Quercetin alleviates incontinence-associated dermatitis via IKK/NF-κB pathway

Quercetin alleviates incontinence-associated dermatitis via IKK/NF-κB pathway | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Quercetin alleviates incontinence-associated dermatitis via IKK/NF-κB pathway Yan Zhang, Ge Zhao, Junfang Duan, Dajiang Yuan, Chenli Xu, Lijuan Song, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6255462/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jan, 2026 Read the published version in Scientific Reports → Version 1 posted 13 You are reading this latest preprint version Abstract Incontinence-associated dermatitis (IAD) is a prevalent inflammatory skin condition caused by prolonged exposure to urine and feces, leading to significant morbidity, particularly in elderly and critically ill patients. The pathogenesis of IAD is closely linked to chronic inflammation, which results in the excessive release of pro-inflammatory cytokines and skin barrier dysfunction. This study investigates the therapeutic potential of quercetin, a natural flavonoid with known anti-inflammatory and antioxidant properties, in a rat model of IAD. We found that quercetin significantly downregulated the expression and phosphorylation of IKKα/β and NF-κB, leading to a reduction in pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Furthermore, quercetin promoted skin barrier repair, as evidenced by improved transepidermal water loss measurements and histological findings showing enhanced epidermal integrity and reduced inflammatory cell infiltration. Our findings suggest that quercetin mitigates inflammation and accelerates skin barrier repair in IAD by targeting the IKK/NF-κB pathway, offering a promising therapeutic strategy for this debilitating condition. Health sciences/Medical research/Drug development Health sciences/Molecular medicine Health sciences/Risk factors incontinence-associated dermatitis quercetin anti-inflammatory NF-κB Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Incontinence-associated dermatitis (IAD) is an inflammatory skin condition affecting the perianal and perineal regions, caused by prolonged exposure to urine and feces in patients with urinary or fecal incontinence 1 , 2 . IAD represents a significant global health concern, particularly among elderly and critically ill patients in Intensive Care Units (ICUs) 1 , 3 – 9 . Reported incidence rates in ICU patients can reach from 6.89% up to 50%. IAD often leads to complications such as skin ulceration, pain, and increased patient discomfort, contributing to stress-related injuries and higher treatment costs 1 , 3 – 9 . Additionally, IAD is associated with secondary infections and pressure ulcers, both of which are linked to prolonged hospital stays and increased in-hospital mortality 1 , 3 – 9 . The pathogenesis of Incontinence-Associated Dermatitis (IAD) is complex and involves multiple pathophysiological processes, among which chronic inflammation is a central component 10 . Studies have shown that irritants in urine and feces, such as urea, ammonia, and proteases, can directly activate the inhibitor of kappa B kinase (IKK) in keratinocytes and immune cells, leading to the activation of the NF-κB signaling pathway 11 , 12 . This activation triggers the excessive release of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, resulting in a vicious cycle of localized inflammatory responses 11 , 12 . Furthermore, the overactivation of the NF-κB pathway suppresses the expression of skin barrier-related proteins, such as filaggrin and keratins, further compromising the skin's barrier function 11 , 12 . However, current treatment modalities are insufficient in effectively inhibiting the overactivation of the NF-κB pathway and fail to systemically regulate inflammatory responses. Therefore, identifying anti-inflammatory agents that can specifically target the IKK/NF-κB pathway to provide more comprehensive therapeutic effects, while integrating them with conventional care strategies, holds significant clinical importance. Quercetin, a naturally occurring flavonoid found abundantly in fruits, vegetables, and traditional herbal medicines, exhibits a wide range of biological activities, including antioxidant, anti-inflammatory, anti-tumor, immunomodulatory, and cardiovascular protective effects 13 – 15 . Despite its broad pharmacological potential, the therapeutic efficacy of quercetin in treating IAD remains largely unexplored. In this study, we aim to investigate the effects of orally administered quercetin on inflammation modulation, skin repair, and its intervention in the IKK/NF-κB pathway using a rat model of IAD. By elucidating the mechanisms underlying quercetin's actions, this research seeks to provide a novel therapeutic approach for managing IAD. Materials and Methods Synthesis of Artificial Urine Artificial urine was synthesized following a previously established protocol 12 . The composition of the synthetic urine was as follows: 0.2% (wt/vol) creatinine, 2.5% (wt/vol) urea, 0.3% (wt/vol) ammonium chloride, 0.9% (wt/vol) sodium chloride, 0.25% (wt/vol) anhydrous disodium hydrogen orthophosphate, and 1% (wt/vol) ammonium hydroxide. Sodium hydroxide was added to the synthetic urine solution, which was combined with 0.25% (wt/vol) trypsin, and the pH was adjusted to 8.0. IAD Rat Model Generation Eight-week-old male Sprague-Dawley rats weighing 180-200g were obtained from GemPharmatech Co., Ltd (Nanjing, China). The IAD model was established as follows: a cotton ball saturated with synthetic urine containing trypsin was applied to a selected area on the dorsal skin of the rat. The cotton ball was secured with adhesive tape and further wrapped with an elastic bandage. To maintain moisture, 5 mL of synthetic urine with trypsin solution was applied to the cotton ball twice daily (morning and afternoon). Rats in the control group were treated with cotton balls soaked in normal saline. On days 1, 3, and 5 post-modeling, the dorsal skin of the rats was rinsed with physiological saline, and excess moisture was absorbed using sterile gauze. Transepidermal water loss (TEWL) was measured using an AquaFlux™ AF200 TEWL Measurement Device (Biox, UK) under controlled environmental conditions (25°C, 60% humidity). Five days after modeling, rats from both the IAD and