Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea

Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea | 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 Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea Yi Yang², Zheng Zhao¹, Lulu Lu¹, Na Gao¹, Jiangang Hu¹, Xiulian Zhang¹, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6911583/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Rosacea is a chronic skin disease with unclear causes, involving skin barrier issues and lipid changes. This study analyzed lipid profiles in rosacea patients' skin surface lipids (SSLs) to explore potential causes. The study included 10 rosacea patients and 10 healthy controls in Beijing. Transepidermal water loss (TEWL) was evaluated to assess the skin barrier function. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and multivariate data analysis were employed to investigate SSLs alterations. The results showed that rosacea patients had higher TEWL values than healthy controls (16.59 ± 3.95 versus 7.87 ± 2.52, p < 0.01). LC-MS/MS revealed significant differences in the lipidomic profiles and identified 48 species of SSLs that differed between the two groups. Triacylglycerol (TAG) were particularly abundant and varied in rosacea patients, which had 8 down-regulated differential lipids and 28 up-regulated lipids in rosacea patients. TAG, diacylglycerols (DAG), lysophosphatidylcholine (LPC), phosphatidylcholine (PC) were positively correlated with TEWL value (p < 0.05), but FFA were negatively correlated with TEWL value (p < 0.05). The present study indicated that patients with rosacea have impaired skin barrier function and altered SSL composition. Certain SSL species identified in this study may be potential targets for future studies on the pathogenesis and treatment of rosacea. Health sciences/Diseases/Skin diseases Biological sciences/Immunology/Inflammation Biological sciences/Biochemistry/Lipidomics Lipidomics Rosacea Skin surface lipids Skin barrier function Triacylglycerol Fatty acids Figures Figure 1 Figure 2 Figure 3 Introduction Rosacea is a common, chronic disorder that can present with a variety of cutaneous or ocular manifestations. Cutaneous involvement primarily affects the central face, with findings such as persistent centrofacial redness, papules, pustules, flushing, telangiectasia, and phymatous skin changes. The pathways that lead to the development of rosacea are not well understood. Proposed contributing factors include immunity, genetic factors, microorganisms, ultraviolet radiation (UV), neurovascular dysfuction [ 1 , 2 ] . Epidermal inflammation and higher concentrations of cathelicidins lead to disruption of lipid synthesis and stratum corneum formation, which affects the barrier function [ 3 ] . It has been proposed that barrier dysfunction is one of the key contributors to the pathogenesis of rosacea [ 4 ] . Skin surface lipids, primarily composed of ceramides (Cer), fatty acids (FFA), triglycerides (TAG), and cholesterol, originate from sebaceous glands-secreted lipids and epidermal disintegration lipids [ 5 ] . The equilibrium of these skin surface including their relative abundance, composition, molecular organization, dynamics, and intricate interactions, is crucial for maintaining healthy skin [ 6 ] . Consequently, even subtle alterations in the properties or overall profile of skin surface lipids have been associated with the aetiology of various common skin diseases such as atopic dermatitis, psoriasis, xerosis, ichthyosis and acne [ 7 ] . However, the role of skin surface lipids in the pathogenesis of rosacea remains underexplored. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is an advanced analytical technique used in lipidomics to identify and quantify cellular lipid species [ 8 ] . This study aims at investigating the differences in the lipidome of facial sebumbetween rosacea patients and the healthy controls residingin Beijing area, thereby providing a scientific basis for clinical treatment strategies. Results 2.1 Characteristics of the participants The clinical characteristics of the patients enrolled in this study and the control group are summarized in Table 1 . All participants were recruited between July 2024 and November 2024. Among the 10 rosacea patients (6 with erythematous type and 4 with papulopustular type), 3 were male and 7 were female, with a mean age of 37.70 ± 8.03 years. In the control group of 10 individuals, 3 were male and 7 were female, with a mean age of 37.6 ± 4.30 years. There were no significant differences in age (p = 0.97268) and gender between the two groups (Table 1 ). 2.2 Skin barrier function TEWL is frequently employed to evaluate the barrier function of human skin. An increase in TEWL generally indicates impairment of the skin barrier [ 8 ] . In this study, rosacea patients exhibited significantly higher TEWL values compared to healthy controls (16.59 ± 3.95 versus 7.87 ± 2.52, p < 0.01) (Table 1 ). These findings suggest that rosacea is closely linked to dysfunction of the skin barrier [ 9 ] . 2.3 SSL profiles Total lipids were collected from the surface of the left cheek of rosacea patients and healthy controls using the sebutape patchesand subsequently analyzed by LC-MS/MS. No significant difference was observed in the relative average content of total lipids between the rosacea group and the healthy control group (P = 0.218) (Fig. 1 a ). A total of 1082 unique lipids were identified in the lipid extracts. Based on the MS-Dial Lipidomics MSP database, four main classes of identified lipids were classified: 42.5% glycerolipids (GL), 40.0% glycerophospholipids (GP), 11.7% sphingolipids (SP), and 5.7% fatty acyls (FA) (Fig. 1 b). These four main classes were further subdivided into 18 subclasses, with TAG、phosphatidylcholine (PC), sphingomyelin (SM), FFA exhibiting the highest relative abundance within their respective main classes (GL, GP, SP and FA) (Fig. 1 c). 2.4 Differences in SSLs Multivariate data analysis of the 1082 identified lipids using PLS-DA demonstrated a distinct separation between rosacea patients and healthy controls (R 2 = 0.934, Q 2 = 0.822; Fig. 2 ). These findings suggest that variations in the lipid composition of SSLs may be associated with the pathogenesis of rosacea. Based on the PLS-DA analysis and Q-value (false discovery rate) evaluation, several parameters were employed to identify lipid species with significant differences between the rosacea patients and healthy controls. A total of 48 differential lipids were screened using criteria of VIP value > 1 and p value < 0.05. These included 38 GL (79.2%), 8 GP (16.7%) and 2 FA (4.2%) (Fig. 3 a). Compared with healthy controls, rosacea patients exhibited 10 down-regulated and 38 up-regulated differential lipids (Table 2 ). These 48 SSLs belonged to 5 subclasses (Fig. 3 b). TAG, the most abundant and differentially expressed lipids in the GL subclass, showed 8 down-regulated and 28 up-regulated differential lipids in rosacea patients. All 2 diacylglycerols (DAG) in the GL subclass were up-regulated in rosacea patients. In the GP main class, lysophosphatidylcholine (LPC) and PC were up-regulated, while FFA, including docosahexaenoic acid (DHA, FFA 22:6), were all down-regulated in rosacea patients. Subsequently, cluster analysis was performed for the differential lipids, and the heatmap demonstrated a clear distinction in lipid composition between rosacea patients and healthy controls (Fig. 3 c). Correlation analysis further revealed that differential lipids within the same subclass were positively correlated (Fig. 3 d), suggesting that changes at the lipid subclass level are critical in the lipidome alterations observed in rosacea patients. 