---
title: "N-acetylcysteine repurposing review: evidence map, gaps, and research priorities"
id: "plos-one-10-repurposing-landscape-of-n-acetylcysteine-a-scoping-review-of-reviews-toward"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-10-repurposing-landscape-of-n-acetylcysteine-a-scoping-review-of-reviews-toward"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0360434"
published_at: "2026-10-09T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# N-acetylcysteine repurposing review: evidence map, gaps, and research priorities
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-10-repurposing-landscape-of-n-acetylcysteine-a-scoping-review-of-reviews-toward
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0360434)
- **Published At:** 2026-10-09T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This scoping review of reviews mapped 140 published reviews on **N-acetylcysteine (NAC)** across 17 clinical domains to assess repurposing potential and translational maturity. - Searches of five databases (TRIP, CDSR, Google Scholar, Epistemonikos, PubMed) covered reviews published in the prior 10 years; the protocol was registered on OSF and reporting followed PRISMA-ScR and JBI guidance. - Of the 140 reviews, 63 were systematic reviews with meta-analysis; roughly half of those concluded in support of NAC repurposing for their indication based on authors’ conclusions. - Mechanistic rationales most frequently reported included **antioxidant**, anti-inflammatory, and glutamatergic modulatory effects, with additional proposed mechanisms documented across reviews. - Geographic origin of most reviews was China and the United States; the number of NAC reviews increased over time. - Critical appraisal using **AMSTAR-2** and **ROBIS** found a high prevalence of critically low-quality systematic reviews alongside a substantial subset with low risk of bias, enabling stratified evidence mapping. - Corrected Covered Area (**CCA**) analysis identified substantial overlap and redundancy among reviews, particularly within subdomains, indicating potential evidence inflation. - Priority clinical domains for future research identified were psychiatry, reproductive medicine, nephrology, pulmonology, and toxicology, but overall inconsistency in review certainty hinders guideline integration. - The review highlights research waste, evidence heterogeneity, and translational discordance, and calls for precision medicine approaches and targeted trials to clarify NAC’s clinical utility. - Details on extraction, appraisal results, and overlap calculations were provided in the article’s supplementary files; no primary data were generated and no funding or competing interests were declared.
## Clinical Analysis & Structured Key Points
Repurposing landscape of N-acetylcysteine: A scoping review of reviews toward clinical translation | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Reader Comments Figures Figures Abstract Background Growing interest in drug repurposing and oxidative stress has heightened attention on N‑acetylcysteine (NAC). Despite the abundance of reviews across diverse clinical domains, clinical translation remains limited. This review seeks to map the existing evidence, identify critical gaps, and outline priorities for future research. Methods Five databases were systematically searched to identify relevant reviews based on predetermined inclusion and exclusion criteria. Comprehensive data extraction enabled meaningful evidence mapping. To enhance rigor, critical appraisal was conducted using two validated tools assessing methodological quality and risk of bias, thereby allowing stratification of evidence. Additionally, the corrected covered area (CCA) was calculated to detect potential evidence inflation or redundancy. Results Among the 140 retrieved reviews spanning 17 clinical domains, only 63 were systematic reviews with meta‑analysis, representing the highest level of evidence included in this study. Approximately half of these supported NAC repurposing. Beyond its antioxidant, anti‑inflammatory, and glutamatergic modulatory roles, which were most frequently reported, several additional mechanisms have been proposed. The number of NAC reviews has increased over time, with most originating from China and the United States. Appraisals revealed a high prevalence of critically low‑quality systematic reviews, alongside a notable proportion of reviews with low risk of bias. Finally, CCA analysis demonstrated substantial overlap and redundancy across domains, particularly within subdomains. Conclusion This novel overview mapped the extensive NAC evidence landscape, highlighting its pleiotropic roles and repurposing potential while revealing possible research waste and critical gaps across domains and evidence levels. Psychiatry, reproductive medicine, nephrology, pulmonology, and toxicology emerged as priority clinical domains for future exploration. However, the overall inconsistency in review certainty remains a barrier to the integration of NAC into clinical guidelines. By delineating research priorities and highlighting new avenues, this review underscores the need for precision medicine approaches to guide future NAC clinical implementation and research. Citation: Al Alaili MK (2026) Repurposing landscape of N-acetylcysteine: A scoping review of reviews toward clinical translation. PLoS One 21(10): e0360434. https://doi.org/10.1371/journal.pone.0360434 Editor: UDAYAN BHATTACHARYA, Michigan Medicine, UNITED STATES OF AMERICA Received: May 25, 2026; Accepted: September 25, 2026; Published: October 9, 2026 Copyright: © 2026 Mohammed Khaled Al Alaili. