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Biomolecules
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Roles of Alpha-1 Antitrypsin in Human Health and Disease Models
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Roles of Alpha-1 Antitrypsin in Human Health and Disease Models

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (30 April 2026) | Viewed by 8699

Editor

Prof. Dr. Sihong Song

E-Mail Website
Guest Editor
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
Interests: functions and applications of alpha 1 antitrypsin (AAT) and SERPIN; development of novel treatment for autoimmune and inflammatory diseases; gene therapy using recombinant adeno-associated viral vectors (rAAV)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alpha-1 antitrypsin (AAT), a member of serine proteinase inhibitor (SERPIN) superfamily, has multiple functions including the inhibition of proteinases and the regulation of immune system. As a proteinase inhibitor, AAT can reduce tissue damage and degeneration, which is commonly involved in autoimmune and inflammatory diseases. AAT can also interact with immune regulatory molecules and mediate anti-inflammatory effects. Studies have shown that AAT has the therapeutic potential for the treatment of human diseases including AAT deficiency (AATD), graft-versus-host disease (GvHD), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and COVID-19. However, the mechanism(s) underlying the therapeutic effects of AAT remain elusive. In addition, AAT may have unknown functions to be further investigated. This Specific Issue aims to publish recent findings that advance the therapeutic applications and the functional mechanism(s) of AAT and related molecules.

Prof. Dr. Sihong Song
Guest Editor

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Keywords

  • alpha-1 antitrypsin
  • serine proteinase inhibitor (SERPIN)
  • autoimmunity
  • inflammation
  • aging
  • cancer

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Published Papers (6 papers)