control groups were euthanized via CO2 asphyxiation, and skin tissues were collected for further analysis. Quercetin Treatment Quercetin was fully dissolved in corn oil using ultrasonication. Starting from day 5 post-IAD modeling, rats were administered 2 mL of quercetin solution orally once daily. The doses of quercetin administered were 25, 50, and 100 mg/kg, respectively, with an equivalent volume of corn oil administered to the control group. In addition to experimental treatments, the affected skin of each rat received standardized routine care to minimize secondary complications and support recovery. This included daily cleansing with physiological saline to remove debris and prevent infection, followed by the application of sterile gauze to protect the exposed area. TEWL measurements and photographic documentation were performed on days 1, 3, and 5 post-treatment. Skin tissues were collected after 5 days of treatment for further analysis. Evaluation of the IKK/NF-κB Pathway-related Proteins by Western Blotting Evaluation of the IKK/NF-κB Pathway-related Proteins by Western Blotting Total proteins were extracted from skin tissues using RIPA lysis buffer, and protein concentrations were quantified using a BCA assay kit. Proteins were separated by SDS-polyacrylamide gel electrophoresis and transferred onto PVDF membranes. The membranes were blocked with 5% non-fat milk and subsequently incubated with primary antibodies (Servicebio, Wuhan, China) against NF-κB p65 (1:2000), p-NF-κB p65 (1:2000), IKKα (1:2000), p-IKKα (1:2000), IKKβ (1:2000), p-IKKβ (1:2000), and β-actin (1:5000), followed by incubation with corresponding secondary antibodies (1:1000). β-actin served as the loading control for protein normalization. Detection of Inflammatory Factors by ELISA The concentrations of inflammatory cytokines, including IFN-γ, IL-1β, IL-6, and TNF-α, in rat skin tissues were quantified using commercially available ELISA kits (Beyotime, Shanghai, China) according to the manufacturer’s instructions. Histological Analysis Skin tissues were fixed, dehydrated, and embedded in paraffin. Sections of 4 µm thickness were prepared, dewaxed, and rehydrated for subsequent staining. Hematoxylin and eosin (H&E) staining, F4/80 immunohistochemical staining and TUNEL staining were performed with Rabbit anti-rat F4/80 primary antibody (Proteintech, Wuhan, China) and TUNEL Cell Apoptosis Detection Kit (Beyotime, Shanghai, China). Histological examination was conducted using a light microscope (OLYMPUS, Tokyo, Japan) at 200× magnification. The number of nucleated cells, F4/80-positive cells, and TUNEL-positive cells was counted in five randomly selected fields per sample, and the average was calculated to determine the mean number of cells per unit area. Statistical Analysis Data were analyzed using GraphPad Prism 9.0 software. Normality and homogeneity of variance were assessed. Normally distributed data were expressed as mean ± standard deviation (SD). Comparisons among multiple groups were performed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test. Comparisons between two groups were conducted using Student’s t-test. A p-value < 0.05 was considered statistically significant. Ethics All experimental procedures were conducted in accordance with ARRIVE guidelines and the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Ethical Committee of Second Hospital of Shanxi Medical University. Results Increased Inflammatory Factors and Upregulated IKK/NF-κB Pathway in the IAD Rat Model Representative images of the affected skin are shown in Fig. 1 A. Visual inspection revealed minimal damage to the dorsal skin of control rats, whereas the skin of IAD model rats exhibited severe damage characterized by erythema, epidermal loss, and rash in a time-dependent manner. TEWL measurements demonstrated a significant increase over the five-day observation period (Fig. 1 B, p < 0.05). Evaluation of the IKK/NF-κB pathway revealed elevated expression levels of NF-κB and IKKα/β, as well as increased phosphorylation of these proteins in the affected skin (Fig. 1 C-D, p < 0.05). Furthermore, the concentrations of inflammatory cytokines (IL-1β, IL-6, IFN-γ, and TNF-α) in the skin of IAD model rats were significantly higher than those in the control group (Fig. 1 E, p < 0.05). Histological analysis via H&E staining confirmed epidermal loss and an increased number of nucleated cells in the superficial dermis of IAD model rats (Fig. 1 F-G, p < 0.05). Collectively, these findings indicate that the IAD model is associated with significant inflammation, activation of the IKK/NF-κB pathway, and disruption of skin barrier function. Quercetin Accelerates Skin Barrier Repair in IAD Quercetin treatment alleviated skin damage in IAD rats in a dose-dependent manner, with significant improvements observed at doses of 50 mg/kg and above (Fig. 2 , left). TEWL measurements further supported these observations, showing a continuous decline in TEWL values in rats treated with 50 and 100 mg/kg quercetin, indicative of enhanced skin barrier repair (Fig. 2 , right, p < 0.05). These results demonstrate that quercetin promotes the restoration of skin barrier integrity in IAD. Quercetin Attenuates Inflammatory Response and Downregulates the IKK/NF-κB Pathway in IAD Western blot analysis revealed that quercetin treatment dose-dependently reduced the expression and phosphorylation of IKKα/β and NF-κB in IAD rats, with maximal effects observed at doses of 50 mg/kg and above (Fig. 3 A-B, p < 0.001). Similarly, ELISA results demonstrated a significant reduction in the levels of inflammatory cytokines (IL-1β, IL-6, IFN-γ, and TNF-α) in quercetin-treated rats compared to untreated IAD controls (Fig. 3 C, p < 0.05). These findings suggest that quercetin mitigates inflammation in IAD by suppressing the IKK/NF-κB signaling pathway. Quercetin Improves Histological Outcomes and Inhibits Cell Death in IAD Histological examination revealed that quercetin treatment at doses of 50 and 100 mg/kg resulted in a more intact epidermal structure and reduced infiltration of nucleated cells in the dermis (Fig. 4 A-B, p < 0.05). Furthermore, immunohistochemical assessment using F4/80 staining revealed a marked reduction in macrophage infiltration following quercetin treatment (Fig. 4 C-D, p < 0.05). Quantitative analysis