Clinical Insights into the Pathogenesis and Treatment Strategies of Acanthosis Nigricans: A Bibliometric Study of Current Trends and Future Directions

Abstract

Background

Acanthosis nigricans (AN) is a recognized cutaneous marker of insulin resistance and metabolic syndrome. Despite its clinical significance and associations with various comorbidities, a comprehensive, quantitative overview of the research landscape is lacking.

Objective

This study aimed to conduct a bibliometric analysis to map the global research output, identify key themes and trends, and elucidate the comorbidity network and potential therapeutic strategies for AN.

Methods

We performed a bibliometric analysis using publications retrieved from the Web of Science Core Collection (until May 13, 2024). Data from 2098 publications were analyzed using VOSviewer for co-authorship and keyword co-occurrence networks, CiteSpace for temporal trend and burst detection, and the R package bibliometrix for thematic mapping and publication metrics.

Results

Analysis revealed that original articles constituted 85.7% of the literature. Research output has accelerated markedly since 2010. Four core research clusters were identified: obesity/metabolic, hormonal, genetic, and malignancy-related. Key comorbidities with strong bibliometric linkages included psoriasis, hidradenitis suppurativa (HS), and acne, centered on shared mechanisms of insulin resistance and inflammation. The analysis highlighted emerging therapeutic directions, particularly the potential of GLP-1 receptor agonists (eg, semaglutide) due to their dual metabolic and anti-inflammatory (eg, TNF-α, IL-17 inhibition) effects, and the complex role of biologics targeting Th1/Th17 pathways.

Conclusion

This first bibliometric study of AN delineates its evolving research architecture, confirming its position at the intersection of dermatology, endocrinology, and immunology. The findings underscore shared pathophysiological pathways with several inflammatory skin diseases and point to novel, mechanism-based therapeutic strategies. Future research should prioritize clinical trials to validate these targeted interventions.

Introduction

Acanthosis nigricans (AN) is a dermatosis characterized by symmetric, hyperpigmented, velvety plaques, predominantly in intertriginous areas such as the neck, axillae, and groin.¹ It is a well-established cutaneous marker of insulin resistance and is frequently associated with obesity, type 2 diabetes mellitus, and polycystic ovary syndrome.² Beyond its metabolic correlations, AN can serve as a paraneoplastic sign of internal malignancy or manifest in genetic syndromes involving insulin receptor mutations.²

The global epidemic of obesity and metabolic syndrome has heightened clinical concern regarding AN. Early epidemiological studies underscore its significant burden and ethnic predisposition; for instance, it was identified in 7.1% of an unselected adolescent population, with prevalence rates soaring to 38% in certain high-risk Native American communities.^3,4 Furthermore, AN can be induced pharmacologically, with systematic reviews documenting associations with agents such as nicotinic acid, insulin, oral corticosteroids, and oral contraceptives.⁵

As a visible sentinel of underlying insulin resistance, AN provides a critical opportunity for early identification of metabolic dysfunction, prompting timely intervention.^6,7 Consequently, scientific interest in AN has grown substantially, reflected in a rapidly expanding body of literature. While individual studies have advanced our understanding of its pathogenesis and management, a macro-level, systematic analysis of the overall research landscape, evolution, and intellectual structure is conspicuously absent.

Bibliometrics, a quantitative method for analyzing publication patterns, collaborations, and knowledge domains, has proven invaluable in mapping research trends in fields like dermatology.^8–10 However, a comprehensive bibliometric synthesis dedicated to AN remains lacking. To address this gap, this study employs bibliometric techniques to analyze the scientific literature on AN. Our aims are: to quantify and visualize the growth trajectory, core contributors (authors, institutions, countries, and journals), and collaboration networks in AN research; to identify and analyze the evolution of key research themes, hotspots, and knowledge frontiers; and to synthesize these findings to provide clinical insights into pathogenesis and treatment strategies, thereby illuminating current trends and future directions for the field.

Materials and Methods

Study Design and Data Source

This study is a descriptive bibliometric analysis of the scientific literature on acanthosis nigricans (AN). The Web of Science (WOS) Core Collection database was selected as the primary data source for its comprehensive coverage of high-impact literature across disciplines and its compatibility with mainstream bibliometric software, which facilitates robust data extraction and analysis. The search encompassed the Science Citation Index Expanded (SCIE) and Social Sciences Citation Index (SSCI).

Search Strategy and Study Period

A systematic literature search was conducted to identify all relevant publications. After verifying that “Acanthosis Nigricans” has no widely accepted synonyms in MeSH, the term “melanosis” was included to broaden the scope. The final search query was: TS=((“Acanthosis Nigricans”) OR melanosis). The search was limited to documents published in English. The study period included all publications from the inception of the database until May 13, 2024. The initial search yielded 2098 records.