2.5 Associations between SSL alterations and skin barrier damage To investigate whether certain SSLs components are associated with the impaired skin barrier function in rosacea patients, the correlations between TEWL and lipids categories were analyzed. The results demonstrated that FFA were negatively correlated with TEWL, whereas TAG, DAG, LPC and PC were positively correlated (Table 3). Discussion Rosacea is a common, chronic disorder that can present with a variety of cutaneous or ocular manifestations. The pathogenesis of rosacea is multifactorial, encompassing a range of triggers that elicit both inflammatory and vascular responses. In addition to genetic predispositions, various factors such as microbial agents (including Demodex mites), ultraviolet radiation, dietary influences, neurovascular dysregulation, and psychologicalstress, and immune system dysfunction, have been implicated in its development [ 1 – 3 ] . The stratum corneum lipid matrix, along with sebum- derived lipids from sebaceous glands, forms a highly complex and unique blend of skin surface lipids [ 10 ] . This lipid composition exhibits significant heterogeneity and provides the skin with its essential protective barrier [ 11 ] . Investigations into skin surface lipids in rosacea dates back to the 20th century. However, only one study has specifically examined skin lipidomics in rosacea patients: conducted by Pye et al., this study involved a limited cohort of patients and analyzed lipid components, particularly cholesterol, FFA, TAG, esters, and squalene [ 12 ] . Their findings indicated no differences between rosacea patients and controls, nor between genders or based on disease severity [ 12 ] . Another noteworthy study exploring the skin barrier in rosacea revealed down regulation of the ABCA12 gene, which encodes the lipid transporter ABCA12, a key player in lipid lamellae formation [ 13 ] . An increasing body of evidence suggests that an abnormal skin barrier structure and function are associated with the etiology and pathological processes of rosacea [ 14 , 15 ] . In this study, we also reached the same conclusion. It was found that rosacea patients exhibit a reduced skin barrier function compared to asymptomatic control subjects. The relative contents of TAG, DAG, LPC, and PC in rosacea patients were positively correlated with their TEWL, whereas FFA exhibited a negative correlation with TEWL. Impairment of the epidermal barrier function allows external irritants to penetrate the skin, leading to production of proinflammatory mediators such as TSLP (Thymic stromal lymphopoietin), which is an IL-7–like cytokine, IL-4, IL-13, IL-25, and IL-33 [16;17] . Thus, these increased inflammatory cytokines induce immune cell accumulation, which leads to formation of nitrogen oxide and reactive oxygen species [ 18 ] . TAG is one of the primary components of sebum on the skin surface [ 19 ] . When the synthesis of TAG lipids decreases or their breakdown becomes excessive, transepidermal water loss increases, weakening the skin's barrier function and making it more susceptible to invasion by harmful external substances, thereby triggering an inflammatory response [ 20 , 21 ] . Additionally, TAG can be dehydrated to generate DAG, which acts as a signaling molecule and synergistically activates the members of the PKC family with calcium ions (Ca²⁺). This process regulates cell proliferation, differentiation, apoptosis, and participates in inflammatory responses (such as NF-κB activation) [ 22 ] . The inflammatory mediators released by immune cells stimulate nerve endings, leading to increased neuropeptide release, vasodilation and enhanced vascular permeability, resulting in facial flushing and rashes. Furthermore, metabolic imbalance may impair vascular endothelial cell function, causing abnormal vascular regulation, exacerbating rosacea symptoms. This study found that compared to healthy controls, DAG levels were significantly elevated in rosacea patients, suggesting its potential role in rosacea through the aforementioned pathways. Abnormal TAG lipid metabolism was observed in rosacea patients and palmitoyl chains in TAG, while the levels of TAG with DHA chains decreased significantly. Lliterature reports indicate that locally supplementing or regulating the structure of TAG (such as synthesizing TAG with specific fatty acid chains) can improve the skin barrier, and alleviate the symptoms of acne, atopic dermatitis (AD) and other diseases [ 7 , 23 ] . This approach is also applicable to rosacea and represents a promising new direction for its treatment. The FFA in the surface lipids of the skin constitute a critical component of the lipid matrix of the stratum corneum [ 7 , 24 ] . According to the literature, long-chain FFA play a significant role in maintaining the stability of the skin barrier. The carbon chain length of FFA directly influences the density and hydrophobicity of the lipid layer [ 25 ] . In patients with papulopustular rosacea, an abnormal composition of sebaceous FFA has been observed, characterized by reduced levels of long-chain saturated FFA [ 25 ] . This study, identified a significant reduction in a long-chain FFA with a carbon chain length of 40. This reduction may enhance the fluidity of the lipid layer, thereby compromising the skin barrier function in rosacea [ 25 ] . Additionally, DHA, another significantly downregulated FFA discovered in this study, corresponds to the downregulation of TAGs containing DHA chains. DHA is known to activate peroxisome proliferator-activated receptor (PPARγ) [ 26 ] , promoting the expression of genes involved in keratinocyte lipid synthesis such as FFA binding protein, and enhancing barrier repair [ 27 ] . Furthermore, DHA exhibits significant regulatory effects on immune cells and immune factors. Specifically, DHA competitively inhibits the metabolism pathway of arachidonic acid, thereby reducing the production of pro-inflammatory mediators [ 28 ] . Additionally, DHA modulates T cells function by suppressing the differentiation of Th1 and Th17 cells, and decreasing the secretion of associated cytokines [ 28 ] . A reduction in the relative levels of DHA impairs the timely repair of the skin barrier and the suppression of inflammatory responses in stimulated skin, consequently exacerbating rosacea symptoms. Animal studies have demonstrated that DHA supplementation effectively decreases the expression of skin inflammation markers, such as IL-4 and IL-13 [ 28 , 29 ] . This finding may represent a novel research avenue for elucidating the pathogenesis and treatment of rosacea. Abnormal levels of LPC in the surface lipids of the skin may contribute to disease progression by modulating keratinocytes function, immune responses, and skin barrier integrity [ 20 , 30 ] . Elevated LPC levels could potentially exacerbate abnormal hair follicle keratinization and inflammatory responses through alterations in the FFA composition of sebum, such as increased ratios of linoleic acid/linolenic acid [ 20 ] . Furthermore, LPC has been shown to induce T-lymphocyte chemotaxis and thereby help to maintain the chronic inflammation found in psoriatic epidermis [ 31 ] . In another study, it was realized that LPC upregulated IL17, recruited neutrophils more efficiently, and exacerbated DNFB (2,4-Dinitrofluorobenzene)-induced skin inflammation [ 32 ] . Additionally, LPC promotes the inflammatory activation of CD4 + T cells via G protein-coupled receptor G2A signaling, which further compromises epidermal barrier function and exacerbates immune dysregulation [ 33 ] . PC is essential for maintaining skin barrier integrity. Its unique amphipathic property enables PC to form a stable lipid bilayer on the skin surface, thereby reinforcing the physical barrier. This structural feature not only prevents transepidermal water loss but also shields the skin from external environmental stressors. PC interacts synergistically with other skin lipids, including ceramides and cholesterol, to establish an organized lipid network that strengthens the skin's protective function. Moreover, PC plays a regulatory role in skin lipid metabolism by promoting the synthesis of key lipids like ceramides, thus ensuring the maintenance of skin lipid homeostasis [ 33 , 34 ] . In inflammatory skin conditions such as psoriasis and atopic dermatitis, disrupted skin lipid metabolism leads to reduced PC levels, which in turn compromises barrier function and exacerbates inflammatory responses. Research indicates that PC can modulate cutaneous immune responses and inflammation-related signaling pathways, thereby attenuating inflammatory symptoms. Topical application of PC-containing formulations has been demonstrated to enhance skin barrier recovery and