Abstract
Rosacea is a prevalent skin disorder in which neurogenic inflammation plays a significant role in its pathogenesis. Gabapentin (GBP) has garnered attention as a therapeutic option; however, its precise mechanism of action in treating rosacea remains unclear. Through a comprehensive analysis of experimental and clinical data, the research team has elucidated the molecular mechanism by which GBP inhibits neurogenic inflammation, particularly through modulating the NF-κB signaling pathway to alleviate rosacea inflammation. Using a murine rosacea model induced by LL37, the efficacy of GBP was compared to Minocycline and Hydroxychloroquine combination therapy. Various techniques assessed marker expression, transcriptomic profiles, and in vitro cell experiments with BV2 cells. Clinical data from 60 rosacea patients were analyzed through a randomized trial, comparing GBP therapy to the combination treatment. Results showed GBP effectively reduced skin inflammation and facial redness in mice and patients. Metabolomic analysis indicated significant changes in metabolites post-GBP treatment, correlating with inflammatory factors. The study concludes that GBP mitigates rosacea progression by targeting neurogenic inflammation via NF-κB pathway regulation, shedding light on novel treatment mechanisms through transcriptomics and metabolomics for future clinical application in rosacea research.
Data availability
The sequencing data has been deposited in the NCBI database with the following details: - Submission: SUB15316822 - BioProject: PRJNA1262076. The SRA IDs are listed below: Control group: - SRR33537231 - SRR33537230 - SRR33537229. LL37 group: - SRR33537228 - SRR33537227 - SRR33537226. GBP group: - SRR33537225 - SRR33537224 - SRR33537223. Uncropped and unedited blot/gel images (Supplementary fig. 5) are provided in the Supplementary Information. Numerical source data underlying the graphs and charts presented in the main figures can be found in Supplementary Data file.
References
van Zuuren, E. J. et al. Rosacea: new concepts in classification and treatment. Am. J. Clin. Dermatol 22, 457–465 (2021).
Sharma, A. et al. Rosacea management: A comprehensive review. J. Cosmet. Dermatol. 21, 1895–1904 (2022).
Rodrigues-Braz, D. et al. Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models. Mol. Vis. 27, 323–353 (2021).
Nowicka, D., Chilicka, K., Dzieńdziora-Urbińska, I. & Szyguła, R. Skincare in rosacea from the cosmetologist’s perspective: a narrative review. JCM 12, 115 (2022).
Passeron, T. et al. Adult skin acute stress responses to short-term environmental and internal aggression from exposome factors. Acad. Dermatol Venereol. 35, 1963–1975 (2021).
Hwang, J. & Lio, P. A. Topical corticosteroid withdrawal (‘steroid addiction’): an update of a systematic review. J. Dermatological Treat. 33, 1293–1298 (2021).
Li, J. et al. Comparison of different anti-demodex strategies: a systematic review and meta-analysis. Dermatology 239, 12–31 (2022).
Li, T., Wang, H., Wang, C. & Hao, P. Tofacitinib for the treatment of steroid-induced rosacea. CCID 15, 2519–2521 (2022).
Luo, Y. et al. Rosacea treatment with mussel adhesive protein delivered via microneedling: In vivo and clinical studies. J. Cosmet. Dermatol. 23, 1654–1662 (2024).
Ma, G. et al. Gabapentin improves the flushing of rosacea, but not other rosacea symptoms or quality of life: Results from a multicenter, randomized, double-blind, placebo-controlled pilot study. J. Am. Acad. Dermatol. 92, 920–922 (2025).
Madaan, P. et al. Exploring the therapeutic potential of targeting purinergic and orexinergic receptors in alcoholic neuropathy. Neurotox. Res 40, 646–669 (2022).
Li, J., Xu, K., Ding, H. & Xi, Q. Gabapentin reduces alcohol intake in rats by regulating NF-κB Signaling Pathway Via PPAR γ. Alcohol Alcohol. 57, 234–241 (2021).
Ivanic, M. G. et al. Neurogenic rosacea treatment: a literature review. JDD 22, 566–575 (2023).
Marek-Jozefowicz, L. et al. Molecular mechanisms of neurogenic inflammation of the skin. IJMS 24, 5001 (2023).
Aramini, A. et al. Ketoprofen, lysine and gabapentin co-crystal magnifies synergistic efficacy and tolerability of the constituent drugs: Pre-clinical evidences towards an innovative therapeutic approach for neuroinflammatory pain. Biomedicine Pharmacother. 163, 114845 (2023).
Nürnberger, F. et al. Gabapentinoids suppress lipopolysaccharide-induced interleukin-6 production in primary cell cultures of the rat spinal dorsal horn. Neuroimmunomodulation 30, 1–14 (2022).
Salau, V. F. et al. Ferulic acid mitigates diabetic cardiomyopathy via modulation of metabolic abnormalities in cardiac tissues of diabetic rats. Fundamemntal Clin. Pharma 37, 44–59 (2022).
Ahmed, O. M. et al. Efficiency of bone marrow-derived mesenchymal stem cells and hesperetin in the treatment of streptozotocin-induced type 1 diabetes in wistar rats. Pharmaceuticals 16, 859 (2023).