Inclusion and Exclusion Criteria

Documents were included if they: primarily focused on AN; were article or review article types; and were published in English. Exclusion criteria were: documents not related to AN (eg, those discussing melanosis in other contexts); non-research document types such as meeting abstracts, editorials, or letters; and duplicate publications. Furthermore, studies focusing exclusively on malignant (paraneoplastic) AN were excluded to maintain a focus on the metabolic and dermatologic aspects of the condition. The study selection process is detailed in a flow diagram (Supplementary Figure 1). The detailed analysis approach and derivation steps are clearly explained in Figure 1.

Figure 1.

Comprehensive search strategy and logical analysis methodology for Acanthosis Nigricans (AN) literature review.

Data Extraction and Bibliometric Analysis

All bibliographic records from the filtered dataset were extracted and analyzed using a combination of analytical tools to ensure robustness and comprehensiveness. Performance Analysis: Publication trends, leading contributors (countries, institutions, authors, journals), and citation metrics were analyzed using the inherent analytical functions of the WOS platform and bibliometrix (v4.3.0) package in R.¹¹ Science Mapping: Network visualization and clustering were performed to elucidate intellectual structures. VOSviewer (v1.6.17)¹² was used to construct and visualize networks of co-authorship (institutions, authors) and co-occurrence of keywords, highlighting collaborative relationships and core research themes.¹³ CiteSpace (v5.7.R5W)¹⁴ was employed specifically for temporal analysis, including detection of citation bursts and evolution of research frontiers over time, complementing the static network analysis. Descriptive statistics were compiled using Microsoft Excel 2016.

Results

Overall Analysis of Acanthosis Nigricans Research Publications

Analysis of the 2098 publications retrieved from the Web of Science Core Collection revealed that 85.7% were original research articles and 14.3% were reviews. This composition suggests that the AN research field is currently in an active phase of empirical investigation and data generation, with a relative predominance of primary studies over comprehensive synthesis.

Global Trends and Research Hotspots

AN research spans multiple disciplines, with major contributions from endocrinology (23.6%), dermatology (18.2%), and metabolic research (15.8%) (Figure 2A). Annual publication output has shown a consistent upward trend since 1975, with a marked acceleration in growth rate after 2010 (Figure 2B). A Sankey diagram illustrates the key linkages between frequently occurring keywords, contributing countries, and major research topics (Figure 2C). The United States, Germany, and the United Kingdom have historically led in publication volume. Notably, publication activity from China has also shown a marked increase in the most recent years reflected in the dataset (Figure 2D). The global collaboration network reveals strong and active research partnerships, particularly among institutions in North America and Europe (Figure 2E).

Figure 2.

Bibliometric overview of AN publications. The figure is composed of five panels arranged in two rows: the upper row (A–C) and the lower row (D and E). (A) Distribution of publications across major research disciplines. (B) Annual and cumulative number of publications on AN over time. (C) Sankey diagram illustrating the flow and relationships between high-frequency keywords, contributing countries, and major research topics. (D) Geographical distribution of publication output across different countries/regions. (E) Global collaboration network among institutions/countries in AN research, visualized using VOSviewer.

Keyword Evolution and Journal Analysis

Keyword analysis identified “obesity” and related terms as the most frequent in the literature (Figure 3A). Co-occurrence network analysis delineated four primary research clusters: obesity-related (eg, BMI, insulin resistance, metabolic syndrome); hormone-related (eg, hyperandrogenism, PCOS, metformin); genetic-related (eg, FGFR3 mutations); and tumor-related (eg, malignant AN) (Figure 3B–D). Over time, research focus has shifted, with sustained emphasis on obesity and metabolic aspects, while relative attention to genetic topics has decreased (Figure 3E–G). Key journals publishing AN research include the Journal of Clinical Endocrinology & Metabolism and Pediatric Dermatology (Supplementary Figure 2A-B and Appendix Table 1).

Figure 3.

Evolution and clustering of keywords in AN research. The figure contains seven panels arranged in three rows: the upper row (A–C), the middle row (D and E), and the lower row (F and G). (A) Treemap of the top 50 keywords ranked by frequency of occurrence. (B) This cluster visualization of keyword co-occurrence was generated using VOSviewer and illustrates four major thematic categories. (C) Temporal overlay view of the keyword co-occurrence cluster presented in (B). (D) Density visualization of research focus (VOSviewer). The color gradient (blue to yellow-orange) indicates publication concentration, with warmer colors representing higher publication density in a given research field. (E) Trend topics analysis depicting the evolution of high-frequency keywords (occurrence >15) over time. (F) Heatmap of annual keyword frequency. (G) Heatmap of cumulative keyword occurrence over time.

