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. 2026 Jul 10;47:102704. doi: 10.1016/j.bbrep.2026.102704

RL-QN15 accelerates vaginal mucosal repair by regulating inflammatory, autophagic, and apoptotic responses

Yue Jia a,1, Yuying Pang b,1, Ying Liu a, Zhiling Yan a, Youqin Ruan a, Jinwei Liu a, Yuye Li a, Die Li a, Linlin Yang c,⁎, Yan Hu a,⁎⁎
PMCID: PMC13380780  PMID: 42473657

Abstract

Background

Vaginal mucosal injury, caused by infection, trauma, or estrogen deficiency, poses a significant clinical challenge with limited effective therapies. Autophagy and apoptosis are critical regulators of mucosal repair, yet their modulation by therapeutic peptides remains poorly understood.

Objective

This study aimed to investigate whether the amphibian-derived peptide RL-QN15 promotes vaginal mucosal repair and to elucidate its underlying mechanisms.

Methods

The therapeutic efficacy and mechanisms of RL-QN15 were investigated in both in vitro and in vivo models of LPS-induced inflammatory injury. In vitro, RL-QN15 treatment was evaluated for its effects on rat vaginal epithelial cell proliferation (CCK-8 and EdU assays), IL-6 secretion (ELISA), apoptosis (TUNEL and Annexin V-FITC/PI flow cytometry), and expression of autophagy/apoptosis markers (LC3-II/I, Beclin1, p62, Bax, Bcl-2, and cleaved caspase-3) by Western blot. Therapeutic outcomes of RL-AN15 against LPS-injured rat vaginal mucosa were evaluated by mucosal thickness and IL-6 levels, and the autophagy and apoptosis pathway key markers were analyzed via Western blot to confirm RL-QN15-mediated regulation at the tissue level.

Results

RL-QN15 significantly reversed LPS-induced suppression of proliferation and autophagy, while inhibiting apoptosis and IL-6 expression in vitro. In vivo, RL-QN15 reduced mucosal thickness, enhanced epithelial integrity, and suppressed IL-6, outperforming erythromycin ointment via direct statistical comparison. Mechanistically, RL-QN15 restored autophagic flux (LC3-II/I, Beclin1, p62) and rebalanced apoptosis (Bax/Bcl-2, caspase-3) in both cellular and tissue models.

Conclusions

RL-QN15 promotes vaginal mucosal regeneration by modulating autophagy, apoptosis and alleviating inflammation, positioning it as a promising multitarget peptide therapeutic for mucosal injury.

Keywords: RL-QN15, Vaginal mucosa damage, Autophagy, Apoptosis, Inflammation

Highlights

  • •

    RL-QN15 is a novel peptide that effectively promotes vaginal mucosal repair.

  • •

    It modulates the balance between autophagy and apoptosis to facilitate healing.

  • •

    RL-QN15 acts as a multi-target therapeutic candidate for restoring mucosal integrity.

1. Introduction

As a critical barrier in the female reproductive system, the vaginal mucosa provides physical protection through its stratified squamous epithelium and collaborates with mucosal immune cells (including macrophages and T lymphocytes) to establish a local defense network [1,2]. However, this barrier remains vulnerable to pathological insults including infection, mechanical trauma, iatrogenic procedures (radiotherapy/surgery), and estrogen deficiency [[3], [4], [5]]. This impairment induces microbiota dysbiosis, chronic inflammation, and heightened susceptibility to sexually transmitted infections (including HIV), potentially progressing to infertility or pelvic inflammatory disease [3,5]. Consequently, vaginal mucosal repair is essential for maintaining reproductive health, infection resistance, and life quality [6]. The clinical burden remains substantial, with vaginal infections affecting approximately 40% of reproductive-age women worldwide and estrogen-deficient mucosal atrophy developing in >50% of postmenopausal women [7,8]. Therefore, developing novel therapeutics and elucidating repair mechanisms for vaginal mucosal injury represent critical research priorities.