of TUNEL staining showed a dose-dependent decrease in apoptotic cell population in quercetin-treated skin (Fig. 4 E-F, p < 0.05). These findings collectively suggest that quercetin exerts protective effects in IAD through multiple mechanisms, including preservation of tissue architecture, suppression of apoptotic cell death, and modulation of inflammatory cell recruitment. Discussion In this study, we investigated the therapeutic potential of quercetin in a rat model of IAD, focusing on its ability to modulate inflammation, promote skin barrier repair, and regulate the IKK/NF-κB signaling pathway. Our findings demonstrate that quercetin significantly alleviates skin damage, reduces inflammatory responses, and enhances histological recovery in IAD, providing a promising approach for the development of novel therapeutic strategies. The pathogenesis of IAD is closely linked to chronic inflammation, driven by the overactivation of the IKK/NF-κB pathway 12 . Our results confirm that the IAD model exhibits elevated levels of NF-κB and IKKα/β, along with increased phosphorylation of these proteins, which correlates with the excessive release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These cytokines perpetuate a cycle of inflammation, leading to further skin barrier dysfunction and tissue damage. Quercetin, however, effectively downregulated the expression and phosphorylation of IKKα/β and NF-κB, thereby attenuating the inflammatory cascade. This anti-inflammatory effect was further supported by the significant reduction in cytokine levels observed in quercetin-treated rats, highlighting its potential to disrupt the vicious cycle of inflammation in IAD. Additional studies have corroborated the anti-inflammatory properties of quercetin. For instance, research by Ha AT et al. demonstrated that quercetin inhibits the production of pro-inflammatory cytokines in keratinocytes and melanoma cells by suppressing the NF-κB pathway 16 . Similarly, a study found that quercetin reduces the expression of COX-2 and MPO, enzymes involved in the inflammatory response 17 – 19 . Furthermore, quercetin has been shown to modulate the MAPK pathway, another critical regulator of inflammation, by inhibiting the phosphorylation of ERK, JNK, and p38 MAPKs 20 – 23 . These mechanisms collectively contribute to quercetin's ability to mitigate inflammation and protect against tissue damage in various inflammatory conditions, including IAD. In addition to its anti-inflammatory properties, quercetin demonstrated a remarkable ability to accelerate skin barrier repair. TEWL measurements revealed a dose-dependent improvement in skin barrier function, particularly at doses of 50 mg/kg and above. This suggests that quercetin not only mitigates inflammation but also promotes the restoration of epidermal integrity, which is critical for preventing further complications such as infections and ulcerations. The histological findings further corroborated these results, showing a more intact epidermal structure and reduced infiltration of inflammatory cells in quercetin-treated skin. Moreover, the reduction in apoptotic cells and macrophage infiltration indicates that quercetin exerts protective effects against cell death and immune-mediated tissue damage. The mechanisms underlying quercetin's ability to promote tissue repair and regeneration, particularly in the skin, have been explored in various studies. For instance, quercetin has been shown to enhance keratinocyte proliferation and migration, which are essential processes for re-epithelialization during wound healing 24 . Additionally, quercetin upregulates the expression of growth factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β), which play pivotal roles in angiogenesis and extracellular matrix remodeling, respectively 25 . Furthermore, quercetin's antioxidant properties contribute to its tissue-repairing effects by reducing oxidative stress, which is known to impair wound healing and exacerbate tissue damage 26 , 27 . These mechanisms collectively enhance the repair of damaged skin and promote the regeneration of healthy tissue. The dual role of quercetin in modulating inflammation and promoting tissue repair aligns with its well-documented pharmacological properties, including its antioxidant and immunomodulatory activities. By targeting the IKK/NF-κB pathway, quercetin addresses a key driver of IAD pathogenesis, offering a more comprehensive therapeutic approach compared to conventional treatments that primarily focus on symptom management. Furthermore, the oral administration of quercetin presents a practical and non-invasive treatment option, which could be easily integrated into existing care protocols for patients with IAD. Despite these promising findings, several limitations should be acknowledged. First, the study was conducted in a rodent model, and further research is needed to validate the efficacy and safety of quercetin in human subjects. Second, the long-term effects of quercetin treatment remain to be explored, particularly in terms of its potential to prevent IAD recurrence. Finally, the precise molecular mechanisms underlying quercetin's effects on skin barrier repair warrant further investigation, as this could reveal additional therapeutic targets for IAD management. In summary, Our study provides compelling evidence that quercetin effectively mitigates inflammation, promotes skin barrier repair, and improves histological outcomes in a rat model of IAD through IKK/NF-κB pathway. Quercetin offers a novel and multifaceted approach to IAD treatment, with the potential to enhance patient outcomes and reduce the burden of this debilitating condition. Declarations Competing interests The authors declare no competing interests. Funding This work was supported by Second Hospital of Shanxi Medical University Hospital Fund(202204-5)and Science and Technology Innovation Project of college in Shanxi Province༈2023L067༉. Author Contribution Yinghui Zhang and Yan Zhang designed this study and wrote the main manuscript text and E.F. prepared figures 1-4; Yan Zhang, Ge Zhao and Junfang Duan performed this study; Dajiang Yuan, Chenli Xu and Lijuan Song analyzed the data.All authors reviewed the manuscript. Data Availability Data is provided within the manuscript or supplementary information files References Deprez, J. et al. Beeckman D. Prognostic factors for the development of incontinence-associated dermatitis (IAD): A systematic review. Int. Wound J. 21 , e14962 (2024). Sommana, C., Banharak, S., Sim-Im, S. & Ransinyo, K. Effects of Nursing Program in Preventing Incontinence-Associated Dermatitis by Applying Zinc Oxide and Petroleum Jelly Skin Protection Products Among Older Patients in Semi-Intensive Medical Care Units: A Pilot Study. J. Multidiscip Healthc. 