. Clinics in liver disease 13 35868681
2017 Evaluation of Alpha-1 Antitrypsin Levels and SERPINA1 Gene Polymorphisms in Sickle Cell Disease. Frontiers in immunology 13 29163550
2000 Technology evaluation: transgenic alpha-1-antitrypsin (AAT), PPL therapeutics. Current opinion in molecular therapeutics 13 11249642
1993 Alpha 1-antitrypsin deficiency: an overview. Acta clinica Belgica 13 8396299
2025 A1AT dysregulation of metabolically stressed hepatocytes by Kupffer cells drives MASH and fibrosis. Experimental & molecular medicine 12 39939782
1994 Alpha-1-antitrypsin deficiency and liver disease. Digestive diseases (Basel, Switzerland) 12 7988061

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