Current vaginal mucosal injury management relies on broad-spectrum antibiotics to prevent secondary infection and topical estrogen therapy to promote epithelial regeneration [[9], [10], [11]]. However, these approaches are limited by antibiotic resistance, estrogen-related risks such as endometrial hyperplasia, and failure to fully restore mucosal barrier structure and function [12,13]. Molecular analyses reveal that repair mechanisms primarily involve three biological processes: activation of the basal stem cell niche driving epithelial regeneration [14], dynamic remodeling of the stromal extracellular matrix (ECM) to maintain structural integrity [15], and coordinated crosstalk between mucosal immunity and commensal microbiota [16]. Consequently, emerging therapeutic strategies, such as biodegradable hydrogel scaffolds providing physical support through slow-release bioactive factors, probiotics restoring microecological balance, and small-molecule compounds targeting key signaling pathways-offer promising alternatives [[17], [18], [19], [20]]. Nevertheless, patient heterogeneity and incomplete understanding of multi-target coordination remain major clinical challenges. Elucidating mucosal repair mechanisms and developing novel therapeutics are therefore essential for advancing reproductive medicine and women's health.

Autophagy, an evolutionarily conserved lysosomal degradation pathway, maintains cellular homeostasis (including metabolic balance, inflammation regulation, and oxidative stress responses), by clearing damaged organelles, pathogens, and misfolded proteins [[21], [22], [23]]. Recent studies demonstrate the promising therapeutic potential of autophagy in mucosal injury repair [24,25]. For instance, autophagy promotes gastrointestinal mucosal repair via MTOR-ULK1-mediated goblet cell differentiation and facilitates respiratory mucosal repair by inhibiting NLRP3 inflammasome activation to reduce inflammation [26]. Notably, autophagy mediates vaginal mucosal repair by facilitating tissue restoration through pathogen clearance, inflammatory microenvironment modulation via TLR4/MyD88/NF-κB signaling blockade, and epithelial regeneration involving LC3-II-mediated cytoskeletal remodeling that drives basal stem cell differentiation into functional epithelial layers [27]. In addition, reduced expression of key autophagy genes (such as ATG5 and Beclin-1) correlates with recurrent candidal vaginitis [28]. However, tissue-specific regulatory networks, systemic toxicity from non-targeted activator delivery, and uncharacterized autophagy interactions with estrogen signaling and local microbiomes present significant translational challenges [24,29].

Amphibian bioactive peptides represent a valuable natural peptide library for tissue repair therapeutics, owing to their high bioactivity, stability, biocompatibility, and targeting potential [30,31]. Notably, the peptide RL-QN15, isolated from Rana limnocharis skin secretion by our group, inhibits inflammation and promotes keratinocyte proliferation and migration through modulation of the MAPK/ERK and TGF-β/SMAD2/3 pathways, demonstrating efficacy in diabetic chronic wounds and oral ulcers [32]. This study firstly elucidated the molecular mechanism underlying RL-QN15-mediated promotion of vaginal mucosal regeneration, involving a regulatory network of autophagy, apoptosis, and inflammation. In lipopolysaccharide-induced rat vaginal epithelial cell injury, RL-QN15 treatment significantly suppressed IL-6 expression and enhanced proliferation. Similarly, in a rat vaginal mucosa mechanical injury model, local RL-QN15 administration markedly reduced inflammation and accelerated mucosal injury recovery. Mechanistically, RL-QN15 downregulated the anti-apoptotic protein Bcl-2, upregulated the pro-apoptotic protein Bax, and reduced Caspase-3 activity, thereby facilitating the apoptosis of necrotic tissue to promote mucosal repair. Furthermore, RL-QN15 enhanced the LC3-II/I ratio, increased Beclin-1 expression, and promoted p62 degradation, thus enhancing autophagy and subsequent mucosal tissue regeneration. Collectively, RL-QN15 promotes functional vaginal mucosal regeneration by activating protective autophagy, restoring apoptosis/pro-survival balance, and remodeling the immune microenvironment, supporting its potential as a novel candidate for peptide-based, mucosa-targeted repair therapies.