17 , 3619–3636 (2024). Atli, N. & Kaplan Serin, E. Prevention and management of urinary incontinence-associated dermatitis: A systematic review. J. Tissue Viability . 33 , 985–991 (2024). Cunich, M. et al. Corrigendum to The costs, health outcomes and cost-effectiveness of interventions for the prevention and treatment of incontinence-associated dermatitis: A systematic review [Int. J. Nurs. Stud. 129 104216]. 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Supplementary Files Sdata.pdf Cite Share Download PDF Status: Published Journal Publication published 30 Jan, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 31 Oct, 2025 Reviews received at journal 30 Oct, 2025 Reviewers agreed at journal 24 Oct, 2025 Reviewers agreed at journal 23 Oct, 2025 Reviewers agreed at journal 21 Oct, 2025 Editor invited by journal 21 Oct, 2025 Reviews received at journal 25 Jun, 2025 Reviewers agreed at journal 17 Jun, 2025 Reviewers agreed at journal 11 Jun, 2025 Reviewers invited by journal 11 Jun, 2025 Editor assigned by journal 02 Apr, 2025 Submission checks completed at journal 27 Mar, 2025 First submitted to journal 27 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6255462","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":469868430,"identity":"465b4d59-2e99-4767-b97a-d925eb1880a5","order_by":0,"name":"Yan Zhang","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Zhang","suffix":""},{"id":469868431,"identity":"c37c771f-927e-41a6-abee-01e98edbe4f6","order_by":1,"name":"Ge Zhao","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ge","middleName":"","lastName":"Zhao","suffix":""},{"id":469868433,"identity":"925e9dfe-78e6-45ec-b7f8-f715912550fc","order_by":2,"name":"Junfang Duan","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Junfang","middleName":"","lastName":"Duan","suffix":""},{"id":469868434,"identity":"cdf33a82-7e3d-4af4-af29-67bc6b797746","order_by":3,"name":"Dajiang Yuan","email":"","orcid":"","institution":"Shanxi Cardiovascular Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dajiang","middleName":"","lastName":"Yuan","suffix":""},{"id":469868435,"identity":"068489ee-9071-4e74-b435-b8b91eb4ce41","order_by":4,"name":"Chenli Xu","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chenli","middleName":"","lastName":"Xu","suffix":""},{"id":469868436,"identity":"06b86ee9-7740-4fb7-9e52-92c2971a861e","order_by":5,"name":"Lijuan Song","email":"","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lijuan","middleName":"","lastName":"Song","suffix":""},{"id":469868437,"identity":"26c28584-213a-46ab-b3a4-daed0734c36d","order_by":6,"name":"Yinghui Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYBACA3YehgMQRmPjgw9EaWGGaeE53Gw4g1gtEIZEeps0BzFazJl5Dx742VaXuF3yYYM0A4OdnG4DAS2WzXwJB3vb2BJ3zk5sMC5gSDY2O0DIYYd5DA4ztvEkbrid2JA8g+FA4jYitUgkbrh5sOEwDwlaDBI33GBsbCZSC9AvPecSjDecSWxmnGFAjF+O9x7+8KOsTnbD8ePPf3yosJMjqAUGHBsgJhCpHATsSVA7CkbBKBgFIw0AANvKSH1FV7FgAAAAAElFTkSuQmCC","orcid":"","institution":"Second Hospital of Shanxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yinghui","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-03-18 17:38:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6255462/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6255462/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-026-37345-w","type":"published","date":"2026-01-30T15:58:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84693735,"identity":"6f0640c9-086e-4e05-aa35-3d0e6b60ddb0","added_by":"auto","created_at":"2025-06-16 10:19:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3201380,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIdentification of NFκB signaling pathway in IAD rat model\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Image of wounded skin of IAD rat model; B: TEWL detection after IAD modeling; C: Image of western blot bands of key signaling proteins of NFκB pathway; D: Quantitating western blot bands of key signaling proteins of NFκB pathway; E: Inflammation factors detected in IAD rat skin by ELISA; F: H＆E staining of IAD rat skin; G: Quantitating the number of nucleated cells of H＆E staining.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6255462/v1/14b1c5cda76a47d9472871b5.jpg"},{"id":84693733,"identity":"77ec6068-5c23-4c7f-833f-b9f6c861382f","added_by":"auto","created_at":"2025-06-16 10:19:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1488278,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuercetin accelerates skin barrier recovery in rats with IAD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Image of wounded skin of IAD rat model treated with quercetin; B: TEWL detection after quercetin treatment.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6255462/v1/72c11f9dcacb9e5d2fa3855c.jpg"},{"id":84695354,"identity":"f87cd525-301f-428f-acac-5cd310953040","added_by":"auto","created_at":"2025-06-16 10:35:14","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":609365,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuercetin downregulates IKK/NFκB signaling pathway in rats with IAD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Image of western blot bands of key signaling proteins of NFκB pathway with quercetin treatment; B: Quantitating western blot bands of key signaling proteins of NFκB pathway with quercetin treatment; C: Inflammation factors detected in IAD rat skin with quercetin treatment.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6255462/v1/dbf9a7adda47b61b68b4ea5c.jpg"},{"id":84693740,"identity":"edadb3e3-7a0f-4749-b943-436dfd533bf2","added_by":"auto","created_at":"2025-06-16 10:19:14","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3832544,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuercetin alleviates skin inflammation in rats with IAD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: H＆E staining of IAD rat skin with quercetin treatment; B: Quantitating the number of nucleated cells of H＆E staining with quercetin treatment; C: F4/80 immunohistochemical staining of IAD rat skin with quercetin treatment; D: Quantitating the number of F4/80 positive cells of immunohistochemical staining with quercetin treatment; E: TUNEL immunofluorescence staining of IAD rat skin with quercetin treatment; F: Quantitating the number of TUNEL positive cells of immunofluorescence staining with quercetin treatment.