N-acetylcysteine (NAC) is a long-established molecule with diverse mechanistic plausibility, including roles as a glutathione precursor, mucolytic, antioxidant, anti-inflammatory agent, and glutamatergic modulator. Its approved clinical uses—as an antidote for acetaminophen toxicity and as a mucolytic in selected pulmonary settings—stand in contrast with a broad and growing off-label literature. This scoping review of reviews aimed to map the breadth of published syntheses on NAC repurposing across clinical indications, identify mechanistic themes and therapeutic signals, detect patterns of redundancy or evidence saturation, and set priorities for future clinical research and translational efforts.
The review specifically sought to clarify where trial prioritization is warranted, which indications show the most promise according to existing reviews, and how evidence maturity and certainty vary across domains to inform precision repurposing strategies.
The review followed the Joanna Briggs Institute (JBI) framework and adhered to PRISMA-ScR reporting. A protocol was prospectively registered on the Open Science Framework (OSF). Ethical approval was not required because the study synthesized previously published, publicly available reviews and generated no primary data.
Five databases were systematically searched: TRIP, Cochrane Database of Systematic Reviews (CDSR), Google Scholar, Epistemonikos, and PubMed. The search targeted reviews published in the prior ten years to balance comprehensiveness with relevance. A keyword-based strategy centered on N-acetylcysteine was adapted to each database; in Google Scholar the operator allintitle: was used to reduce noise and ensure NAC was the principal focus. All review types in English were eligible; indirect or incidental mentions of NAC were excluded to keep the mapping treatment-focused.
Duplicate records were removed and reference lists screened. The flow of identification, screening, exclusion, and retention is reported in the PRISMA flowchart within the source article.
Data extraction used a predetermined sheet capturing title, authors, year, country of origin, clinical indication, derived clinical domain, review type, included study types and numbers, population characteristics, conclusions, signal classification (supportive, neutral, or against NAC use based on each review’s conclusion), reported dose ranges and routes, mechanisms of action, limitations, and reported evidence certainty. Nuances such as biomarker-only effects, subgroup signals, and safety concerns were recorded when available. A small random subset of extractions underwent independent checking for quality control; discrepancies were resolved by discussion. The complete extraction table is provided in the article’s supplementary materials.
Although optional for scoping reviews, critical appraisal was performed to enhance interpretability. Systematic reviews with or without meta-analyses were assessed using AMSTAR-2, which classifies reviews as critically low, low, moderate, or high based on seven critical domains (including protocol registration, adequacy of search, risk of bias assessment, and exploration of publication bias). Reviews were independently rated and summarized.
Complementary assessment used ROBIS to evaluate the risk of bias across domains including eligibility criteria, identification and selection of studies, data collection and appraisal, and synthesis. Overall ROBIS judgments were reported, and visualization of stratified domain results was provided in stacked bar charts. The dual appraisal approach enabled stratified evidence mapping and highlighted methodological strengths and limitations across the evidence base.
To identify redundancy among systematic reviews and meta-analyses addressing similar indications, the corrected covered area (CCA) was calculated. The CCA quantifies overlap between reviews by comparing the total number of included studies across reviews with the number of unique primary studies. Results were categorized to indicate slight, moderate, high, or very high overlap. This measure was used to detect evidence inflation due to repeated inclusion of the same primary studies across multiple reviews, particularly within subdomains.
A total of 140 reviews spanning 17 clinical domains were retained. Of these, 63 were systematic reviews with meta-analysis—the subset offering the highest level of review evidence in this mapping. Approximately half of the systematic reviews with meta-analyses drew conclusions in support of NAC repurposing for the respective indications based on the reviews’ stated conclusions.
The number of NAC-focused reviews increased over time, with most reviews originating from China and the United States. Appraisal using AMSTAR-2 identified a high prevalence of critically low-quality systematic reviews alongside a notable fraction judged to have low risk of bias by ROBIS. This heterogeneity in methodological quality permitted stratified mapping but also underscored limitations in certainty across domains.
CCA analysis demonstrated substantial overlap and redundancy across domains, especially within subdomains, suggesting potential evidence inflation and repeated synthesis of the same primary studies rather than independent corroboration.
Reviews most frequently reported roles for NAC as an antioxidant, anti-inflammatory agent, and glutamatergic modulator. Additional proposed mechanisms included direct free radical scavenging, modulation of glutathione synthesis, redox regulation, mitochondrial stabilization, and disruption of disulfide bonds in mucin proteins (the latter underpinning mucolytic activity). Meta-analytic data summarized in reviews also indicated effects on oxidative stress and inflammatory biomarkers, though the translation of biomarker changes to consistent clinical outcomes varied across indications.
Based on mapped evidence, gaps, and translational signals, the review identified psychiatry, reproductive medicine, nephrology, pulmonology, and toxicology as priority domains for further investigation and targeted trials. However, the review emphasizes that inconsistency in evidence certainty and methodological quality across reviews remains a key obstacle to integrating NAC into clinical guidelines outside its established indications.
This overview mapped a large and growing NAC evidence landscape, documenting its pleiotropic mechanisms and repurposing potential while revealing important research waste, redundancy, and critical gaps. The findings call for higher-quality systematic reviews where needed, reduction of redundant syntheses, and prioritization of well-designed clinical trials—preferably within precision medicine frameworks—to resolve translational discordance. Supplementary files provide extraction tables, appraisal results, and overlap calculations. The author declared no funding and no competing interests for the work.