N ‐acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, double‐blind, placebo‐controlled trial
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Objective: Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double‐blind, placebo‐controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N ‐acetylcysteine (NAC). Methods: A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. Disease activity was evaluated monthly by the British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index (SLEDAI), and the Fatigue Assessment Scale (FAS) before, during, and after a 3‐month treatment period. Mitochondrial transmembrane potential and mTOR were assessed by flow cytometry. Forty‐two healthy subjects matched to patients for age, sex, and ethnicity were studied as controls. Results: NAC up to 2.4 gm/day was tolerated by all patients, while 33% of those receiving 4.8 gm/day had reversible nausea. Placebo or NAC 1.2 gm/day did not influence disease activity. Considered together, 2.4 gm and 4.8 gm NAC reduced the SLEDAI score after 1 month ( P = 0.0007), 2 months ( P = 0.0009), 3 months ( P = 0.0030), and 4 months ( P = 0.0046); the BILAG score after 1 month ( P = 0.029) and 3 months ( P = 0.009); and the FAS score after 2 months ( P = 0.0006) and 3 months ( P = 0.005). NAC increased Δψm ( P = 0.0001) in all T cells, profoundly reduced mTOR activity ( P = 0.0009), enhanced apoptosis ( P = 0.0004), reversed expansion of CD4−CD8− T cells (mean ± SEM 1.35 ± 0.12‐fold change; P = 0.008), stimulated FoxP3 expression in CD4+CD25+ T cells ( P = 0.045), and reduced anti‐DNA production ( P = 0.049). Conclusion: This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.
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Dietary supplementation with N-acetylcysteine inhibits the mTOR pathway, restores mitochondrial membrane potential and increases mitochondrial mass in lymphocytes from patients with SLE.
“Dietary supplementation with N-acetylcysteine (a precursor of glutathione) inhibits the mTOR pathway, restores the mitochondrial membrane potential and increases the mitochondrial mass in lymphocytes from patients with SLE85,86”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [85]
The Results section reports that NAC reduced mTOR activity and increased mitochondrial mass, particularly in double-negative T cells. But it also reports that NAC increased mitochondrial hyperpolarization in lupus T cells; it does not describe this as restoring membrane potential to normal. The claim also generalizes the mitochondrial-mass finding from a T-cell subset to lymphocytes broadly. (LLM, conf=0.88)
Experimental — accuracy not yet measuredmTOR blockade in SLE patients treated with N-acetylcysteine or rapamycin reduces pro-inflammatory T cells and disease activity, suggesting drugs regulating mitochondrial dynamics might be novel therapeutic avenues for mitigating autoantibody production in SLE.
“Additionally, mTOR blockade in patients with SLE treated with N-acetylcysteine or rapamycin reduces both pro-inflammatory T cells and disease activity85,260, suggesting that dietary supplementation or drugs that regulate mitochondrial dynamics might constitute novel therapeutic avenues for mitigating autoantibody production in SLE.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [85]
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- Authors
- Lai, Z., Hanczko, R., Bonilla, E., Caza, T. N., Clair, B., Bartos, A., Miklossy, G., Jimah, J., Doherty, E., Tily, H., Francis, L., Garcia, R., Dawood, M., Yu, J., Ramos, I., Coman, I., Faraone, S. V., Phillips, P. E., & Perl, A.
- Affiliations
- SUNY Upstate Medical University (US)
- ORCID
- Venue
- Arthritis & Rheumatism
- Publisher
- Wiley
- Published
- 2012-08-27
- Volume
- 64
- Issue
- 9
- Pages
- 2937-2946
- ISSN
- 0004-3591 (ISSN-L)
- 1529-0131
- PMC
- PMC3411859
- OpenAlex
- W2015010210
- Cited by
- 428
- References
- 32
- Citations by year
- 2026: 29 · 2025: 31 · 2024: 39 · 2023: 35 · 2022: 36 · 2021: 40 · 2020: 42 · 2019: 36 · 2018: 45 · 2017: 16 · 2016: 25 · 2015: 23 · 2014: 11 · 2013: 17 · 2012: 3
- FWCI
- 13.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arthritis & Rheumatism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI072648, R01AI072648)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (U01AR076092)
- National Center for Complementary and Integrative Health (AT-004332, R01AT004332)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- systemic lupus erythematosus, N-acetylcysteine, glutathione precursor, mTOR inhibition, T cell dysfunction, mitochondrial membrane potential, disease activity, fatigue, apoptosis, CD4+CD8+ T cells, drug safety and tolerability, immunomodulatory therapy, SLEDAI, BILAG index, Fatigue Assessment Scale
- MeSH terms
- Acetylcysteine, Adult, Double-Blind Method, Female, Humans, Lupus Erythematosus, Systemic, Male, Middle Aged, Pilot Projects, Placebos, Severity of Illness Index, T-Lymphocytes, Free Radical Scavengers, Treatment Outcome, Membrane Potential, Mitochondrial, TOR Serine-Threonine Kinases
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