Gomolin T., Cline A., Pereira F. Treatment of rosacea during pregnancy. DOJ. 2021;27. https://doi.org/10.5070/d327754360.
Sardana, K. & Sachdeva, S. Role of nutritional supplements in selected dermatological disorders: A review. J. Cosmet. Dermatol. 21, 85–98 (2021).
Wang, B. et al. Paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the Prospective Rosacea Refractory Erythema Randomized Clinical Trial. J. Am. Acad. Dermatol. 88, 1300–1307 (2023).
Deng, Z. et al. Aspirin alleviates skin inflammation and angiogenesis in rosacea. Int. Immunopharmacol. 95, 107558 (2021).
Choe, J. & Barbieri, J. S. Emerging medical therapies in rosacea: a narrative review. Dermatol Ther. (Heidelb.) 13, 2933–2949 (2023).
Li, X. et al. Gabapentin alleviates brain injury in intracerebral hemorrhage through suppressing neuroinflammation and apoptosis. Neurochem Res 47, 3063–3075 (2022).
Marchitto, M. C. & Chien, A. L. Mast cell stabilizers in the treatment of rosacea: a review of existing and emerging therapies. Dermatol Ther. (Heidelb.) 11, 1541–1549 (2021).
Schwab, V. D. et al. Neurovascular and Neuroimmune Aspects in the Pathophysiology of Rosacea. J. Investigative Dermatol. Symp. Proc. 15, 53–62 (2011).
Kim, J. & Kim, K. Elucidating the potential pharmaceutical mechanism of Gyejibokryeong-hwan on rosacea using network analysis. Medicine 102, e33023 (2023).
Liu T. et al. Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea. JCI Insight. 7. https://doi.org/10.1172/jci.insight.161870 (2022).
Wang, A. R., May, D., Bourne, P. & Scott, G. PGP9.5. Am. J. Surgical Pathol. 23, 1401 (1999).
Day, I. N. M. & Thompson, R. J. UCHL1 (PGP 9.5): Neuronal biomarker and ubiquitin system protein. Prog. Neurobiol. 90, 327–362 (2010).
Allen, B. L. et al. Imbalance of proresolving lipid mediators in persistent allodynia dissociated from signs of clinical arthritis. Pain 161, 2155–2166 (2020).
Khan, A. et al. Antinociceptive properties of 25-methoxy hispidol A, a triterpinoid isolated from Poncirus trifoliata (Rutaceae) through inhibition of NF-κB signalling in mice. Phytother. Res. 33, 327–341 (2018).
Godad, A. P. et al. An Update On Proficiency of Voltage-gated Ion Channel Blockers in theTreatment of Inflammation-associated Diseases. CDT 23, 1290–1303 (2022).
Abdelnaser, M., Alaaeldin, R., Attya, M. E. & Fathy, M. Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB/MAPK signaling pathways. Life Sci. 320, 121562 (2023).
He, Y. et al. A transcriptomics-based analysis of the toxicity mechanisms of gabapentin to zebrafish embryos at realistic environmental concentrations. Environ. Pollut. 251, 746–755 (2019).
Jin, G. J., Peng, X., Chen, Z. G., Wang, Y. L. & Liao, W. J. Celastrol attenuates chronic constrictive injury-induced neuropathic pain and inhibits the TLR4/NF-κB signaling pathway in the spinal cord. J. Nat. Med 76, 268–275 (2021).
Hao T. et al. An Injectable Dual-Function Hydrogel Protects Against Myocardial Ischemia/Reperfusion Injury by Modulating ROS/NO Disequilibrium. Advanced Science. 2022;9. https://doi.org/10.1002/advs.202105408
Cruz-Pulido, D. et al. Comparative Transcriptome Profiling of Human and Pig Intestinal Epithelial Cells after Porcine Deltacoronavirus Infection. Viruses 13, 292 (2021).
Deng Z. et al. A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea. EMBO Mol Med. 13. https://doi.org/10.15252/emmm.202013560 (2021).
Zeng, Q. et al. Celastrol inhibits LL37-induced rosacea by inhibiting Ca2+/CaMKII-mTOR-NF-κB activation. Biomedicine Pharmacother. 153, 113292 (2022).
Han, S. B., Kim, H., Cho, S. H., Chung, J. H. & Kim, H. S. Protective Effect of Botulinum Toxin Type A Against Atopic Dermatitis–Like Skin Lesions in NC/Nga Mice. Dermatol Surg. 43, S312–S321 (2017).
Buapratoom, A., Wanasuntronwong, A., Khongsombat, O. & Tantisira, M. H. Anti-nociceptive effects of ECa 233 a standardized extract of Centella asiatica (L.) Urban on chronic neuropathic orofacial pain in mice. J. Ethnopharmacol. 283, 114737 (2022).
Rodríguez-Nogales, A. et al. Calcium Pyruvate Exerts Beneficial Effects in an Experimental Model of Irritable Bowel Disease Induced by DCA in Rats. Nutrients 11, 140 (2019).