\u003c/p\u003e","description":"","filename":"figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6255462/v1/2450ab6d0691841a840fdbfc.jpg"},{"id":101690427,"identity":"5dd37c60-4908-4956-bdac-207e8b3bb466","added_by":"auto","created_at":"2026-02-02 16:02:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9875435,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6255462/v1/ac02cbfa-685b-47df-b3cf-91a53f4277c2.pdf"},{"id":84695018,"identity":"9ff3e36e-9575-4af0-a605-0c6264085199","added_by":"auto","created_at":"2025-06-16 10:27:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":424558,"visible":true,"origin":"","legend":"","description":"","filename":"Sdata.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6255462/v1/927f76ffb5a61a2698fa82e2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Quercetin alleviates incontinence-associated dermatitis via IKK/NF-κB pathway","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIncontinence-associated dermatitis (IAD) is an inflammatory skin condition affecting the perianal and perineal regions, caused by prolonged exposure to urine and feces in patients with urinary or fecal incontinence\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. IAD represents a significant global health concern, particularly among elderly and critically ill patients in Intensive Care Units (ICUs)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Reported incidence rates in ICU patients can reach from 6.89% up to 50%. IAD often leads to complications such as skin ulceration, pain, and increased patient discomfort, contributing to stress-related injuries and higher treatment costs\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Additionally, IAD is associated with secondary infections and pressure ulcers, both of which are linked to prolonged hospital stays and increased in-hospital mortality\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe pathogenesis of Incontinence-Associated Dermatitis (IAD) is complex and involves multiple pathophysiological processes, among which chronic inflammation is a central component\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Studies have shown that irritants in urine and feces, such as urea, ammonia, and proteases, can directly activate the inhibitor of kappa B kinase (IKK) in keratinocytes and immune cells, leading to the activation of the NF-κB signaling pathway\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This activation triggers the excessive release of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, resulting in a vicious cycle of localized inflammatory responses\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Furthermore, the overactivation of the NF-κB pathway suppresses the expression of skin barrier-related proteins, such as filaggrin and keratins, further compromising the skin's barrier function\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, current treatment modalities are insufficient in effectively inhibiting the overactivation of the NF-κB pathway and fail to systemically regulate inflammatory responses. Therefore, identifying anti-inflammatory agents that can specifically target the IKK/NF-κB pathway to provide more comprehensive therapeutic effects, while integrating them with conventional care strategies, holds significant clinical importance.\u003c/p\u003e \u003cp\u003eQuercetin, a naturally occurring flavonoid found abundantly in fruits, vegetables, and traditional herbal medicines, exhibits a wide range of biological activities, including antioxidant, anti-inflammatory, anti-tumor, immunomodulatory, and cardiovascular protective effects\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Despite its broad pharmacological potential, the therapeutic efficacy of quercetin in treating IAD remains largely unexplored. In this study, we aim to investigate the effects of orally administered quercetin on inflammation modulation, skin repair, and its intervention in the IKK/NF-κB pathway using a rat model of IAD. By elucidating the mechanisms underlying quercetin's actions, this research seeks to provide a novel therapeutic approach for managing IAD.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSynthesis of Artificial Urine\u003c/h2\u003e \u003cp\u003eArtificial urine was synthesized following a previously established protocol\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The composition of the synthetic urine was as follows: 0.2% (wt/vol) creatinine, 2.5% (wt/vol) urea, 0.3% (wt/vol) ammonium chloride, 0.9% (wt/vol) sodium chloride, 0.25% (wt/vol) anhydrous disodium hydrogen orthophosphate, and 1% (wt/vol) ammonium hydroxide. Sodium hydroxide was added to the synthetic urine solution, which was combined with 0.25% (wt/vol) trypsin, and the pH was adjusted to 8.0.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIAD Rat Model Generation\u003c/h3\u003e\n\u003cp\u003eEight-week-old male Sprague-Dawley rats weighing 180-200g were obtained from GemPharmatech Co., Ltd (Nanjing, China). The IAD model was established as follows: a cotton ball saturated with synthetic urine containing trypsin was applied to a selected area on the dorsal skin of the rat. The cotton ball was secured with adhesive tape and further wrapped with an elastic bandage. To maintain moisture, 5 mL of synthetic urine with trypsin solution was applied to the cotton ball twice daily (morning and afternoon). Rats in the control group were treated with cotton balls soaked in normal saline. On days 1, 3, and 5 post-modeling, the dorsal skin of the rats was rinsed with physiological saline, and excess moisture was absorbed using sterile gauze. Transepidermal water loss (TEWL) was measured using an AquaFlux\u0026trade; AF200 TEWL Measurement Device (Biox, UK) under controlled environmental conditions (25\u0026deg;C, 60% humidity). Five days after modeling, rats from both the IAD and control groups were euthanized via CO2 asphyxiation, and skin tissues were collected for further analysis.