mitigate inflammation [ 35 , 36 ] . However, it should be noted that elevated PC levels on the skin surface have been shown to increase transepidermal water loss, underscoring the importance of maintaining an optimal balance of skin lipids for overall skin health. In conclusion, this study demonstrates that the composition and structure of lipids on the skin surface of rosacea patients differ significantly from those of healthy controls, particularly in the abnormal structure composition of TAG. Moreover, these lipid differences may contribute to the skin barrier dysfunction. Furthermore, these lipid alterations are not only associated with skin barrier impairment but also closely linked to the onset and progression of rosacea. These findings will provide potential new targets for future research into the pathogenesis and treatment of rosacea. While this study offers valuable insights into the skin surface lipidomics of rosacea, it has certain limitations. Future research should validate these results with larger sample sizes and delve deeper into the specific mechanisms of lipid- metabolism disruption in rosacea to better support its diagnosis and treatment. Methods 4.1 Chemicals and reagents Acetonitrile (ACN), methanol, isopropanol (IPA), and methyl tert-butyl ethe (MTBE) Optima™ LC/MS Grade were obtained from Thermo Fisher Scientific (Waltham, MA, USA). Sebutape was purchased from CuDerm Corporation (Dallas, TX, USA). 4.2 Participants The study was approved by the Ethics Committee of Peking University International Hospital. All procedures adhered to relevant guidelines and regulations, and informed consent was obtained from all participants prior to enrollment. 20 participants from the Beijing area were enrolled in the study, including ten rosacea patients and ten healthy controls. All ten patients were diagnosed as rosacea by two identical dermatologists (refer to "Chinese Guidelines for Diagnosis and Treatment of Rosacea (2021 Edition)"). All 20 participants had not received any treatments or medications that could potentially interfere with the study assessment within the preceding 6 months. The exclusion criterion encompassed topical or oral drugs, physical treatments such as phototherapy, cardiovascular medications, antiepileptic drugs, antibiotics, and antipsychotic drugs. Additionally, none of the participants exhibited local skin lesions, including acne, eczema, melasma, psoriasis or scars, nor did they have any systemic diseases that might influence the skin condition. The study protocol ensured strict matching of participants based on demographic characteristics of sex and age. 4.3 TEWL measurement Both healthy individuals and patients with rosacea were selected for examination. Transepidermal water loss (TEWL) measurements were conducted on the left cheek using a portable VapoMeter (TM300; CK, Cologne, Germany). All tests were conducted in standardized ambient conditions with average humidity of 50% and average temperature of 23°C. Prior to measurement, participants' faces were cleaned with warm water without any cosmetics applied. The skin was then allowed to acclimate for 20 min. Subsequently, the detection probe was positioned on the target area, three consecutive readings were obtained from the same site for each participant, which were subsequently averaged. 4.4 SSL sampling Before sample collection, participants were instructed to acclimatize in a controlled environment (room temperature 23°C and humidity 50%) for 30 minutes. Sebum was collected from an approximately 4cm 2 area at the same site left cheek using Sebutape. Prior to sebum collection, the collection area was wiped with a 5% saline swab and one Sebutape patch was placed on the target site. The Sebutape patch was left in place for 10 min, and then removed to a sterile centrifuge tube using curved forceps. All samples were immediately stored at − 80°C until further analysis. 4.5 Sample preparation Samples were retrieved from the − 80°C freezer and transferred to pre-chilled tubes. To each tube, 680µL of a MTBE/methanol/water (400:80:200) extraction solvent was added. Samples were vortex-mixed for 10 minutes to ensure homogeneity, followed by centrifugation at 3000×g for 15 minutes to facilitate phase separation. Post-centrifugation, the supernatant (organic phase) was carefully collected, while the lower aqueous phase was discarded. The organic phase lipid extracts were then dried using a low-temperature concentrator (Speed Vac SPD131P; Thermo Fisher Scientific) and stored for subsequent analysis. Prior to mass spectrometry, lyophilized samples were reconstituted in 400 µL of methanol/isopropanol (3:1, v/v) to ensure optimal solubility. Quality control (QC) samples were prepared by pooling aliquots of all study samples to monitor analytical reproducibility, which were analyzed alongside experimental samples using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) [ 37 ] . 4.6 LC-MS/MS analysis and identification Chromatographic separation was performed on a Phenomenex Kinetex 1.7 µm EVO C18 column (2.1 × 50 mm, 100 Å; Agilent, USA) under reversed-phase liquid chromatography (RPLC) conditions. The mobile phase system consisted of: (A) 50% acetonitrile-water containing 10 mM ammonium formate, and (B) isopropanol (IPA) with 10% formic acid and 10 mM ammonium formate. A gradient elution program was applied: starting with 90% solvent A, linearly decreasing to 0% A over 11 minutes, holding at 100% B for 6 minutes, then immediately re-equilibrating to 90% A and maintaining this condition for 3 minutes. Mass spectrometry was conducted using a Triple TOF 5600 + orthogonal accelerated time-of-flight mass spectrometer (AB SCIEX, USA) equipped with an electrospray ionization (ESI) source. Data acquisition was performed in both positive and negative ion modes for each chromatographic run. Full-scan mass spectra were collected over an m/z range of 50–1500, with data-dependent acquisition (IDA) mode employed to enhance metabolite coverage. Mass accuracy was ensured by referencing a lock-mass ion throughout the analysis using MS-Dial software (ver. 3.70; 17 April 2019). Metabolite identification was achieved by matching detected ions against the MS-Dial Lipidomics MSP database ( http://prime.psc.riken.jp/compms/msdial/main.html ) [ 38 ] . 4.7 Statistical analysis Raw mass spectrometry data were processed using MS-Dial (Ver. 3.70), with the Lipidomics MSP database integrated into the software to support peak detection, filtering, and alignment. Following preprocessing, a two-dimensional data matrix was generated, encompassing lipid identifiers, retention times, lipid classes, mass-to-charge ratios (m/z), peak areas, and raw Excel data. Multivariate statistical analysis, including partial least-squares discriminant analysis (PLS-DA), was performed using MetaboAnalyst 5.0 ( http://www.metaboanalyst.ca/MetaboAnalyst/ ) to characterize lipid distributions and identify differential metabolites between senile rosacea patients and healthy controls. PLS-DA models were validated via 10-fold cross-validation with unit variance scaling. Model fitness was evaluated using R² (goodness of fit) and Q² (predictive ability). Between-group comparisons of integrated peak intensities were conducted using a two-tailed Welch’s t-test within MetaboAnalyst 5.0, with statistical significance defined as p 1.0 [ 37 ] . Abbreviations ACN:Acetonitrile; IPA:Sopropanol; SSL:Skin surface lipids; MTBE:Methyl tert-butyl ether; TEWL:Transepidermal water loss; LC-MS/MS:Liquid chromatography coupled tandem mass spectrometry; PLS-DA: Partial least squares; UV:ultraviolet radiatio; Cer:Ceramides; FFA:Fatty acids; TAG:Triacylglycero; GL:Glycerolipids; GP:Glycerophospholipids; SP:Sphingolipids; FA:Fatty acyls; PC:Phosphatidylcholine; SM:Sphingomyelin; DAG:Diacylglycerols; LPC:Lysophosphatidylcholine; DHA:Docosahexaenoic acid; TSLP:Thymic stromal lymphopoietin; Ca²⁺:calcium ions; AD: Atopicdermatitis; PPARγ:Peroxisome proliferator-activated receptor; DNFB:2,4-Dinitrofluorobenzene; Declarations Author contributions Xiaolei Ma: Data collection and analysis.Yi Yang: Writing the original draft, reviewing, and editing. Lulu Lu, Na Gao: Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and