2. Materials and methods

2.1. Cell culture

Rat Vaginal Epithelial Cells derived from Wuhan Procell System Life Sciences Co., Ltd (CP-R202). Immortalized rat vaginal epithelial cells were cultured in DMEM supplemented with 10% (v/v) fetal bovine serum (FBS; HyClone, USA) and Penicillin-Streptomycin Solution (100×, beyotime, C0222), at 37 °C in a humidified incubator with 5% CO2.

2.2. CCK-8 assay

CCK-8 assay was performed to test the proliferation of rat vaginal epithelial cells after the treatment of RL-QN15 in the excessive inflammatory condition induced by Lipopolysaccharide (LPS, medchemexpress, HY-D1056, 1 μg/mL). RL-QN15 peptide (QNSYADLWCQFHYMC) was commercially synthesized by Wuhan Bioyeargene Biotechnology Co., Ltd. (Wuhan, China) to purities above 95%. Cells were seeded into 96-well plates at a density of 2 × 104 cells/well. Following adherence, cells were pre-treated for 2 h with either PBS (normal model), LPS (injury model) or 10 μM chloroquine (medchemexpress, HY-17589A). Subsequently, LPS-primed cells were exposed to PBS, RL-QN15 (10 μM), or dexamethasone (DEX, 100 nM, MedChemExpress, HY-14648G), a potent glucocorticoid positive control widely employed to validate anti-inflammatory efficacy in epithelial inflammation models [33], for 24 h. After treatment, 10 μL of CCK-8 reagent (beyotime, C0038) was added to each well according to the manufacturer's instructions and incubated at 37 °C in the dark for 2 h. Absorbance was then measured at 450 nm using a microplate reader, and data were analyzed using GraphPad Prism 8 software [34].

2.3. TUNEL stain

TUNEL fluorescence staining was performed to test the apoptosis in rat vaginal epithelial cells, following previous protocols [35]. Briefly, cells were seeded at a density of 2 × 104 cells/well into 4-well plates containing coverslips. Following adherence, cells were treated for 2 h with either PBS (vehicle) or LPS (1 μg/mL). Subsequently, LPS-injured cells were treated with PBS, 10 μM RL-QN15, 100 nM DEX or trehalose (100 mM) for 24 h. After treatment, the medium was aspirated and cells were washed three times with PBS, fixed with 4% paraformaldehyde (PFA, yeasen, 60536ES60) for 20 min at room temperature (RT), and permeabilized with 0.1% Triton X-100 for 10 min at RT. Following three additional PBS washes, TUNEL staining was performed according to the one step TUNEL apoptosis assay kit (beyotime, C1090) manufacturer's instructions by incubating cells with the reagent at 37 °C for 60 min. Coverslips were then washed, counterstained with DAPI (beyotime, C1002), and mounted for observation. Cells were visualized using laser scanning confocal microscopy, and fluorescence intensity was quantified using ImageJ software. Statistical analysis was performed using GraphPad Prism 8 software.

2.4. Flow cytometry

Annexin V-FITC/PI double staining was used to assessed the apoptosis in rat vaginal epithelial cells according to previous study [36]. Rat vaginal epithelial cells were seeded in 6-well plates at 1 × 106 cells/well. After adherence, cells were treated with LPS (1 μg/mL) for 2 h to establish inflammatory injury models. Next, LPS-injured cells were treated with PBS, RL-QN15 (10 μM), or DEX (100 nM) for 24 h. Subsequently, cells were harvested by trypsinization (0.25% trypsin-EDTA, thermofisher, 25200056, 37 °C, 3 min), neutralized with complete culture medium, and centrifuged at 1000 × g for 5 min at 4 °C. The cell pellets were washed twice with ice-cold PBS, resuspended in 200 μL of 1× binding buffer, and incubated with 5 μL of Annexin V-FITC and 10 μL of PI (Beyotime, C1062S) for 15 min at room temperature in the dark. Prior to flow cytometry, stained cell suspensions were filtered through a 40-μm cell strainer to remove aggregates. Flow cytometric acquisition was performed within 1 h using a flow cytometer (BD LSRFortessa), and apoptosis rates were quantified with FlowJo software (v10.8.1). Statistical analyses were conducted using GraphPad Prism 8.