\u003c/p\u003e\n\u003ch3\u003eQuercetin Treatment\u003c/h3\u003e\n\u003cp\u003eQuercetin was fully dissolved in corn oil using ultrasonication. Starting from day 5 post-IAD modeling, rats were administered 2 mL of quercetin solution orally once daily. The doses of quercetin administered were 25, 50, and 100 mg/kg, respectively, with an equivalent volume of corn oil administered to the control group. In addition to experimental treatments, the affected skin of each rat received standardized routine care to minimize secondary complications and support recovery. This included daily cleansing with physiological saline to remove debris and prevent infection, followed by the application of sterile gauze to protect the exposed area. TEWL measurements and photographic documentation were performed on days 1, 3, and 5 post-treatment. Skin tissues were collected after 5 days of treatment for further analysis.\u003c/p\u003e\n\u003ch3\u003eEvaluation of the IKK/NF-κB Pathway-related Proteins by Western Blotting\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eEvaluation of the IKK/NF-κB Pathway-related Proteins by Western Blotting\u003c/div\u003e \u003cp\u003eTotal proteins were extracted from skin tissues using RIPA lysis buffer, and protein concentrations were quantified using a BCA assay kit. Proteins were separated by SDS-polyacrylamide gel electrophoresis and transferred onto PVDF membranes. The membranes were blocked with 5% non-fat milk and subsequently incubated with primary antibodies (Servicebio, Wuhan, China) against NF-κB p65 (1:2000), p-NF-κB p65 (1:2000), IKKα (1:2000), p-IKKα (1:2000), IKKβ (1:2000), p-IKKβ (1:2000), and β-actin (1:5000), followed by incubation with corresponding secondary antibodies (1:1000). β-actin served as the loading control for protein normalization.\u003c/p\u003e\n\u003ch3\u003eDetection of Inflammatory Factors by ELISA\u003c/h3\u003e\n\u003cp\u003eThe concentrations of inflammatory cytokines, including IFN-γ, IL-1β, IL-6, and TNF-α, in rat skin tissues were quantified using commercially available ELISA kits (Beyotime, Shanghai, China) according to the manufacturer\u0026rsquo;s instructions.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eHistological Analysis\u003c/h2\u003e \u003cp\u003eSkin tissues were fixed, dehydrated, and embedded in paraffin. Sections of 4 \u0026micro;m thickness were prepared, dewaxed, and rehydrated for subsequent staining. Hematoxylin and eosin (H\u0026amp;E) staining, F4/80 immunohistochemical staining and TUNEL staining were performed with Rabbit anti-rat F4/80 primary antibody (Proteintech, Wuhan, China) and TUNEL Cell Apoptosis Detection Kit (Beyotime, Shanghai, China). Histological examination was conducted using a light microscope (OLYMPUS, Tokyo, Japan) at 200\u0026times; magnification. The number of nucleated cells, F4/80-positive cells, and TUNEL-positive cells was counted in five randomly selected fields per sample, and the average was calculated to determine the mean number of cells per unit area.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using GraphPad Prism 9.0 software. Normality and homogeneity of variance were assessed. Normally distributed data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Comparisons among multiple groups were performed using one-way analysis of variance (ANOVA) followed by Tukey\u0026rsquo;s post hoc test. Comparisons between two groups were conducted using Student\u0026rsquo;s t-test. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e All experimental procedures were conducted in accordance with ARRIVE guidelines and the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Ethical Committee of Second Hospital of Shanxi Medical University.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eIncreased Inflammatory Factors and Upregulated IKK/NF-κB Pathway in the IAD Rat Model\u003c/h2\u003e \u003cp\u003eRepresentative images of the affected skin are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA. Visual inspection revealed minimal damage to the dorsal skin of control rats, whereas the skin of IAD model rats exhibited severe damage characterized by erythema, epidermal loss, and rash in a time-dependent manner. TEWL measurements demonstrated a significant increase over the five-day observation period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Evaluation of the IKK/NF-κB pathway revealed elevated expression levels of NF-κB and IKKα/β, as well as increased phosphorylation of these proteins in the affected skin (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC-D, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Furthermore, the concentrations of inflammatory cytokines (IL-1β, IL-6, IFN-γ, and TNF-α) in the skin of IAD model rats were significantly higher than those in the control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Histological analysis via H\u0026amp;E staining confirmed epidermal loss and an increased number of nucleated cells in the superficial dermis of IAD model rats (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF-G, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Collectively, these findings indicate that the IAD model is associated with significant inflammation, activation of the IKK/NF-κB pathway, and disruption of skin barrier function.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eQuercetin Accelerates Skin Barrier Repair in IAD\u003c/h2\u003e \u003cp\u003eQuercetin treatment alleviated skin damage in IAD rats in a dose-dependent manner, with significant improvements observed at doses of 50 mg/kg and above (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, left). TEWL measurements further supported these observations, showing a continuous decline in TEWL values in rats treated with 50 and 100 mg/kg quercetin, indicative of enhanced skin barrier repair (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, right, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). These results demonstrate that quercetin promotes the restoration of skin barrier integrity in IAD.