Comorbidity Associations Excluding Malignant AN

A focused analysis of 1118 publications excluding malignant AN revealed strong bibliometric associations between AN and other inflammatory skin diseases, notably psoriasis, hidradenitis suppurativa (HS), and acne (Figure 4A and B). Keywords such as “insulin resistance” and “adipocytokines” were central to connecting these comorbidities (Figure 4C). Thematic mapping further emphasized “obesity” and “metabolic syndrome” as core, well-developed themes linking AN to other conditions (Figure 4D).

Figure 4.

Keyword and thematic analysis excluding tumor-related AN. The figure contains four panels arranged in two rows: the upper row (A and B) and the lower row (C and D). (A) Cluster visualization of keyword co-occurrence from the filtered dataset. (B) Temporal overlay view of the keyword co-occurrence cluster presented in (A). (C) Top 20 keywords with the strongest citation bursts, identified by CiteSpace burst detection analysis. (D) Thematic map (generated using the bibliometrix R package) depicting the development and relevance of major research themes in AN comorbidity research.

Disease-Specific Comorbidity Mechanisms

AN and Psoriasis

The keyword network highlights shared pathways involving obesity, chronic inflammation, and insulin resistance, suggesting a complex, interacting pathophysiology (Figure 5A).

Figure 5.

Comorbidity analysis revealing AN mechanisms. The figure contains six panels arranged in three rows: the upper row (A and B), the middle row (C and D), and the lower row (E and F). (A) Thematic view of the keyword co-occurrence network linking AN and psoriasis. (B) Cluster visualization of the keyword co-occurrence network linking AN and acne. (C) Labeled view of the keyword network for AN and acne shown in (B). (D) Thematic association diagram for keywords related to AN and acne. (E) Cluster visualization of the keyword co-occurrence network linking AN and hidradenitis suppurativa (HS). (F) Labeled view of the keyword network for AN and HS shown in (E).

AN and Acne

Cluster analysis demonstrates a strong association with hyperandrogenism and polycystic ovary syndrome (PCOS). Thematic mapping positions metformin as a relevant metabolic intervention in this context (Figure 5B–D).

AN and Hidradenitis Suppurativa (HS)

The co-occurrence network reveals overlapping mechanisms among AN, HS, psoriasis, and atopic dermatitis, indicating shared pathophysiological grounds that may inform treatment approaches (Figure 5E and F).

Collaboration Networks and Therapeutic Context

Analyses of author and country collaboration networks demonstrate strengthening interdisciplinary ties, particularly within metabolic research (Supplementary Figures 3 & 4). An examination of treatment-focused documents (n=422) linked AN management discussions primarily to psoriasis, acne, and HS, with minimal focus on neoplastic associations (Supplementary Figure 5).

Molecular Targeted Therapy Research in AN

Analysis of treatment-focused literature uncovered two promising directions for AN management (Figure 6):

Figure 6.

Proposed multi-pathway mechanisms of semaglutide in treating acanthosis nigricans (AN) and its comorbidities. Downward arrows (↓) indicate metabolic and inflammatory markers consistently reported to decrease after semaglutide treatment in obesity-related studies: body weight, body mass index (BMI), waist circumference, white adipose tissue inflammation, serum triglycerides (TG), total cholesterol (CHO), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), pro-inflammatory cytokines [including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and interleukin-17 (IL-17)], and homeostasis model assessment of insulin resistance (HOMA-IR). Semaglutide also inhibits the activation of the NF-κB and TNF-α signaling pathways. Upward arrows (↑) indicate markers reported to increase: browning of white adipose tissue and circulating adiponectin levels. By comprehensively improving these key parameters of metabolism and chronic inflammation, semaglutide addresses the core insulin resistance and hyperinsulinemia driving AN, positioning it as a promising candidate for AN treatment.^15–19

● GLP-1 receptor agonists (eg, semaglutide): Supported by evidence of improving systemic inflammation in conditions like HS via inhibition of TNF-α, IL-17, and NF-κB pathways—mechanisms relevant to AN.

● Biologics targeting immune pathways: IL-4/IL-13 inhibitors (eg, dupilumab): Case reports link their use to the induction of AN lesions, implicating Th2 immunity.

TNF-α and IL-17 inhibitors (eg, adalimumab): Evidence from psoriasis and HS, along with AN case reports, suggests potential benefit by modulating Th1/Th17 pathways.

Discussion

The present bibliometric analysis systematically maps the intellectual structure and evolving trends in AN research. Our findings align with and extend the understanding of AN as a cutaneous marker of systemic dysfunction.