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: No primary data were generated in this study. All review-level extraction datasets and other relevant supporting information are included within the article and its supplementary materials. Funding: The author(s) received no specific funding for this work. Competing interests: The author has declared that no competing interests exist. Abbreviations: AMSTAR, A MeaSurement Tool to Assess systematic Reviews; CCA, Corrected Covered Area;; CDSR, Cochrane Database of Systematic Reviews; COPD, Chronic Obstructive Pulmonary Disease; COVID-19, Coronavirus Disease 2019; FDA, Food and Drug Administration; GRADE, Grading of Recommendations Assessment, Development and Evaluation; JBI, Joanna Briggs Institute; NAC, N-acetylcysteine; NAPQI, N-acetyl-p-benzoquinone imine; OSF, Open Science Framework; PCC, Population, Concept and Context; PRISMA-ScR, Preferred Reporting Items for Systematic reviews and Meta-Analyses for Scoping Reviews; RCT, Randomized Controlled Trial; ROBIS, Risk Of Bias In Systematic reviews; STEMI, ST-Segment Elevation Myocardial Infarction; TRIP, Turning Research Into Practice database 1. Introduction N-acetylcysteine (NAC) is a long-recognized molecule with antioxidant properties that possesses exceptional mechanistic versatility [ 1 , 2 ]. Its sulfur content enables glutathione synthesis, forming the basis of its adoption in paracetamol toxicity, where it mitigates N-acetyl-p-benzoquinone imine (NAPQI) accumulation [ 3 ]. Although less potent than cysteine and glutathione, NAC’s free sulfur group allows it to disrupt disulfide bonds in mucin proteins, supporting its use as a mucolytic adjuvant in pulmonary conditions such as acute and chronic bronchitis, pneumonia, cystic fibrosis and diagnostic procedures [ 4 ]. These remain the only FDA‑approved and guideline‑endorsed clinical indications for NAC [ 5 ]. Nevertheless, growing interest in oxidative stress [ 6 , 7 ] and adjunctive therapies [ 8 ] has expanded NAC’s off‑label applications, such as in non‑paracetamol liver and kidney injury. Its broad biological plausibility and network pharmacology have advanced more rapidly than definitive evidence synthesis [ 9 ]. Its mechanistic diversity has rationalized its wide applicability potential, as NAC has been proposed to act as an antioxidant precursor, direct antioxidant, glutathione modulator, redox regulator, and mitochondrial stabilizer [ 2 ]. Meta‑analytic evidence further demonstrates its significant impact on oxidative stress and inflammatory biomarkers [ 10 ]. Drug repurposing, also termed repositioning, refers to the use of a drug beyond its conventional or approved indications [ 11 ]. This approach has accelerated in recent years and is increasingly advocated to reduce polypharmacy and promote rational drug use, particularly for low‑cost and globally accessible therapeutics [ 12 ]. Outcomes of repurposing may encompass clinical and comparative effectiveness, tolerability, mechanistic or biomarker insights, and population‑specific benefits [ 13 ]. NAC repurposing has emerged through recognition of shared pathobiological mechanisms across heterogeneous clinical conditions [ 14 ]. The expanding interest in NAC reflects a broader shift toward multi‑target agents capable of modulating convergent biological pathways implicated in both acute and chronic diseases [ 15 ]. While many off‑label indications are extrapolated from its antioxidant and anti‑inflammatory properties, additional mechanisms, such as glutamatergic modulation, have shown promise in psychiatric and neurological disorders [ 1 ]. Collectively, these features underscore NAC as a multi-system molecule with strong potential candidacy for repurposing, supported by its favorable safety profile, affordability, and wide availability, particularly in resource‑limited settings [ 16 ]. For instance, in low-income countries, where non-acetaminophen acute liver injury is more prevalent [ 17 ], NAC would stand to offer greater benefit from repurposing, in contrast to high-income countries where its primary use remains as an antidote for acetaminophen-induced liver failure. However, no single indication predominates, raising critical questions about why NAC demonstrates variable success and inconsistent clinical efficacy despite compelling mechanistic rationale. This inconsistency represents the central challenge addressed by this review. Over the years, numerous studies have investigated NAC, prompting an exponential rise in reviews aimed at consolidating evidence and identifying new indications [ 18 – 21 ]. However, the absence of umbrella‑level synthesis focusing on NAC raises some concerns. Previous reviews have largely focused on single indications, providing valuable but isolated insights. Despite extensive exploration, no new indications have been firmly established, and the available literature remains limited, with evidence dispersed across specialties and characterized by heterogeneity. This redundancy and uncertainty—where signals vary in strength—contributes to clinician confusion and guideline development delay. Signal dilution further obscures promising indications within fragmented evidence. To date, the clinical field lacks a unified, mature translational framework across indications. In particular, there is limited understanding of the comparative maturity of evidence, areas of saturation versus scarcity, and the degree of concordance between mechanistic rationale and clinical