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eQuercetin Attenuates Inflammatory Response and Downregulates the IKK/NF-κB Pathway in IAD\u003c/h2\u003e \u003cp\u003eWestern blot analysis revealed that quercetin treatment dose-dependently reduced the expression and phosphorylation of IKKα/β and NF-κB in IAD rats, with maximal effects observed at doses of 50 mg/kg and above (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-B, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, ELISA results demonstrated a significant reduction in the levels of inflammatory cytokines (IL-1β, IL-6, IFN-γ, and TNF-α) in quercetin-treated rats compared to untreated IAD controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). These findings suggest that quercetin mitigates inflammation in IAD by suppressing the IKK/NF-κB signaling pathway.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eQuercetin Improves Histological Outcomes and Inhibits Cell Death in IAD\u003c/h2\u003e \u003cp\u003eHistological examination revealed that quercetin treatment at doses of 50 and 100 mg/kg resulted in a more intact epidermal structure and reduced infiltration of nucleated cells in the dermis (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-B, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Furthermore, immunohistochemical assessment using F4/80 staining revealed a marked reduction in macrophage infiltration following quercetin treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC-D, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Quantitative analysis of TUNEL staining showed a dose-dependent decrease in apoptotic cell population in quercetin-treated skin (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE-F, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). These findings collectively suggest that quercetin exerts protective effects in IAD through multiple mechanisms, including preservation of tissue architecture, suppression of apoptotic cell death, and modulation of inflammatory cell recruitment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we investigated the therapeutic potential of quercetin in a rat model of IAD, focusing on its ability to modulate inflammation, promote skin barrier repair, and regulate the IKK/NF-κB signaling pathway. Our findings demonstrate that quercetin significantly alleviates skin damage, reduces inflammatory responses, and enhances histological recovery in IAD, providing a promising approach for the development of novel therapeutic strategies.\u003c/p\u003e \u003cp\u003eThe pathogenesis of IAD is closely linked to chronic inflammation, driven by the overactivation of the IKK/NF-κB pathway\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Our results confirm that the IAD model exhibits elevated levels of NF-κB and IKKα/β, along with increased phosphorylation of these proteins, which correlates with the excessive release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These cytokines perpetuate a cycle of inflammation, leading to further skin barrier dysfunction and tissue damage. Quercetin, however, effectively downregulated the expression and phosphorylation of IKKα/β and NF-κB, thereby attenuating the inflammatory cascade. This anti-inflammatory effect was further supported by the significant reduction in cytokine levels observed in quercetin-treated rats, highlighting its potential to disrupt the vicious cycle of inflammation in IAD. Additional studies have corroborated the anti-inflammatory properties of quercetin. For instance, research by Ha AT et al. demonstrated that quercetin inhibits the production of pro-inflammatory cytokines in keratinocytes and melanoma cells by suppressing the NF-κB pathway\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Similarly, a study found that quercetin reduces the expression of COX-2 and MPO, enzymes involved in the inflammatory response\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Furthermore, quercetin has been shown to modulate the MAPK pathway, another critical regulator of inflammation, by inhibiting the phosphorylation of ERK, JNK, and p38 MAPKs\u003csup\u003e\u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. These mechanisms collectively contribute to quercetin's ability to mitigate inflammation and protect against tissue damage in various inflammatory conditions, including IAD.\u003c/p\u003e \u003cp\u003eIn addition to its anti-inflammatory properties, quercetin demonstrated a remarkable ability to accelerate skin barrier repair. TEWL measurements revealed a dose-dependent improvement in skin barrier function, particularly at doses of 50 mg/kg and above. This suggests that quercetin not only mitigates inflammation but also promotes the restoration of epidermal integrity, which is critical for preventing further complications such as infections and ulcerations. The histological findings further corroborated these results, showing a more intact epidermal structure and reduced infiltration of inflammatory cells in quercetin-treated skin. Moreover, the reduction in apoptotic cells and macrophage infiltration indicates that quercetin exerts protective effects against cell death and immune-mediated tissue damage. The mechanisms underlying quercetin's ability to promote tissue repair and regeneration, particularly in the skin, have been explored in various studies. For instance, quercetin has been shown to enhance keratinocyte proliferation and migration, which are essential processes for re-epithelialization during wound healing\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Additionally, quercetin upregulates the expression of growth factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β), which play pivotal roles in angiogenesis and extracellular matrix remodeling, respectively\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Furthermore, quercetin's antioxidant properties contribute to its tissue-repairing effects by reducing oxidative stress, which is known to impair wound healing and exacerbate tissue damage\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. These mechanisms collectively enhance the repair of damaged skin and promote the regeneration of healthy tissue.