Interpretation of Key Findings in Context

Our study confirms the central role of metabolic syndrome, with obesity and insulin resistance constituting the most robust and persistent research cluster. This is consistent with AN’s established pathophysiology.²⁰ The strong bibliometric links between AN and other inflammatory skin diseases (psoriasis, HS, acne) revealed herein are supported by shared mechanistic pathways. For instance, the psoriatic Th1-driven immune response can disrupt insulin signaling and angiogenesis, pathways also implicated in AN.²⁰ Notably, therapies like calcipotriol (effective in psoriasis) have shown efficacy in AN, while biologics such as dupilumab (anti-IL-4/IL-13) have paradoxically been associated with inducing AN lesions, highlighting the complex and sometimes antagonistic interplay of immune axes (Th1/Th17 vs Th2) in AN pathogenesis.^21–23

The association with PCOS and acne underscores the role of hormonal dysregulation. Hyperandrogenism stimulates sebaceous gland activity, while adipokines like adiponectin (which regulates insulin sensitivity and sebum composition) are often dysregulated in these conditions.^24–26 This reinforces the rationale for metabolic interventions like metformin, which improves insulin sensitivity and has shown benefit for both AN and acne.^27–29

The link to HS further emphasizes shared metabolic-inflammatory pathways. Reduced adiponectin and elevated IL-17 levels are common to both diseases,^24,30 explaining the observed efficacy of therapies targeting the IL-23/Th17 and TNF-α axes in HS and their potential relevance for AN.²⁸ Collectively, these connections validate our analytical approach and illustrate that AN exists within a spectrum of disorders linked by common metabolic and inflammatory mechanisms.

Implications of Molecular Targeting

Our analysis identifies a growing research direction focusing on molecular targeted therapies beyond traditional weight management. The potential of GLP-1 agonists like semaglutide is particularly compelling. By directly addressing core components of metabolic syndrome and modulating key inflammatory pathways (TNF-α, IL-17, NF-κB) implicated in both HS and AN,²⁵ they represent a promising disease-modifying strategy for obesity-associated AN. Similarly, the documented effects (both inducing and ameliorating) of various biologics on AN lesions provide preliminary clinical evidence that targeted immunomodulation is a viable therapeutic frontier worthy of rigorous clinical investigation.

Strengths and Limitations

The primary strength of this study lies in its comprehensive bibliometric methodology, which provides an unbiased, macro-level overview of the AN research landscape, effectively highlighting interdisciplinary connections and evolving trends. However, several limitations must be acknowledged. As a descriptive, cross-sectional analysis, it identifies associations and generates hypotheses but cannot establish causality. The reliance on a single database (Web of Science), while standard for bibliometrics, may have omitted some relevant literature. Furthermore, the inherent risk of publication bias (toward positive results) in the analyzed literature may slightly skew the represented research landscape.

Conclusion and Future Directions

This study delineates the main themes, collaborations, and evolution of AN research, solidifying its position at the intersection of dermatology, endocrinology, and immunology. The strong bibliometric associations with psoriasis, HS, and acne underscore shared metabolic-inflammatory pathways. Future research should prioritize longitudinal clinical studies to validate the efficacy of mechanism-based therapies, such as GLP-1 agonists and targeted biologics, in managing AN. Additionally, prospective investigations are needed to establish standardized biomarkers for monitoring metabolic dysfunction in AN patients, facilitating early intervention and personalized treatment strategies.

Conclusion

In conclusion, this bibliometric study underscores the significance of acanthosis nigricans (AN) as a key cutaneous marker within the spectrum of metabolic syndrome and its associated dermatological conditions. The findings elucidate the critical interconnections between AN, hormonal dysregulation, and obesity, advocating for a multidisciplinary approach to its clinical management. Furthermore, this review delineates the shared pathophysiological mechanisms between AN and other inflammatory skin diseases, thereby establishing a rationale for future research into specific biomarkers and molecularly targeted therapeutic strategies, such as GLP-1 receptor agonists. The integration of metabolic and immunological perspectives presented here advances the conceptual framework for AN, pointing toward personalized management strategies that extend beyond conventional weight-loss interventions.

These insights address existing knowledge gaps and highlight the imperative for timely clinical translation to potentially improve patient outcomes. Future research efforts should prioritize prospective clinical trials to validate these associations and further investigate the underlying metabolic pathways. Such work will be crucial for deepening the comprehensive understanding of AN pathogenesis and its integrated impact on systemic and cutaneous health.

Funding Statement

This research was funded by the science and technology innovation Program of Hunan Province(2024RC3064); The Excellent Youth Project of Hunan Natural Science Foundation (No.2023JJ20089); The Project of Changsha Natural Science Foundation (kq2403069); The Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (YX202214); National Natural Science Foundation of China (NSFC) Young Scientists Fund (Grant No. 82504257); and the Young Backbone Talent Project of Hunan Provincial Health Commission (Grant No. RC020031).

Data Sharing Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Jinrong Zeng and Yujin Li are co-first authors for this study. Zhibing Fu and Lina Tan are co-correspondence authors for this study. The authors report no conflicts of interest in this work.