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Research

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18 pages, 1567 KB  
Article
Dissociation of the Hepatic and Pulmonary Axes in Alpha-1 Antitrypsin Deficiency: Independent Trajectories of Organ-Specific Disease
by Juan Luis Rodríguez Hermosa, Soha Esmaili, Iman Esmaili, Maria Torres-Duran, Hanan Tanash, Alice M. Turner, Carlota Rodríguez-García, Miriam Barrecheguren, Jens-Ulrik Stæhr Jensen, Vincent Bunel, Angelo Guido Corsico, Kenneth R. Chapman, Jean-François Mornex, Eva Bartošovská-Klinková, Beatriz Lara, José Luis López-Campos, Christian F. Clarenbach, Emily F. A. van ’t Wout, Mariano Fernandez-Acquier and Myriam Calle Rubio
Biomolecules 2026, 16(7), 940; https://doi.org/10.3390/biom16070940 (registering DOI) - 24 Jun 2026
Viewed by 217
Abstract
The interindividual phenotypic heterogeneity in Alpha-1 Antitrypsin Deficiency (AATD), despite a shared genetic etiology (the Z-allele of SERPINA1), is explained by the interaction of dual pathogenic mechanisms (gain-of-function vs. loss-of-function), additional genetic modifiers, and environmental or metabolic factors. Building on recent evidence [...] Read more.
The interindividual phenotypic heterogeneity in Alpha-1 Antitrypsin Deficiency (AATD), despite a shared genetic etiology (the Z-allele of SERPINA1), is explained by the interaction of dual pathogenic mechanisms (gain-of-function vs. loss-of-function), additional genetic modifiers, and environmental or metabolic factors. Building on recent evidence suggesting divergent disease trajectories, we investigated whether pulmonary and hepatic impairments represent coupled manifestations or independent clinical dimensions within a large European cohort. Methods: This international multicenter study utilized the European Alpha-1 Research Collaboration (EARCO) registry (n = 1217). Pulmonary and hepatic severities were quantified using concurrent 0.0–10.0 composite indices. Independence was evaluated via partial Spearman correlations, multivariable multinomial regression, and geometric mapping across a continuous phenotypic space. Results: Cross-domain correlations between respiratory metrics and liver stiffness were near zero (r = −0.03), demonstrating statistical independence. Phenotypic dominance classification isolated distinct profiles; the lung-dominant group exhibited a higher age (57.0 vs. 54.0 years; p < 0.001) and tobacco exposure, while the liver-dominant group registered a higher body mass index (25.8 vs. 24.4 kg/m2; p < 0.001). Multivariable models identified age (OR 1.03; 95% CI 1.02–1.05) and smoking as independent predictors of lung dominance, whereas body mass index was independently associated with liver dominance (OR 1.04; 95% CI 1.01–1.07). Geometric mapping revealed advanced disease clusters at orthogonal margins rather than forming a systemic continuum. Conclusions: Hepatic and pulmonary impairments in AATD operate as independent clinical dimensions modulated by distinct metabolic and environmental factors. Risk stratification must transition toward organ-specific prognostic models. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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16 pages, 2220 KB  
Article
Adaptive Regulation of mTOR Activity by AMPK, Akt, and ATF6 Pathways in Pi*Z Alpha-1 Antitrypsin Deficient Hepatocytes
by Yuanqing Lu, Jungnam Lee, Naweed Mohammad and Mark L. Brantly
Biomolecules 2026, 16(4), 506; https://doi.org/10.3390/biom16040506 - 27 Mar 2026
Viewed by 859
Abstract
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by intracellular retention of mutant Z (Pi*Z) alpha-1 antitrypsin (AAT) within hepatocytes, resulting in progressive liver disease. Currently, no approved pharmacological therapies exist for AATD-associated hepatic injury. Emerging preclinical evidence indicates that inhibition of [...] Read more.
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by intracellular retention of mutant Z (Pi*Z) alpha-1 antitrypsin (AAT) within hepatocytes, resulting in progressive liver disease. Currently, no approved pharmacological therapies exist for AATD-associated hepatic injury. Emerging preclinical evidence indicates that inhibition of mammalian target of rapamycin (mTOR) ameliorates liver pathology in AATD; however, the status of mTOR activity and its regulatory mechanisms under Pi*Z AAT-induced cellular stress remains incompletely understood. In this study, we investigated alterations in mTOR signaling and its upstream regulatory pathways using a gene-edited human hepatocyte model harboring the Pi*Z mutation (Huh7.5Z cells) and a Pi*Z AAT transgenic mouse model. Attenuation of mTORC1 activity was observed in both cellular and murine Pi*Z models. In vitro analyses demonstrated activation of AMP-activated protein kinase (AMPKα), a key inhibitory regulator of mTORC1, accompanied by paradoxical activation of Akt and the unfolded protein response (UPR) branch ATF6α. Pharmacological inhibition of mTOR significantly reduced intracellular Pi*Z AAT accumulation, alleviated ER stress, and suppressed apoptotic signaling through enhancement of autophagy. These findings reveal that hepatocytes adapt to Pi*Z AAT-induced stress through coordinated regulation of mTOR by AMPK, Akt, and ATF6α pathways. This study provides mechanistic insight into metabolic and stress-response signaling in AATD and identifies mTOR modulation as a promising therapeutic strategy for AATD-associated liver disease. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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16 pages, 10121 KB  
Article
Alpha-1 Antitrypsin Protects Against Cisplatin-Induced Acute Kidney Injury by Restoring Redox and Mitochondrial Homeostasis
by Mina Kim, Se-Hyun Oh, Jin Han, Ji-Sun Ahn, Eun-Joo Oh, Hee-Yeon Jung, Ji-Young Choi, Jang-Hee Cho, Sun-Hee Park, Chan-Duck Kim, Yong-Lim Kim, You Hyun Jeon and Jeong-Hoon Lim
Biomolecules 2026, 16(2), 222; https://doi.org/10.3390/biom16020222 - 2 Feb 2026
Viewed by 802
Abstract
Cisplatin is an effective chemotherapeutic agent, yet its clinical utility is limited by dose-dependent nephrotoxicity. Alpha-1 antitrypsin (AAT) has cytoprotective, anti-inflammatory, and antiapoptotic properties, but its therapeutic potential in cisplatin-induced acute kidney injury (AKI) remains unclear. A murine cisplatin–AKI model was used to [...] Read more.