2.5. EDU staining

To determine whether trehalose-induced autophagy reverses LPS-mediated suppression of cell proliferation, rat vaginal epithelial cells were seeded in 4-well plates at 1 × 105 cells/well and allowed to adhere overnight. Cells were then stimulated with LPS (10 μg/mL) for 2 h, followed by 24 h treatment with PBS (vehicle) or trehalose (100 mM). Proliferation was assessed using a BeyoClick™ EdU-488 kit (Beyotime, C0071S) per the manufacturer's protocol. Briefly, cells were incubated with 10 μM EdU for 2 h at 37 °C, fixed with 4% paraformaldehyde (15 min, RT), permeabilized with 0.3% Triton X-100 (10 min), and reacted with Click cocktail (containing Alexa Fluor® 488-azide) for 30 min in the dark. Nuclei were counterstained with Hoechst 33342 for 10 min. Fluorescence images were captured at 200× magnification (Olympus), and ≥5 random fields per sample were analyzed. EdU-positive cells were counted against total Hoechst-stained nuclei using ImageJ, and the proliferation rate was expressed as the percentage of EdU-positive cells. All experiments were performed in triplicate, with data presented as mean ± SEM and analyzed with GraphPad Prism 8.

2.6. Rat vaginal mucosal injury model

To establish a rat model of vaginal mucosal injury, female Sprague-Dawley (SD) rats (8 weeks old, 180–220 g) were obtained from Kunming medical university and acclimatized for one week and subsequently randomized into control and model groups. All animal care and handling procedures were approved and performed in accordance with the Kunming Medical University Ethics Committee (kmmu20241183). Rats were anesthetized via intraperitoneal injection of 3% pentobarbital sodium (40 mg/kg), fixed in a supine position, and injected with lipopolysaccharide (LPS; 10 μM) into the vaginal mucosa to induce an excessive inflammatory injury model [37,38]. On day 2 post-model establishment, treatments were administered: 10 μM RL-QN15, or erythromycin ointment (Guangdong Hengjian Pharmaceutical Co., Ltd, 10 mg/kg) injection (positive control). Erythromycin [39], a macrolide antibiotic commonly used topically for skin and mucosal infections, was selected as a clinically relevant comparator to benchmark the healing efficacy of the anti-inflammatory peptide RL-QN15. Following 15 consecutive days of treatment, rat serum and vaginal mucosal tissues were collected for subsequent analyses. Finally, euthanasia was performed following an intraperitoneal injection of an overdose of pentobarbital sodium (150 mg/kg).

2.7. H&E stain

To assess regeneration in injured rat mucosal tissues, hematoxylin and eosin (H&E) staining was performed following established methods [40]. Paraffin-embedded tissue sections (5 μm thickness) were sequentially dewaxed, rehydrated through an ethanol gradient, and Hematoxylin-Eosin (HE) stain kit-stained (solarbio, G1120). Regeneration was evaluated by light microscopy at uniform magnification. For morphometric analysis, mucosal thickness formation was quantified using ImageJ software (NIH, USA). From each animal, three non-adjacent sections were examined, and at least five randomly selected fields per section were analyzed within the central wound area, with careful exclusion of wound edges to avoid margin artefacts. Mucosal thickness was determined by manually tracing the epithelial layer from the basement membrane to the luminal surface. All quantitative data were subjected to statistical analysis using GraphPad Prism 8 (GraphPad Software, USA).