Ji, B., Perani, E. G. & Grosset, J. H. Effectiveness of clarithromycin and minocycline alone and in combination against experimental Mycobacterium leprae infection in mice. Antimicrob. Agents Chemother. 35, 579–581 (1991).
Lovelace J. W., Ethell I. M., Binder D. K., Razak K. A. Minocycline Treatment Reverses Sound Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome. Front Neurosci. 14. https://doi.org/10.3389/fnins.2020.00771 (2020).
Li, J. et al. Hydroxychloroquine is a novel therapeutic approach for rosacea. Int. Immunopharmacol. 79, 106178 (2020).
Park, M. J. et al. Establishment of a humanized animal model of systemic sclerosis in which T helper-17 cells from patients with systemic sclerosis infiltrate and cause fibrosis in the lungs and skin. Exp. Mol. Med 54, 1577–1585 (2022).
Xie, B., Lu, C., Chen, C., Zhou, J. & Deng, Z. miR-135a Alleviates Silica-Induced Pulmonary Fibrosis by Targeting NF-κB/Inflammatory Signaling Pathway. Mediators Inflamm. 2020, 1–13 (2020).
Yang Z., Zhang Y., Yang S., Ding Y., Qu Y. Low-Dose Resveratrol Inhibits RIPK3-Mediated Necroptosis and Delays the Onset of Age-Related Hearing Loss. Front Pharmacol. 13. https://doi.org/10.3389/fphar.2022.910308 (2022).
Chen, T. C. et al. NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity. Cancers 14, 6065 (2022).
Wang Y. et al. MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program. Sci Adv. 7. https://doi.org/10.1126/sciadv.abb6075 (2021).
Yun T. J. et al. Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells. Sci Immunol. 6. https://doi.org/10.1126/sciimmunol.abc7302 (2021).
Hong M., et al. RNA sequencing: new technologies and applications in cancer research. J Hematol Oncol. 13. https://doi.org/10.1186/s13045-020-01005-x (2020).
Du Y. et al. The Epithelial to Mesenchymal Transition Related Gene Calumenin Is an Adverse Prognostic Factor of Bladder Cancer Correlated With Tumor Microenvironment Remodeling, Gene Mutation, and Ferroptosis. Front Oncol. 11. https://doi.org/10.3389/fonc.2021.683951 (2021).
Wu Y., Liu X., Li G. Integrated bioinformatics and network pharmacology to identify the therapeutic target and molecular mechanisms of Huangqin decoction on ulcerative Colitis. Sci Rep. 12. https://doi.org/10.1038/s41598-021-03980-8 (2022).
Dai F. et al. Integrated Bioinformatic Analysis of DNA Methylation and Immune Infiltration in Endometrial Cancer. BioMed Research International. 2022. https://doi.org/10.1155/2022/5119411 (2022).
Ma J. D., et al. A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Res Ther. 21. https://doi.org/10.1186/s13075-019-1935-6 (2019).
Gallo, R. L. et al. Standard classification and pathophysiology of rosacea: The 2017 update by the National Rosacea Society Expert Committee. J. Am. Acad. Dermatol. 78, 148–155 (2018).
Moore, A., Derry, S. & Wiffen, P. Gabapentin for Chronic Neuropathic Pain. JAMA 319, 818 (2018).
Zheng, F. et al. Development of a plasma pseudotargeted metabolomics method based on ultra-high-performance liquid chromatography–mass spectrometry. Nat. Protoc. 15, 2519–2537 (2020).
Hou, J. Y. et al. Integrated transcriptomics and metabolomics analysis reveals that C3 and C5 are vital targets of DuZhi Wan in protecting against cerebral ischemic injury. Biomedicine Pharmacother. 155, 113703 (2022).
Zhang, Q. F. et al. CDK4/6 inhibition promotes immune infiltration in ovarian cancer and synergizes with PD-1 blockade in a B cell-dependent manner. Theranostics 10, 10619–10633 (2020).
Zhao, X. et al. Correlation study and clinical value analysis between cerebral microbleeds and white matter hyperintensity with high-field susceptibility-weighted imaging. Medicine 102, e35003 (2023).
Acknowledgements
This study was supported by Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (2024MSXM069), Sponsored by Natural Science Foundation of Chongqing (CSTB2023NSCQ-MSX0078), National Natural Science Foundation of China (82404174).
Author information
Authors and Affiliations
Contributions
Z.Q.J., T.D., and Y.Z. contributed equally to study design, experimental work, and data analysis. M.L. and Y.T. assisted in conducting transcriptomic and metabolomic experiments and provided technical support. Y.X.Z. participated in clinical data collection and statistical analysis. B.W. conceived and supervised the study, provided critical revisions, and finalized the manuscript. All authors reviewed and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Communications Biology thanks Marek Sanak and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Connie Wong and Joao Valente.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Jiang, Z., Ding, T., Zhao, Y. et al. Transcriptomic and metabolomic insights into gabapentin’s therapeutic role in neurogenic inflammation of rosacea. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09662-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s42003-026-09662-3