multivariate data analysis. Zheng Zhao, Xiulian Zhang: Transepidermal water loss detection. Gangwen Han: Clinical cases collection and experimental guidance. The authors read and approved the final manuscript. Availability of data and materials All data generated or analysed during this study are available from the correspongding author on reasonable request. Ethics approval and consent to participate. Ethics approval and consent to participate: The study was approved by the Ethics Committee of Peking University International Hospital. All procedures adhered to relevant guidelines and regulations, and informed consent was obtained from all participants prior to enrollment. Consent for publication: All the participants consent for publication of their individual details. Funding: The work was supported by research grant from National Natural Science Foundation of China, Grant/Award Number:82404136 to Xiaolei Ma. Ethics approval and consent to participate The study was reviewed and approved by the ethics committee of Peking University International Hospital. Informed consent to participate in the study was obtained from each patient and healthy person before enrolling in the study. Clearance No for Ethical approval:2018–065(BMR). Consent for publication All the participants had signed the consent for publication in the informed consent in our institutional consent form. Competing interests No competing interest Supplementary information Supplementary information accompanies this paper References Maden S. Rosacea: An Overview of Its Etiological Factors, Pathogenesis, Classification and Therapy Options. Dermato. 2023;3(4):241-262. Kulkarni NN, Takahashi T, Sanford JA, et al. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression. J Invest Dermatol. 2020;140:645-655. Woo YR, Lim JH, Cho DH, Park HJ. Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory Condition. Int J Mol Sci. 2016;17(9):1562. Addor FA. Skin barrier in rosacea. 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Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and T cells differentiation via glycolysis. Nădăban A, Rousel J, El Yachioui D, Gooris GS, Beddoes CM, Dalgliesh RM, Malfois M, Rissmann R, Bouwstra JA. Effect of sphingosine and phytosphingosine ceramide ratio on lipid arrangement and barrier function in skin lipid models. J Lipid Res. 2023 Aug;64(8):100400. Nowowiejska J, Baran A, Flisiak I. Lipid Alterations and Metabolism Disturbances in Selected Inflammatory Skin Diseases. Int J Mol Sci. 2023 Apr 11;24(8):7053. Ma Y, Cui L, Tian Y, He C. Lipidomics analysis of facial lipid biomarkers in females with self-perceived skin sensitivity. Health Sci Rep. 2022 May 6;5(3):e632. Ma X, Lu L, Zhao Z, Cai M, Gao N, Han G. Lipidomics profiling of skin surface lipids in senile pruritus. Lipids Health Dis. 2020 Jul 16;19(1):171. Tsugawa H, Cajka T, Kind T, Ma Y, Higgins B, Ikeda K, et al. MS-DIAL: data independent MS/MS deconvolution for comprehensive metabolome analysis. Nat Methods. 2015;12(6):523–526. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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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-6911583","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":479171942,"identity":"382c3e81-7ed9-4ffd-9fc7-b79f94c6cf46","order_by":0,"name":"Yi Yang²","email":"","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Yang²","suffix":""},{"id":479171946,"identity":"305c2ace-bd82-4416-9f0e-66dfd1a531e9","order_by":1,"name":"Zheng Zhao¹","email":"","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zheng","middleName":"","lastName":"Zhao¹","suffix":""},{"id":479171949,"identity":"f5950683-50ac-4262-868d-aa2cbfd70c6b","order_by":2,"name":"Lulu Lu¹","email":"","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lulu","middleName":"","lastName":"Lu¹","suffix":""},{"id":479171951,"identity":"762c9c56-b5a0-42cc-bb32-779e6b1b3df3","order_by":3,"name":"Na Gao¹","email":"","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Gao¹","suffix":""},{"id":479171953,"identity":"a6c98633-a8a5-4a6f-91d8-c7132014f5bb","order_by":4,"name":"Jiangang Hu¹","email":"","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiangang","middleName":"","lastName":"Hu¹","suffix":""},{"id":479171955,"identity":"f00d0e13-88af-483c-bff0-5ea607a3e87e","order_by":5,"name":"Xiulian Zhang¹","email":"","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiulian","middleName":"","lastName":"Zhang¹","suffix":""},{"id":479171956,"identity":"390253dc-0e61-4909-815c-a72d80231f72","order_by":6,"name":"Gangwen Han¹","email":"","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":false,"prefix":"","firstName":"Gangwen","middleName":"","lastName":"Han¹","suffix":""},{"id":479171958,"identity":"e681cbf3-a11c-4c45-9943-a66c7b5b5cc3","order_by":7,"name":"Xiaolei Ma¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYFADZiB+wCAhx8befoAELQkMEsZ8PGcSSLAJqDZxnoSDAV5F8jNyDz6uzLFjMDjO/PBBQoVFepsEUOePim04tRjcyEs2PLstmUGymc3YIOGMRG6bdOMBxp4zt3Frkcgxk2zcxszAz8xgJpHYBtQicyCBmbENtxb5GTnmPxu31TOwMbN/k0j8J5HOJpFggFcLw40cM8bGbYeBtvAAbWmQSCCoxeDMu2Sgw47zSDbzFBskHJMwbAMG8kF8fpFvzz34sXFbtZzB+eMbH3yoqZOXb28/+OBHBR6HMfAgkTBwAI96DMWjYBSMglEwCjABADYvT6ninWGDAAAAAElFTkSuQmCC","orcid":"","institution":"Peking University International Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaolei","middleName":"","lastName":"Ma¹","suffix":""}],"badges":[],"createdAt":"2025-06-17 07:38:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6911583/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6911583/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-24539-x","type":"published","date":"2025-11-07T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85993384,"identity":"607cbc02-1292-4638-af9b-1d2f37e2cca6","added_by":"auto","created_at":"2025-07-04 05:39:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":369189,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of lipids identified in the lipid extracts. (a) Relative average content of total lipids in samples. (b)The proportion of main classes of identified lipids.FA, fatty acyls; GL, glycerolipids; GP, glycerophospholipids; SP,sphingolipids. (c)The proportion of lipid subclasses in each main class.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6911583/v1/c077507f4c3869f94ef0210b.png"},{"id":85993387,"identity":"a76b62e8-865e-4d8b-8eb8-333afd43102f","added_by":"auto","created_at":"2025-07-04 05:39:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":143646,"visible":true,"origin":"","legend":"\u003cp\u003ePLS-DA score plot of SSL from rosacea patients and healthy controls. SSL profiles of rosacea patients (red dots) and controls (blue dots) are obviously separated. R\u003csup\u003e2\u003c/sup\u003e = 0.934，Q\u003csup\u003e2\u003c/sup\u003e = 0.822\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6911583/v1/d7202ce90375ece78e039072.png"},{"id":85993911,"identity":"4259b08d-cd14-455d-81b6-8f7b11911e07","added_by":"auto","created_at":"2025-07-04 05:47:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2389890,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of differential lipids in rosacea patients and healthy controls. (a) The proportion of main classes of differential lipids. (b) The counts of up- or down-regulated differential lipids in rosacea patients versus healthy controls at the subclass level. (c) The heatmap showing the cluster analysis of differential lipids. The color key represrnts the fold change of up- (red) or down-regulated (blue) differential lipids in rosacea patients versus healthy controls. The class represents the group of rosacea patients (patient, the red block) and healthy controls(control, the green block). (d) The heatmap showing the correlation analysis of differential lipids.The intensity of the colors represents the degree of association between each differential lipid as measured by Spearman’s correlations.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6911583/v1/1348ddf1d6f082a9caa7b7aa.png"},{"id":95564862,"identity":"e5c05a78-86cc-44d4-85e9-713d9e56ba0e","added_by":"auto","created_at":"2025-11-10 16:10:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3831287,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6911583/v1/5aed1798-2c0e-45f4-8825-9162c926e3b3.pdf"},{"id":85993385,"identity":"d872951e-25e4-4377-ac1e-34ff8b06e5cc","added_by":"auto","created_at":"2025-07-04 05:39:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":565329,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6911583/v1/5ebeb39eebc1ad47b1cf2528.