2.8. IF stain

Rat vaginal epithelial cells (2 × 104) were seeded in 4-well chamber slides. After adherence, normal and LPS-induced injury models were established by treating cells with PBS, 10 μM RL-QN15, 10 μM chloroquine or LPS (1 μg/mL, 2 h), respectively. LPS-injured models were then treated with PBS, or 100 nM dexamethasone (DEX) for 24 h. Subsequently, cells were washed with PBS, fixed with 4% paraformaldehyde (PFA, 15 min, RT), and permeabilized with 0.1% Triton X-100 in PBS (10 min, RT). Non-specific binding was blocked with 2% bovine serum albumin (BSA, medchemexpress, HY-D0842, 1 h, RT). After PBST washes, cells were incubated with LC3B primary antibody (Proteintech, 14600-1-AP, 1:500 dilution, 4 °C overnight). Following additional PBST washes, species-appropriate fluorescent secondary antibody (Elab Fluor 594, elabscience, E-AB-1060, 1:300) was applied (1 h, RT) and nuclei were counterstained with DAPI (10 min, beyotime, C1002). Mounted slides were imaged by fluorescence microscopy. LC3B fluorescence intensity was quantified using ImageJ and statistically analyzed in GraphPad Prism 8 software [41].

2.9. Elisa assay

Rat vaginal epithelial cells (2 × 105) were seeded in 6-well plates. After adherence, normal and injury models were established by treating cells with PBS or 1 μg/mL LPS, respectively. LPS-injured cells were then treated with PBS, 10 μM RL-QN15, or 100 nM DEX for 24 h. Cell culture supernatants were collected, centrifuged (1000 rpm, 4 °C, 10 min), and stored for inflammatory factor analysis. To evaluate systemic effects, whole blood was collected from rats after 7 days of topical treatment with PBS, 10 μM RL-QN15, or 10 mg/kg erythromycin ointment, followed by serum isolation. IL-6 expression levels in both in vitro supernatants and in vivo serum samples were quantified using commercial ELISA kits (neobioscience, ERC003.48) according to manufacturer protocols [42].

2.10. Western blot

Protein expression of apoptosis-related markers (Bcl-2, Bax, cleaved caspase-3) and autophagy-related proteins (LC3-II/I, p62, Beclin1) was evaluated in both cultured cells and rat vaginal mucosal tissues. Cells (1 × 106/well in 6-well plates) or tissue samples were lysed in RIPA buffer (Beyotime, P0013B) supplemented with 1% PMSF (Beyotime, ST506) and Phosphatase inhibitor cocktail A (beyotime, P1081). Lysates were centrifuged at 14,000×g for 20 min at 4 °C, and the supernatants were collected. Protein concentrations were determined using a BCA assay (Beyotime, P0012S). Equal amounts of protein (30 μg per lane) were mixed with 4× loading buffer (1:4, v/v), denatured at 95 °C for 15 min, resolved by 10% SDS-PAGE, and transferred onto PVDF membranes (thermofisher, 88518). Membranes were blocked with 5% non-fat milk in TBST for 1 h at room temperature, followed by overnight incubation at 4 °C with primary antibodies: Bcl-2, Bax, cleaved caspase-3, LC3B, anti-p62, Beclin1, and β-actin. After three TBST washes, membranes were incubated with HRP-conjugated secondary antibody (1:5000, Proteintech, SA00001-2) for 1 h at 37 °C. Immunoreactive bands were visualized using developer and fixer kit (P0020, Beyotime Biotechnology, Shanghai, China) and quantified with Image Lab software (Bio-Rad). Band intensities were normalized to β-actin, and statistical analyses were performed using GraphPad Prism 8 [43]. All primary antibody information is summarized in Supplementary Table S1.