Cisplatin is an effective chemotherapeutic agent, yet its clinical utility is limited by dose-dependent nephrotoxicity. Alpha-1 antitrypsin (AAT) has cytoprotective, anti-inflammatory, and antiapoptotic properties, but its therapeutic potential in cisplatin-induced acute kidney injury (AKI) remains unclear. A murine cisplatin–AKI model was used to evaluate whether AAT (80 mg/kg) ameliorates renal injury. Renal function, oxidative stress, NADPH oxidase (NOX) isoforms, mitochondrial metabolism, inflammatory mediators, apoptosis, and fibrosis-related markers were assessed using biochemical, histological, immunohistochemical, and Western blot analyses. Cisplatin markedly impaired renal function and induced tubular injury; meanwhile, AAT significantly reversed these changes. Cisplatin also induced severe oxidative stress and disrupted the balance of NOX isoforms; AAT restored redox homeostasis. Cisplatin upregulated CPT1A/PDK4 and suppressed CPT2, UCP3, PGC1α, and DRP1, inducing maladaptive mitochondrial changes, indicating impaired β-oxidation and defective mitochondrial dynamics; AAT reversed these alterations, restoring normal mitochondrial metabolism. IL-1β, IL-6R, OPN, and F4/80 expression, recovery of the Bax/Bcl-2 ratio, and MAPK activation were reduced, indicating decreased inflammation and apoptosis; profibrotic markers were also reduced. AAT confers multifaceted protection against cisplatin-induced AKI by restoring redox balance, mitochondrial homeostasis, and inflammatory and apoptotic signaling. These findings support AAT as a promising therapeutic agent for preventing cisplatin nephrotoxicity. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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17 pages, 2898 KB  
Article
Human Alpha-1 Antitrypsin Suppresses Melanoma Growth by Promoting Tumor Differentiation and CD8+ T-Cell-Mediated Immunity
by Takeshi Yamauchi, Yuchun Luo, Dinoop Ravindran Menon, Kasey Couts, Sana Khan, Aanchal Goel, Charles A. Dinarello, Zili Zhai and Mayumi Fujita
Biomolecules 2026, 16(1), 122; https://doi.org/10.3390/biom16010122 - 12 Jan 2026
Viewed by 892
Abstract
Alpha-1 antitrypsin (AAT) is a serine protease inhibitor with potent anti-inflammatory and immunomodulatory properties, but its role in cancer is context-dependent across tumor types. We integrated transcriptomic analyses of human melanoma cohorts, in vivo studies using AAT-transgenic (hAAT-TG) mice, and in vitro assays [...] Read more.
Alpha-1 antitrypsin (AAT) is a serine protease inhibitor with potent anti-inflammatory and immunomodulatory properties, but its role in cancer is context-dependent across tumor types. We integrated transcriptomic analyses of human melanoma cohorts, in vivo studies using AAT-transgenic (hAAT-TG) mice, and in vitro assays in murine and human melanoma cells to define the biological functions of AAT in melanoma. SERPINA1 expression increased progressively from normal skin to nevi and metastatic melanoma, yet higher intratumoral levels correlated with improved overall survival in metastatic disease. In hAAT-TG mice, melanoma growth was markedly inhibited compared with wild-type controls, and the inhibitory effect required CD8+ T cells and was enhanced by CD4+ T-cell depletion, demonstrating that AAT promotes cytotoxic T-cell activity while attenuating regulatory T-cell suppression. Histologic analysis showed heavily pigmented tumors in hAAT-TG mice. In vitro, hAAT upregulated melanocytic differentiation markers (MITF, TYR, PMEL, MART-1) and increased melanin production in murine and human melanoma lines, suggesting enhanced tumor immunogenicity. In conclusion, hAAT exerts antitumor effects in melanoma indirectly by reprogramming the tumor microenvironment toward differentiation and immune activation. These findings highlight a previously unrecognized role for AAT as a dual immunoregulatory and differentiation-promoting factor and support AAT as a potential immunoregulatory adjuvant in melanoma. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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14 pages, 2405 KB  
Article
The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways
by Ahmed S. Elshikha, Georges Abboud, Rigena Avdiaj, Laurence Morel and Sihong Song
Biomolecules 2025, 15(1), 43; https://doi.org/10.3390/biom15010043 - 1 Jan 2025
Cited by 3 | Viewed by 2310
Abstract
Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing [...] Read more.
Endosomal toll-like receptors (TLRs) TLR7, TLR8, and TLR9 play an important role in systemic lupus erythematosus (SLE) pathogenesis. The proteolytic processing of these receptors in the endolysosome is required for signaling in response to DNA and single-stranded RNA, respectively. Targeting this proteolytic processing may represent a novel strategy to inhibit TLR-mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on endosomal TLRs remains elusive. In this study, we first tested the effect of hAAT on TLR9 signaling in dendritic cells (DCs). We showed that hAAT inhibited TLR9-mediated DC activation and cytokine production. Human AAT also lowered the expressions of interferon signature genes. Western blot analysis showed that hAAT reduced the expression of the active form (cleaved) of TLR9 in DCs, indicating a novel mechanism of hAAT function in the immune system. We next tested the effect of hAAT on TLR7/8 signaling. Similar to the effect on TLR9 signaling, hAAT also inhibited R848 (TLR7 and 8 agonist)-induced DC activation and functions and lowered the expressions of interferon signature genes. Our in vivo studies using hAAT transgenic mice also showed that hAAT attenuated R848-induced pathogenesis. Specifically, hAAT completely blocked the R848 induction of germinal center T cells (GC T), B cells (GC B), and plasma cells (GC PCs), as well as T follicular T helper cells (TFH), which are all critical in lupus development. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight into the clinical application of hAAT. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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Review