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRosacea is a common, chronic disorder that can present with a variety of cutaneous or ocular manifestations. Cutaneous involvement primarily affects the central face, with findings such as persistent centrofacial redness, papules, pustules, flushing, telangiectasia, and phymatous skin changes. The pathways that lead to the development of rosacea are not well understood. Proposed contributing factors include immunity, genetic factors, microorganisms, ultraviolet radiation (UV), neurovascular dysfuction \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Epidermal inflammation and higher concentrations of cathelicidins lead to disruption of lipid synthesis and stratum corneum formation, which affects the barrier function\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. It has been proposed that barrier dysfunction is one of the key contributors to the pathogenesis of rosacea\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Skin surface lipids, primarily composed of ceramides (Cer), fatty acids (FFA), triglycerides (TAG), and cholesterol, originate from sebaceous glands-secreted lipids and epidermal disintegration lipids\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The equilibrium of these skin surface including their relative abundance, composition, molecular organization, dynamics, and intricate interactions, is crucial for maintaining healthy skin\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Consequently, even subtle alterations in the properties or overall profile of skin surface lipids have been associated with the aetiology of various common skin diseases such as atopic dermatitis, psoriasis, xerosis, ichthyosis and acne\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. However, the role of skin surface lipids in the pathogenesis of rosacea remains underexplored. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is an advanced analytical technique used in lipidomics to identify and quantify cellular lipid species\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. This study aims at investigating the differences in the lipidome of facial sebumbetween rosacea patients and the healthy controls residingin Beijing area, thereby providing a scientific basis for clinical treatment strategies.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Characteristics of the participants\u003c/h2\u003e\n \u003cp\u003eThe clinical characteristics of the patients enrolled in this study and the control group are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. All participants were recruited between July 2024 and November 2024. Among the 10 rosacea patients (6 with erythematous type and 4 with papulopustular type), 3 were male and 7 were female, with a mean age of 37.70\u0026thinsp;\u0026plusmn;\u0026thinsp;8.03 years. In the control group of 10 individuals, 3 were male and 7 were female, with a mean age of 37.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.30 years. There were no significant differences in age (p\u0026thinsp;=\u0026thinsp;0.97268) and gender between the two groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Skin barrier function\u003c/h2\u003e\n \u003cp\u003eTEWL is frequently employed to evaluate the barrier function of human skin. An increase in TEWL generally indicates impairment of the skin barrier\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. In this study, rosacea patients exhibited significantly higher TEWL values compared to healthy controls (16.59\u0026thinsp;\u0026plusmn;\u0026thinsp;3.95 versus 7.87\u0026thinsp;\u0026plusmn;\u0026thinsp;2.52, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). These findings suggest that rosacea is closely linked to dysfunction of the skin barrier\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 SSL profiles\u003c/h2\u003e\n \u003cp\u003eTotal lipids were collected from the surface of the left cheek of rosacea patients and healthy controls using the sebutape patchesand subsequently analyzed by LC-MS/MS. No significant difference was observed in the relative average content of total lipids between the rosacea group and the healthy control group (P\u0026thinsp;=\u0026thinsp;0.218) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea ). A total of 1082 unique lipids were identified in the lipid extracts. Based on the MS-Dial Lipidomics MSP database, four main classes of identified lipids were classified: 42.5% glycerolipids (GL), 40.0% glycerophospholipids (GP), 11.7% sphingolipids (SP), and 5.7% fatty acyls (FA) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb). These four main classes were further subdivided into 18 subclasses, with TAG、phosphatidylcholine (PC), sphingomyelin (SM), FFA exhibiting the highest relative abundance within their respective main classes (GL, GP, SP and FA) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e2.4 Differences in SSLs\u003c/h2\u003e\n \u003cp\u003eMultivariate data analysis of the 1082 identified lipids using PLS-DA demonstrated a distinct separation between rosacea patients and healthy controls (R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.934, Q\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.822; Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). These findings suggest that variations in the lipid composition of SSLs may be associated with the pathogenesis of rosacea. Based on the PLS-DA analysis and Q-value (false discovery rate) evaluation, several parameters were employed to identify lipid species with significant differences between the rosacea patients and healthy controls. A total of 48 differential lipids were screened using criteria of VIP value\u0026thinsp;\u0026gt;\u0026thinsp;1 and p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. These included 38 GL (79.2%), 8 GP (16.7%) and 2 FA (4.2%) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea). Compared with healthy controls, rosacea patients exhibited 10 down-regulated and 38 up-regulated differential lipids (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). These 48 SSLs belonged to 5 subclasses (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb). TAG, the most abundant and differentially expressed lipids in the GL subclass, showed 8 down-regulated and 28 up-regulated differential lipids in rosacea patients. All 2 diacylglycerols (DAG) in the GL subclass were up-regulated in rosacea patients. In the GP main class, lysophosphatidylcholine (LPC) and PC were up-regulated, while FFA, including docosahexaenoic acid (DHA, FFA 22:6), were all down-regulated in rosacea patients.\u003c/p\u003e\n \u003cp\u003eSubsequently, cluster analysis was performed for the differential lipids, and the heatmap demonstrated a clear distinction in lipid composition between rosacea patients and healthy controls (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec). Correlation analysis further revealed that differential lipids within the same subclass were positively correlated (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ed), suggesting that changes at the lipid subclass level are critical in the lipidome alterations observed in rosacea patients.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e2.5 Associations between SSL alterations and skin barrier damage\u003c/h2\u003e\n \u003cp\u003eTo investigate whether certain SSLs components are associated with the impaired skin barrier function in rosacea patients, the correlations between TEWL and lipids categories were analyzed. The results demonstrated that FFA were negatively correlated with TEWL, whereas TAG, DAG, LPC and PC were positively correlated (Table\u0026nbsp;3).