2.11. Statistics analysis

Histological evaluations were performed blindly: image acquisition was conducted by an operator blinded to groups, and quantitative analyses were carried out by two independent blinded observers using randomly coded images; the final data were averaged for statistical analysis. Statistical analyses were performed using GraphPad Prism 8 software. Tukey's test for multiple comparisons following ANOVA, and Student's t-test for two group comparisons. All data are from three independent experiments and are expressed as mean ± SEM.

3. Results

3.1. RL-QN15 suppressed excessive inflammation and apoptosis induced by LPS and promoted the proliferation of rat vaginal epithelial cells

To explore the function of RL-QN15 in vaginal mucosal injury, we detected its effects against rat Vaginal Epithelial Cell. These cells uniformly expressed cytoplasmic pan-CK and membrane-restricted E-cadherin, confirming their stable epithelial phenotype and capacity for polarization, monolayer formation, and subsequent stratification upon implantation (Fig. S1A–B). Firstly, we detected the pro-proliferation effects of RL-QN15 under hyperinflammation condition induced by LPS (Fig. 1A). LPS treatment inhibited the proliferation of rat Vaginal Epithelial cell, whereas RL-QN15 alleviated the effects of LPS and promoted the proliferation of rat Vaginal Epithelial cell (Fig. 1A). To determine whether autophagy contributes to this protection, we examined the functional importance of basal autophagy by treating control cells with chloroquine. Chloroquine markedly reduced both LC3 accumulation and cell viability (Fig. S2A–B), indicating that basal autophagy is essential for cell survival. Conversely, pharmacological activation of autophagy with trehalose (100 mM) in LPS-treated cells significantly increased LC3 accumulation and partially rescued the anti-proliferative and pro-apoptotic effects of LPS, as shown by CCK-8 and TUNEL assays (Fig. S2A–D). These data demonstrate that autophagy activation is sufficient to counteract LPS toxicity. Notably, RL-QN15 alone modestly modulated LC3 expression versus vehicle (Fig. S3A–B), which may indicate a direct, albeit weak, autophagy-inducing effect. These findings indicate that pharmacological autophagy activation is sufficient to counteract LPS toxicity, and suggest that RL-QN15 may exert its protective effects, at least in part, through autophagy modulation to preserve cell viability.

Fig. 1.

Fig. 1

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RL-QN15 promoted the proliferation and reduced excessive inflammation of rat vaginal epithelial cells after the treatment of LPS.

A. MTS assay revealed the pro-proliferation ability of RL-QN15 against rat vaginal epithelial cells under the inflammation condition induced by LPS. Data are from three independent experiments, n = 3. B. RL-QN15 alleviated the excessive inflammation after the treatment of LPS. Data are from three independent experiments, each performed with three technical replicates (total n = 9 per group). ###p < 0.001 indicated the statistics significance between vehicle and LPS group. ∗∗p < 0.001 displayed the statistics significance compared to LPS group. All data derived from three independent experiments.

As shown in Fig. 1B, compared to the vehicle, LPS significantly promoted the expression of IL-6, indicating that LPS successfully induced the inflammatory injury. However, RL-QN15 suppressed the excessive inflammation induced by LPS, as evidencing by the downregulating expression of IL-6 in RL-QN15 group (Fig. 1B). Excessive inflammation cause cell apoptosis, therefore we detected the vaginal epithelial cell apoptosis after treatment of RL-QN15. Compared to vehicle, the treatment of LPS in rat Vaginal Epithelial Cells induced the cell apoptosis, with the apoptosis rate reaching 28.56% (Fig. 2A and B). Interestingly, RL-QN15 inhibited the apoptosis induced by LPS, which reduced the apoptosis rate from 28.56% to 17.74% (Fig. 2A and B). LPS suppressed LC3 expression, indicative of excessive inflammation and autophagy impairment, whereas RL-QN15 treatment upregulated LC3 and restored autophagic activity (Fig. 2C and D). Meanwhile, TUNEL staining confirmed that RL-QN15 inhibited LPS-induced apoptosis (Fig. 2E and F). Collectively, RL-QN15 suppresses excessive inflammation and apoptosis while concurrently promoting proliferation and autophagy, highlighting its therapeutic potential against vaginal mucosal injuries.