\u003c/p\u003e \u003cp\u003eThe dual role of quercetin in modulating inflammation and promoting tissue repair aligns with its well-documented pharmacological properties, including its antioxidant and immunomodulatory activities. By targeting the IKK/NF-κB pathway, quercetin addresses a key driver of IAD pathogenesis, offering a more comprehensive therapeutic approach compared to conventional treatments that primarily focus on symptom management. Furthermore, the oral administration of quercetin presents a practical and non-invasive treatment option, which could be easily integrated into existing care protocols for patients with IAD.\u003c/p\u003e \u003cp\u003eDespite these promising findings, several limitations should be acknowledged. First, the study was conducted in a rodent model, and further research is needed to validate the efficacy and safety of quercetin in human subjects. Second, the long-term effects of quercetin treatment remain to be explored, particularly in terms of its potential to prevent IAD recurrence. Finally, the precise molecular mechanisms underlying quercetin's effects on skin barrier repair warrant further investigation, as this could reveal additional therapeutic targets for IAD management.\u003c/p\u003e \u003cp\u003eIn summary, Our study provides compelling evidence that quercetin effectively mitigates inflammation, promotes skin barrier repair, and improves histological outcomes in a rat model of IAD through IKK/NF-κB pathway. Quercetin offers a novel and multifaceted approach to IAD treatment, with the potential to enhance patient outcomes and reduce the burden of this debilitating condition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by Second Hospital of Shanxi Medical University Hospital Fund(202204-5)and Science and Technology Innovation Project of college in Shanxi Province༈2023L067༉.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYinghui Zhang and Yan Zhang designed this study and wrote the main manuscript text and E.F. prepared figures 1-4; Yan Zhang, Ge Zhao and Junfang Duan performed this study; Dajiang Yuan, Chenli Xu and Lijuan Song analyzed the data.All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDeprez, J. et al. 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Quercetin as a therapeutic agent for skin problems: a systematic review and meta-analysis on antioxidant effects, oxidative stress, inflammation, wound healing, hyperpigmentation, aging, and skin cancer. \u003cem\u003eNaunyn Schmiedebergs Arch. Pharmacol.\u003c/em\u003e (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKant, V., Sharma, M., Jangir, B. L. \u0026amp; Kumar, V. Acceleration of wound healing by quercetin in diabetic rats requires mitigation of oxidative stress and stimulation of the proliferative phase. \u003cem\u003eBiotech. Histochem.\u003c/em\u003e \u003cb\u003e97\u003c/b\u003e, 461\u0026ndash;472 (2022).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"incontinence-associated dermatitis, quercetin, anti-inflammatory, NF-κB","lastPublishedDoi":"10.21203/rs.3.rs-6255462/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6255462/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIncontinence-associated dermatitis (IAD) is a prevalent inflammatory skin condition caused by prolonged exposure to urine and feces, leading to significant morbidity, particularly in elderly and critically ill patients. The pathogenesis of IAD is closely linked to chronic inflammation, which results in the excessive release of pro-inflammatory cytokines and skin barrier dysfunction. This study investigates the therapeutic potential of quercetin, a natural flavonoid with known anti-inflammatory and antioxidant properties, in a rat model of IAD. We found that quercetin significantly downregulated the expression and phosphorylation of IKKα/β and NF-κB, leading to a reduction in pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Furthermore, quercetin promoted skin barrier repair, as evidenced by improved transepidermal water loss measurements and histological findings showing enhanced epidermal integrity and reduced inflammatory cell infiltration. Our findings suggest that quercetin mitigates inflammation and accelerates skin barrier repair in IAD by targeting the IKK/NF-κB pathway, offering a promising therapeutic strategy for this debilitating condition.\u003c/p\u003e","manuscriptTitle":"Quercetin alleviates incontinence-associated dermatitis via IKK/NF-κB pathway","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-16 10:19:09","doi":"10.21203/rs.3.rs-6255462/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-31T10:01:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-31T01:47:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332055039624247580613979946242533521563","date":"2025-10-24T11:46:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29165215065363819154110645234134977296","date":"2025-10-24T03:52:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2329739973735552235549484757509690185","date":"2025-10-22T02:12:20+00:00","index":"hide","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-21T21:27:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-25T17:00:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"40404015447482664804290340487811143449","date":"2025-06-17T05:59:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180856129975300446606127713455260962037","date":"2025-06-11T10:28:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-11T05:41:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-02T10:20:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-27T07:08:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-03-27T07:07:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"878d3fbf-9ad6-4a44-a80f-30a0b25e6679","owner":[],"postedDate":"June 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":49893727,"name":"Health sciences/Medical research/Drug development"},{"id":49893728,"name":"Health sciences/Molecular medicine"},{"id":49893729,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2026-02-02T16:00:20+00:00","versionOfRecord":{"articleIdentity":"rs-6255462","link":"https://doi.org/10.1038/s41598-026-37345-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-01-30 15:58:03","publishedOnDateReadable":"January 30th, 2026"},"versionCreatedAt":"2025-06-16 10:19:09","video":"","vorDoi":"10.1038/s41598-026-37345-w","vorDoiUrl":"https://doi.org/10.1038/s41598-026-37345-w","workflowStages":[]},"version":"v1","identity":"rs-6255462","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6255462","identity":"rs-6255462","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}