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eRosacea is a common, chronic disorder that can present with a variety of cutaneous or ocular manifestations. The pathogenesis of rosacea is multifactorial, encompassing a range of triggers that elicit both inflammatory and vascular responses. In addition to genetic predispositions, various factors such as microbial agents (including Demodex mites), ultraviolet radiation, dietary influences, neurovascular dysregulation, and psychologicalstress, and immune system dysfunction, have been implicated in its development\u003csup\u003e[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. The stratum corneum lipid matrix, along with sebum- derived lipids from sebaceous glands, forms a highly complex and unique blend of skin surface lipids\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. This lipid composition exhibits significant heterogeneity and provides the skin with its essential protective barrier\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Investigations into skin surface lipids in rosacea dates back to the 20th century. However, only one study has specifically examined skin lipidomics in rosacea patients: conducted by Pye et al., this study involved a limited cohort of patients and analyzed lipid components, particularly cholesterol, FFA, TAG, esters, and squalene\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Their findings indicated no differences between rosacea patients and controls, nor between genders or based on disease severity\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Another noteworthy study exploring the skin barrier in rosacea revealed down regulation of the ABCA12 gene, which encodes the lipid transporter ABCA12, a key player in lipid lamellae formation\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAn increasing body of evidence suggests that an abnormal skin barrier structure and function are associated with the etiology and pathological processes of rosacea\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. In this study, we also reached the same conclusion. It was found that rosacea patients exhibit a reduced skin barrier function compared to asymptomatic control subjects. The relative contents of TAG, DAG, LPC, and PC in rosacea patients were positively correlated with their TEWL, whereas FFA exhibited a negative correlation with TEWL. Impairment of the epidermal barrier function allows external irritants to penetrate the skin, leading to production of proinflammatory mediators such as TSLP (Thymic stromal lymphopoietin), which is an IL-7\u0026ndash;like cytokine, IL-4, IL-13, IL-25, and IL-33 \u003csup\u003e[16;17]\u003c/sup\u003e. Thus, these increased inflammatory cytokines induce immune cell accumulation, which leads to formation of nitrogen oxide and reactive oxygen species\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTAG is one of the primary components of sebum on the skin surface\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. When the synthesis of TAG lipids decreases or their breakdown becomes excessive, transepidermal water loss increases, weakening the skin's barrier function and making it more susceptible to invasion by harmful external substances, thereby triggering an inflammatory response\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Additionally, TAG can be dehydrated to generate DAG, which acts as a signaling molecule and synergistically activates the members of the PKC family with calcium ions (Ca\u0026sup2;⁺). This process regulates cell proliferation, differentiation, apoptosis, and participates in inflammatory responses (such as NF-κB activation) \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. The inflammatory mediators released by immune cells stimulate nerve endings, leading to increased neuropeptide release, vasodilation and enhanced vascular permeability, resulting in facial flushing and rashes. Furthermore, metabolic imbalance may impair vascular endothelial cell function, causing abnormal vascular regulation, exacerbating rosacea symptoms. This study found that compared to healthy controls, DAG levels were significantly elevated in rosacea patients, suggesting its potential role in rosacea through the aforementioned pathways. Abnormal TAG lipid metabolism was observed in rosacea patients and palmitoyl chains in TAG, while the levels of TAG with DHA chains decreased significantly. Lliterature reports indicate that locally supplementing or regulating the structure of TAG (such as synthesizing TAG with specific fatty acid chains) can improve the skin barrier, and alleviate the symptoms of acne, atopic dermatitis (AD) and other diseases\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. This approach is also applicable to rosacea and represents a promising new direction for its treatment.\u003c/p\u003e \u003cp\u003eThe FFA in the surface lipids of the skin constitute a critical component of the lipid matrix of the stratum corneum\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. According to the literature, long-chain FFA play a significant role in maintaining the stability of the skin barrier. The carbon chain length of FFA directly influences the density and hydrophobicity of the lipid layer\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. In patients with papulopustular rosacea, an abnormal composition of sebaceous FFA has been observed, characterized by reduced levels of long-chain saturated FFA\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. This study, identified a significant reduction in a long-chain FFA with a carbon chain length of 40. This reduction may enhance the fluidity of the lipid layer, thereby compromising the skin barrier function in rosacea\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Additionally, DHA, another significantly downregulated FFA discovered in this study, corresponds to the downregulation of TAGs containing DHA chains. DHA is known to activate peroxisome proliferator-activated receptor (PPARγ)\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e, promoting the expression of genes involved in keratinocyte lipid synthesis such as FFA binding protein, and enhancing barrier repair\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Furthermore, DHA exhibits significant regulatory effects on immune cells and immune factors. Specifically, DHA competitively inhibits the metabolism pathway of arachidonic acid, thereby reducing the production of pro-inflammatory mediators\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Additionally, DHA modulates T cells function by suppressing the differentiation of Th1 and Th17 cells, and decreasing the secretion of associated cytokines\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. A reduction in the relative levels of DHA impairs the timely repair of the skin barrier and the suppression of inflammatory responses in stimulated skin, consequently exacerbating rosacea symptoms. Animal studies have demonstrated that DHA supplementation effectively decreases the expression of skin inflammation markers, such as IL-4 and IL-13\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. This finding may represent a novel research avenue for elucidating the pathogenesis and treatment of rosacea.\u003c/p\u003e \u003cp\u003eAbnormal levels of LPC in the surface lipids of the skin may contribute to disease progression by modulating keratinocytes function, immune responses, and skin barrier integrity\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Elevated LPC levels could potentially exacerbate abnormal hair follicle keratinization and inflammatory responses through alterations in the FFA composition of sebum, such as increased ratios of linoleic acid/linolenic acid\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Furthermore, LPC has been shown to induce T-lymphocyte chemotaxis and thereby help to maintain the chronic inflammation found in psoriatic epidermis\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. In another study, it was realized that LPC upregulated IL17, recruited neutrophils more efficiently, and exacerbated DNFB (2,4-Dinitrofluorobenzene)-induced skin inflammation\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Additionally, LPC promotes the inflammatory activation of CD4\u0026thinsp;+\u0026thinsp;T cells via G protein-coupled receptor G2A signaling, which further compromises epidermal barrier function and exacerbates immune dysregulation\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePC is essential for