Fig. 2.

Fig. 2

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RL-QN15 reduced the apoptosis induced by LPS and promoted the autophagy after the treatment of LPS.

A. Flow cytometry showed that RL-QN15 significantly inhibited apoptosis induced by LPS treatment. B. Data statistics of RL-QN15 inhibiting apoptosis of rat vaginal epithelial cell. Data are from three independent experiments, n = 3. C. IF staining revealed the LC3 expression under the different treatment of PBS, LPS, LPS + QL-QN15 and LPS + DEX. Scale bar = 10 μm. D. Statistical representative diagram of LC3 fluorescence intensity. Data are from three independent experiments, n = 3. E. IF staining revealed the Tunel fluorescence intensity under the different treatment of PBS, LPS, LPS + QL-QN15 and LPS + DEX. Scale bar = 100 μm. F. Statistical representative diagram of Tunel fluorescence intensity. Data are from three independent experiments, n = 3. ###p < 0.001 and ####p < 0.001 indicated the statistics significance between vehicle and LPS group. ∗∗p < 0.001 and ∗∗∗p < 0.001 displayed the statistics significance compared to LPS group.

3.2. RL-QN15 promoted the regeneration of vaginal mucosal injury in rat

Given the anti-apoptotic, pro-autophagic, and pro-proliferative effects of RL-QN15 observed in vitro, we next evaluated its regenerative efficacy in a rat vaginal mucosal injury model. As shown in Fig. 3A and B, the model group displayed evident epithelial defects and significantly increased mucosal thickness relative to the Vehicle group. Treatment with RL-QN15 markedly promoted mucosal recovery, resulting in a thinner and more continuous epithelial layer compared with the model group. Importantly, direct post hoc comparison between the RL-QN15 and erythromycin-treated groups revealed a significantly greater reduction in mucosal thickness in the RL-QN15 group (P < 0.05; Fig. 3A and B), indicating superior tissue remodeling. In addition, RL-QN15 more effectively suppressed the expression of the pro-inflammatory cytokine IL-6 than did erythromycin (P < 0.05 vs. erythromycin; Fig. 3C), further supporting its enhanced anti-inflammatory activity. Collectively, these findings demonstrate that RL-QN15 exerts superior therapeutic effects over erythromycin ointment in promoting vaginal mucosal regeneration and resolving local inflammation.

Fig. 3.

Fig. 3

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RL-QN15 promoted the vaginal mucosal repair after the treatment of LPS. A. H&E staining demonstrated changes in rat vaginal mucosa architecture, comparing normal tissue, LPS-induced inflammatory injury, and the subsequent effects of treatment with PBS, RL-QN15, or Erythroycin Ointment. B. Quantification of vaginal mucosal epidermal thickness. Data are from three independent experiments, n = 3. C. ELISA assay indicated the expression of IL-6 after different treatment. Data are from three independent experiments, n = 3. ###p < 0.001 and ####p < 0.001 indicated the statistics significance between vehicle and LPS group. ∗∗p < 0.001 and ∗∗∗p < 0.001 displayed the statistics significance compared to LPS group.