translation. In light of these challenges, this scoping review of reviews was undertaken to address existing gaps and, to our knowledge, provide the first comprehensive cross‑disciplinary synthesis, unlike umbrella reviews which aim to synthesize effect sizes. Its objectives are to map and characterize the breadth of evidence on NAC repurposing across clinical indications and domains, and to identify therapeutic signals and mechanistic themes. Furthermore, it seeks to uncover patterns of evidence convergence and translational discordance, while highlighting knowledge gaps, methodological trends, and future priorities for researchers and policymakers. Specifically, this review aims to clarify where trials should be prioritized and where NAC demonstrates clear promise, thereby informing clinical practice and precision repurposing strategies. 2. Methods 2.1. Protocol and reporting standards This review was conducted in accordance with the Joanna Briggs Institute (JBI) framework [ 22 ]. Reporting adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines [ 23 ], with the corresponding checklist provided in S1 File . The review protocol was prospectively registered on the Open Science Framework (OSF), ensuring transparency and reproducibility, and is accessible via the following link: https://doi.org/10.17605/OSF.IO/3VE5J . No major deviations occurred. Ethical approval was not required for this study because it is a review of previously published, publicly available literature. No human participants, animals, tissues or identifiable data were involved. 2.2. Search strategy and selection criteria A pilot search was conducted in November 2025, followed by a comprehensive search initiated in December 2025 after protocol registration and completed in February 2026. To ensure consistency and reduce single-author bias, a subset of the search was replicated to verify results. The overall review process is illustrated in the flow chart in Fig 1 . Five databases—TRIP (Turning Research Into Practice), CDSR (Cochrane Database of Systematic Reviews), Google Scholar, Epistemonikos, and PubMed—were systematically searched using relevant keywords and filters, targeting publications from the past ten years. The search strategy was intentionally based on keywords to maximize search sensitivity and ensure broad coverage, consistent with the objectives of a scoping review. The same conceptual search strategy was adapted for each database while accounting for differences in database-specific syntax and search functionality. Where database features (e.g., study design filters) were unavailable, equivalent restrictions were applied during the screening process through the predefined eligibility criteria. A targeted operator “allintitle:” was employed in Google Scholar to minimize noise and heterogeneity, ensuring that retrieved reviews primarily addressed NAC as the main intervention of interest. This was particularly relevant given our search string revolved mainly around NAC, and the operator ensured that records captured NAC as a central focus rather than incidental mention. The approach aligns with the review question and predefined eligibility criteria, thereby enhancing the specificity of our search strategy. All available results (n = 67) in Google Scholar were screened manually. A ten-year window was selected to balance comprehensiveness with feasibility and because older primary studies are already incorporated within existing reviews. This ensured focus on the most recent and clinically relevant syntheses without unnecessary duplication. All types of reviews were included. Only English-language studies were included to enhance international applicability and reporting consistency. Detailed search parameters (PCC framework, filters, and terms), along with inclusion and exclusion criteria, are presented in Fig 2 . Since no specific search field was restricted, all vocabulary terms related to the keyword N-acetylcysteine were considered in PubMed. For consistency across databases, N-acetylcysteine was the sole search term selected. The search strategy developed for the main database (PubMed) is presented as an example of the search approach. This reporting approach aligns with PRISMA-ScR guidance, which requires at least one detailed database strategy. To enhance rigor and transparency, the characteristics of excluded articles (abstract-level), including the number, type, and topics of non-NAC-focused and inaccessible studies, were mapped and are presented in Fig 3 . Indirect references to NAC were excluded to ensure the review remained treatment-focused rather than disease-focused, preventing data inflation and minimizing heterogeneity. This approach also reduced noise, ensuring alignment with JBI and PRISMA principles, which emphasize mapping evidence directly relevant to the review question. Duplicate records were removed manually, reference lists were screened for additional eligible studies, and titles and abstracts were systematically screened. Download: PNG larger image TIFF original image Fig 1. PRISMA flowchart. The chart shows the number of records identified, screened, excluded, and retained, with reasons for exclusion. This ensures reproducibility and transparency in study selection. CDSR: Cochrane Database of Systematic Reviews. NAC: N-acetylcysteine. TRIP: Turning Research Into Practice. PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses. https://doi.org/10.1371/journal.pone.0360434.g001 Download: PNG larger image TIFF original image Fig 2. Search strategy. This figure outlines the review