maintaining skin barrier integrity. Its unique amphipathic property enables PC to form a stable lipid bilayer on the skin surface, thereby reinforcing the physical barrier. This structural feature not only prevents transepidermal water loss but also shields the skin from external environmental stressors. PC interacts synergistically with other skin lipids, including ceramides and cholesterol, to establish an organized lipid network that strengthens the skin's protective function. Moreover, PC plays a regulatory role in skin lipid metabolism by promoting the synthesis of key lipids like ceramides, thus ensuring the maintenance of skin lipid homeostasis\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. In inflammatory skin conditions such as psoriasis and atopic dermatitis, disrupted skin lipid metabolism leads to reduced PC levels, which in turn compromises barrier function and exacerbates inflammatory responses. Research indicates that PC can modulate cutaneous immune responses and inflammation-related signaling pathways, thereby attenuating inflammatory symptoms. Topical application of PC-containing formulations has been demonstrated to enhance skin barrier recovery and mitigate inflammation\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. However, it should be noted that elevated PC levels on the skin surface have been shown to increase transepidermal water loss, underscoring the importance of maintaining an optimal balance of skin lipids for overall skin health.\u003c/p\u003e \u003cp\u003eIn conclusion, this study demonstrates that the composition and structure of lipids on the skin surface of rosacea patients differ significantly from those of healthy controls, particularly in the abnormal structure composition of TAG. Moreover, these lipid differences may contribute to the skin barrier dysfunction. Furthermore, these lipid alterations are not only associated with skin barrier impairment but also closely linked to the onset and progression of rosacea. These findings will provide potential new targets for future research into the pathogenesis and treatment of rosacea. While this study offers valuable insights into the skin surface lipidomics of rosacea, it has certain limitations. Future research should validate these results with larger sample sizes and delve deeper into the specific mechanisms of lipid- metabolism disruption in rosacea to better support its diagnosis and treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Chemicals and reagents\u003c/h2\u003e \u003cp\u003eAcetonitrile (ACN), methanol, isopropanol (IPA), and methyl tert-butyl ethe (MTBE) Optima\u0026trade; LC/MS Grade were obtained from Thermo Fisher Scientific (Waltham, MA, USA). Sebutape was purchased from CuDerm Corporation (Dallas, TX, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Participants\u003c/h2\u003e \u003cp\u003e The study was approved by the Ethics Committee of Peking University International Hospital. All procedures adhered to relevant guidelines and regulations, and informed consent was obtained from all participants prior to enrollment. 20 participants from the Beijing area were enrolled in the study, including ten rosacea patients and ten healthy controls. All ten patients were diagnosed as rosacea by two identical dermatologists (refer to \"Chinese Guidelines for Diagnosis and Treatment of Rosacea (2021 Edition)\"). All 20 participants had not received any treatments or medications that could potentially interfere with the study assessment within the preceding 6 months. The exclusion criterion encompassed topical or oral drugs, physical treatments such as phototherapy, cardiovascular medications, antiepileptic drugs, antibiotics, and antipsychotic drugs. Additionally, none of the participants exhibited local skin lesions, including acne, eczema, melasma, psoriasis or scars, nor did they have any systemic diseases that might influence the skin condition. The study protocol ensured strict matching of participants based on demographic characteristics of sex and age.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e4.3 TEWL measurement\u003c/h2\u003e \u003cp\u003eBoth healthy individuals and patients with rosacea were selected for examination. Transepidermal water loss (TEWL) measurements were conducted on the left cheek using a portable VapoMeter (TM300; CK, Cologne, Germany). All tests were conducted in standardized ambient conditions with average humidity of 50% and average temperature of 23\u0026deg;C. Prior to measurement, participants' faces were cleaned with warm water without any cosmetics applied. The skin was then allowed to acclimate for 20 min. Subsequently, the detection probe was positioned on the target area, three consecutive readings were obtained from the same site for each participant, which were subsequently averaged.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4.4 SSL sampling\u003c/h2\u003e \u003cp\u003eBefore sample collection, participants were instructed to acclimatize in a controlled environment (room temperature 23\u0026deg;C and humidity 50%) for 30 minutes. Sebum was collected from an approximately 4cm\u003csup\u003e2\u003c/sup\u003e area at the same site left cheek using Sebutape. Prior to sebum collection, the collection area was wiped with a 5% saline swab and one Sebutape patch was placed on the target site. The Sebutape patch was left in place for 10 min, and then removed to a sterile centrifuge tube using curved forceps. All samples were immediately stored at \u0026minus;\u0026thinsp;80\u0026deg;C until further analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Sample preparation\u003c/h2\u003e \u003cp\u003eSamples were retrieved from the \u0026minus;\u0026thinsp;80\u0026deg;C freezer and transferred to pre-chilled tubes. To each tube, 680\u0026micro;L of a MTBE/methanol/water (400:80:200) extraction solvent was added. Samples were vortex-mixed for 10 minutes to ensure homogeneity, followed by centrifugation at 3000\u0026times;g for 15 minutes to facilitate phase separation. Post-centrifugation, the supernatant (organic phase) was carefully collected, while the lower aqueous phase was discarded. The organic phase lipid extracts were then dried using a low-temperature concentrator (Speed Vac SPD131P; Thermo Fisher Scientific) and stored for subsequent analysis. Prior to mass spectrometry, lyophilized samples were reconstituted in 400 \u0026micro;L of methanol/isopropanol (3:1, v/v) to ensure optimal solubility. Quality control (QC) samples were prepared by pooling aliquots of all study samples to monitor analytical reproducibility, which were analyzed alongside experimental samples using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS)\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.6 LC-MS/MS analysis and identification\u003c/h2\u003e \u003cp\u003eChromatographic separation was performed on a Phenomenex Kinetex 1.7 \u0026micro;m EVO C18 column (2.1 \u0026times; 50 mm, 100 \u0026Aring;; Agilent, USA) under reversed-phase liquid chromatography (RPLC) conditions. The mobile phase system consisted of: (A) 50% acetonitrile-water containing 10 mM ammonium formate, and (B) isopropanol (IPA) with 10% formic acid and 10 mM ammonium formate. A gradient elution program was applied: starting with 90% solvent A, linearly decreasing to 0% A over 11 minutes, holding at 100% B for 6 minutes, then immediately re-equilibrating to 90% A and maintaining this condition for 3 minutes. Mass spectrometry was conducted using a Triple TOF 5600\u0026thinsp;+\u0026thinsp;orthogonal accelerated time-of-flight mass spectrometer (AB SCIEX, USA) equipped with an electrospray ionization (ESI) source. Data acquisition was performed in both positive and negative ion modes for each chromatographic run. Full-scan mass spectra were collected over an m/z range of 50\u0026ndash;1500, with data-dependent acquisition (IDA) mode employed to enhance metabolite coverage. Mass accuracy was ensured by referencing a lock-mass ion throughout the analysis using MS-Dial software (ver. 3.70; 17 April 2019). Metabolite identification was achieved by matching detected ions against the MS-Dial Lipidomics MSP database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://prime.psc.riken.jp/compms/msdial/main.html\u003c/span\u003e\u003cspan address=\"http://prime.psc.riken.jp/compms/msdial/main.