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15 pages, 1483 KB  
Review
Alpha-1 Antitrypsin Deficiency and Bronchial Asthma: Current Challenges
by José Luis Lopez-Campos, Belén Muñoz-Sánchez, Marta Ferrer-Galván and Esther Quintana-Gallego
Biomolecules 2025, 15(6), 807; https://doi.org/10.3390/biom15060807 - 3 Jun 2025
Cited by 2 | Viewed by 2389
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition classically associated with pulmonary emphysema and liver disease. However, the potential link between AATD and other respiratory diseases, particularly bronchial asthma, remains poorly understood and highly debated. This narrative review explores the current evidence [...] Read more.
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition classically associated with pulmonary emphysema and liver disease. However, the potential link between AATD and other respiratory diseases, particularly bronchial asthma, remains poorly understood and highly debated. This narrative review explores the current evidence regarding the epidemiological, clinical, and pathophysiological relationship between AATD and asthma. Data from prevalence studies show marked variability in the frequency of AATD-associated alleles among asthma patients, ranging from 2.9% to 25.4%, suggesting either a true association or selection biases. Conversely, asthma prevalence among AATD patients also varies widely, from 1.4% to 44.6%, with higher frequencies observed in countries with long-standing national registries. However, methodological inconsistencies and a lack of standardized diagnostic criteria limit the interpretation of these findings. Current evidence is insufficient to support a direct causal role for AATD mutations in asthma development, and no clear impact of AATD on asthma severity or prognosis has been established. Furthermore, there is no conclusive evidence that augmentation therapy is beneficial in asthma patients carrying AATD mutations. Despite these uncertainties, screening for AATD in selected asthma populations—especially those with severe or atypical phenotypes—may be warranted, as recommended by major respiratory societies. Future research should focus on large, well-powered, prospective studies that evaluate the potential pathophysiological interactions between AATD and specific asthma endotypes, particularly T2-low asthma. These efforts may help clarify the relevance of AATD mutations in asthma pathogenesis and identify potential therapeutic targets. Full article
(This article belongs to the Special Issue Roles of Alpha-1 Antitrypsin in Human Health and Disease Models)
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