concept and framework, the search filters/terms and the adopted inclusion/exclusion criteria. This strategy aligns with the reporting guidelines. https://doi.org/10.1371/journal.pone.0360434.g002 Download: PNG larger image TIFF original image Fig 3. Summary of excluded studies. This chart displays the characteristics of inaccessible and indirect excluded reviews. This mapping demonstrates transparency in the screening process. https://doi.org/10.1371/journal.pone.0360434.g003 2.3. Data extraction To minimize bias and enhance transparency, data extraction was performed using a predetermined extraction sheet. This sheet captured the following variables: title, author, publication year, country/review origin, clinical indication, clinical domains derived through inductive thematic reasoning and analysis of the retained literature, review type, number and type of included studies, population characteristics, conclusions, signal detection categorized as supportive, neutral, or against NAC use based on each article’s conclusion without subjective reinterpretation, limitations, evidence certainty (if reported), dose ranges, route of administration, and mechanism of action. Any nuances such as mixed outcomes, biomarker-only effects, subgroup findings, safety concerns, and multiple indications were documented, if available, in the ‘limitations’ column of the main extraction table in the supplementary file. To ensure the clarity, consistency and accuracy of the extraction process, a small random subset of five included studies was checked by an independent research colleague. Discrepancies were minimal and resolved via discussion. This step served as an informal verification and quality-control measure rather than formal dual screening; therefore, agreement statistics were not calculated. The complete extraction table is provided in S2 File . 2.4. Critical appraisal Although critical appraisal is optional in scoping reviews, it was applied as a descriptive component to ensure rigor, credibility and to enhance interpretability. Only systematic reviews with or without meta-analyses were eligible, with no exclusions applied, aligning with the scoping review objective of mapping and contextualizing the evidence rather than excluding studies based on quality. Review quality was assessed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) [ 24 ], which categorizes studies as critically low, low, moderate, or high. Seven critical domains—protocol registration, adequacy of the literature search, justification of exclusions, risk of bias assessment, appropriateness of meta-analysis (if conducted), consideration of risk of bias in results, and evaluation of publication bias—were prioritized. If two critical flaws were identified, the review was rated as critically low; one flaw resulted in a low rating. Non-critical flaws were then considered: the presence of two downgraded a high rating to moderate, while the presence of all led to a low rating. Each included systematic review was independently rated. Ratings were then summarized by frequency and domain to enable stratified evidence mapping. Given the large number of retained studies and the need for stratified, inferential evidence mapping, ROBIS (Risk Of Bias In Systematic reviews) was additionally applied [ 25 ]. ROBIS focuses specifically on risk of bias across four domains: study eligibility criteria, identification and selection, data collection and appraisal, and synthesis and findings. If any domain was judged to be of high concern, the overall rating was high risk; if none were of concern, the rating was low risk; and if assessment was not possible, the rating was classified as unclear. To balance feasibility, readability and transparency, only overall individual ratings from both tools, with documented reasons where applicable, were reported and provided in S3 File , while stratified results across domains are visualized in stacked bar charts. Using both tools provides complementary perspectives, methodological rigor and bias assessment, underscoring the robustness of this review’s approach. 2.5. Corrected covered area (CCA) Although overlap analysis is more commonly applied in umbrella reviews, it was calculated in this scoping review to strengthen methodological rigor and add transparency to the evidence mapping and its interpretation. For domains addressing similar conditions or indications with multiple systematic reviews and meta-analyses, given their capacity to generate quantitative certainty and effectiveness, percentage overlap was calculated using the CCA [ 26 ]. The purpose was to identify redundancy and mitigate the risk of duplicated primary studies, thereby reducing inflated results and evidence uncertainty, rather than to quantify effectiveness. For example, if three reviews all include the same ten primary studies, the overlap is very high. While this may appear to strengthen confidence in the findings, in reality it inflates the impression of evidence without adding new knowledge, since the same studies are being counted multiple times. The formula applied was: ( , where represents the total number of included studies across all reviews in the selected domain, denotes the number of unique, non-repeated primary studies, and indicates the number of reviews within the domain. Results were categorized as 0–5% (slight overlap), 6–10% (moderate), 11–15% (high), and >15% (very high). These categories indicate whether the evidence base is broad and independent or at risk of redundan
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