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.7 Statistical analysis\u003c/h2\u003e \u003cp\u003eRaw mass spectrometry data were processed using MS-Dial (Ver. 3.70), with the Lipidomics MSP database integrated into the software to support peak detection, filtering, and alignment. Following preprocessing, a two-dimensional data matrix was generated, encompassing lipid identifiers, retention times, lipid classes, mass-to-charge ratios (m/z), peak areas, and raw Excel data. Multivariate statistical analysis, including partial least-squares discriminant analysis (PLS-DA), was performed using MetaboAnalyst 5.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.metaboanalyst.ca/MetaboAnalyst/\u003c/span\u003e\u003cspan address=\"http://www.metaboanalyst.ca/MetaboAnalyst/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to characterize lipid distributions and identify differential metabolites between senile rosacea patients and healthy controls. PLS-DA models were validated via 10-fold cross-validation with unit variance scaling. Model fitness was evaluated using R\u0026sup2; (goodness of fit) and Q\u0026sup2; (predictive ability). Between-group comparisons of integrated peak intensities were conducted using a two-tailed Welch\u0026rsquo;s t-test within MetaboAnalyst 5.0, with statistical significance defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and variable importance in projection (VIP)\u0026thinsp;\u0026gt;\u0026thinsp;1.0\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACN:Acetonitrile; IPA:Sopropanol; SSL:Skin surface lipids; MTBE:Methyl tert-butyl ether; TEWL:Transepidermal water loss; LC-MS/MS:Liquid chromatography coupled tandem mass spectrometry; PLS-DA: Partial least squares; UV:ultraviolet radiatio; Cer:Ceramides; FFA:Fatty acids; TAG:Triacylglycero; GL:Glycerolipids; GP:Glycerophospholipids; SP:Sphingolipids; FA:Fatty acyls; PC:Phosphatidylcholine; SM:Sphingomyelin; DAG:Diacylglycerols; \u0026nbsp; LPC:Lysophosphatidylcholine; DHA:Docosahexaenoic acid; TSLP:Thymic stromal lymphopoietin; Ca\u0026sup2;⁺:calcium ions; AD: Atopicdermatitis; PPAR\u0026gamma;:Peroxisome proliferator-activated receptor; DNFB:2,4-Dinitrofluorobenzene;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiaolei Ma: Data collection and analysis.Yi Yang: Writing the original draft, reviewing, and editing. Lulu Lu, Na Gao: Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and multivariate data analysis. Zheng Zhao, Xiulian Zhang: Transepidermal water loss detection. Gangwen Han: Clinical cases collection and experimental guidance. The authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are available from the correspongding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate. Ethics approval and consent to participate: The study was approved by the Ethics Committee of Peking University International Hospital. All procedures adhered to relevant guidelines and regulations, and informed consent was obtained from all participants prior to enrollment. Consent for publication: All the participants consent for publication of their individual details.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by research grant from National Natural Science Foundation of China, Grant/Award Number:82404136 to Xiaolei Ma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was reviewed and approved by the ethics committee of Peking University International Hospital. Informed consent to participate in the study was obtained from each patient and healthy person before enrolling in the study. Clearance No for Ethical approval:2018\u0026ndash;065(BMR).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the participants had signed the consent for publication in the informed\u003c/p\u003e\n\u003cp\u003econsent in our institutional consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo competing interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary information accompanies this paper\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMaden S. Rosacea: An Overview of Its Etiological Factors, Pathogenesis, Classification and Therapy Options. Dermato. 2023;3(4):241-262.\u003c/li\u003e\n\u003cli\u003eKulkarni NN, Takahashi T, Sanford JA, et al. 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Nat Methods. 2015;12(6):523\u0026ndash;526.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\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":"Lipidomics, Rosacea, Skin surface lipids, Skin barrier function, Triacylglycerol, Fatty acids","lastPublishedDoi":"10.21203/rs.3.rs-6911583/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6911583/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRosacea is a chronic skin disease with unclear causes, involving skin barrier issues and lipid changes. This study analyzed lipid profiles in rosacea patients' skin surface lipids (SSLs) to explore potential causes. The study included 10 rosacea patients and 10 healthy controls in Beijing. Transepidermal water loss (TEWL) was evaluated to assess the skin barrier function. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and multivariate data analysis were employed to investigate SSLs alterations. The results showed that rosacea patients had higher TEWL values than healthy controls (16.59\u0026thinsp;\u0026plusmn;\u0026thinsp;3.95 versus 7.87\u0026thinsp;\u0026plusmn;\u0026thinsp;2.52, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). LC-MS/MS revealed significant differences in the lipidomic profiles and identified 48 species of SSLs that differed between the two groups. Triacylglycerol (TAG) were particularly abundant and varied in rosacea patients, which had 8 down-regulated differential lipids and 28 up-regulated lipids in rosacea patients. TAG, diacylglycerols (DAG), lysophosphatidylcholine (LPC), phosphatidylcholine (PC) were positively correlated with TEWL value (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but FFA were negatively correlated with TEWL value (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The present study indicated that patients with rosacea have impaired skin barrier function and altered SSL composition. Certain SSL species identified in this study may be potential targets for future studies on the pathogenesis and treatment of rosacea.\u003c/p\u003e","manuscriptTitle":"Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-04 05:39:10","doi":"10.21203/rs.3.rs-6911583/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-02T06:35:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-04T16:07:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247644442392634002672041823169483216929","date":"2025-08-04T11:53:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-27T01:54:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"165072860699420097021387022572701967756","date":"2025-07-01T16:06:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-01T07:47:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-01T07:39:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-26T11:17:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-26T06:49:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-06-26T06:46:08+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":"007a6442-096b-464f-a0f3-e939049f529d","owner":[],"postedDate":"July 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":50880522,"name":"Health sciences/Diseases/Skin diseases"},{"id":50880523,"name":"Biological sciences/Immunology/Inflammation"},{"id":50880524,"name":"Biological sciences/Biochemistry/Lipidomics"}],"tags":[],"updatedAt":"2025-11-10T16:09:53+00:00","versionOfRecord":{"articleIdentity":"rs-6911583","link":"https://doi.org/10.1038/s41598-025-24539-x","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-11-07 15:57:09","publishedOnDateReadable":"November 7th, 2025"},"versionCreatedAt":"2025-07-04 05:39:10","video":"","vorDoi":"10.1038/s41598-025-24539-x","vorDoiUrl":"https://doi.org/10.1038/s41598-025-24539-x","workflowStages":[]},"version":"v1","identity":"rs-6911583","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6911583","identity":"rs-6911583","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}