3.3. RL-QN15 inhibited apoptosis and promoted autophagy to boost the regeneration of vaginal mucosal injury

To delineate the therapeutic mechanisms of RL-QN15 in vaginal mucosal repair, we evaluated its dual regulatory effects on autophagy and apoptosis in LPS-induced injury models (Fig. 4A). In rat vaginal epidermal cell model, compared to vehicle, LPS suppressed autophagic activity, evidenced by reduced Beclin1 expression (1.8-fold decrease), diminished LC3-II/LC3-I ratio, and elevated p62 accumulation (2.1-fold increase), while concurrently inducing apoptosis via caspase-3 activation (2.1-fold upregulation) and Bax overexpression (3.5-fold) alongside BCL2 downregulation (0.3-fold) (Fig. 4B–G). RL-QN15 not only restored autophagic markers, normalizing Beclin1, increasing LC3-II/LC3-I ratio, and reducing p62 by 40%,but also attenuated apoptotic signaling, suppressing caspase-3 and Bax to 0.7- and 0.6-fold of LPS-group values while elevating BCL2 by 2.0-fold, demonstrating superior efficacy to dexamethasone (Fig. 4B–G).

Fig. 4.

Fig. 4

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RL-QN15 inhibited apoptosis and promoted autophagy in cellular and animal level in the excessive inflammatory condition induced by LPS.

A. Western blot analysis of Beclin1, p62, LC3-I/II, cleaved caspase-3, Bax, and Bcl-2 expression in rat vaginal epithelial cells following LPS-induced inflammatory injury and subsequent treatment with PBS, RL-QN15, or DEX. B-G. Quantification the expression Beclin1, p62,LC3-Ⅰ/LC3-Ⅱ, cleaved caspase 3, and Bax, as well as the ratio of Bcl2 in rat vaginal epithelial cells. Data are from three independent experiments, n = 3. H. Western blot analysis of Beclin1, p62, LC3-I/II, cleaved caspase-3, Bax, and Bcl-2 expression in rat vaginal mucosal injury tissues following LPS-induced inflammatory injury and subsequent treatment with PBS, RL-QN15, or erythromycin ointment. I–N. Quantification the expression Beclin1, p62,LC3-Ⅰ/LC3-Ⅱ, cleaved caspase 3, and Bax, as well as the ratio of Bcl2 in vaginal mucosal repair tissues of rat. ###p < 0.001 indicated the statistics significance between vehicle and LPS group. Data are from three independent experiments, n = 3. ∗p < 0.05, ∗∗p < 0.001 and ∗∗∗p < 0.001 displayed the statistics significance compared to LPS group.

In the in vivo model, LPS provoked paradoxical autophagy dysregulation, elevating Beclin1 (1.8-fold) and LC3-II/LC3-I (2.1-fold) yet impairing autophagic flux through p62 accumulation (1.5-fold) (Fig. 4H–N). Interestingly, RL-QN15 resolved this dysregulation, reducing Beclin1 and LC3-II/LC3-I to 0.7- and 0.6-fold of LPS levels and suppressing p62 by 40%, indicative of restored lysosomal degradation. Simultaneously, RL-QN15 mitigated apoptosis by downregulating caspase-3 (0.5-fold) and Bax (0.6-fold) while upregulating BCL2 (1.8-fold), correlating with a 35% reduction in necrotic tissue burden (Fig. 4H–N). In summary, RL-QN15 coordinates autophagy and apoptosis by resolving autophagic stagnation through p62/LC3 axis modulation and suppressing inflammation-driven apoptosis via BCL2-mediated signaling, thereby establishing its role as a multitarget agent for inflammatory mucosal regeneration.

4. Discussion

Amphibian-derived pro-healing peptides represent a novel intervention strategy for chronic non-healing wounds, and peptide RL-QN15 has exhibited great therapeutic efficacy in acute and chronic skin wounds, oral ulcer mucosal injuries, and pulmonary fibrosis [32,44]. However, its therapeutic potential for vaginal mucosal injury remained unexplored. In this study, we demonstrated that RL-QN15 exhibits potent therapeutic efficacy for vaginal mucosal injury, surpassing the clinically used erythromycin ointment by modulating autophagy, apoptosis, and inflammatory responses [45]. In conclusion, our results provide the first evidence that RL-QN15 promotes vaginal mucosal repair by mitigating inflammatory damage and enhancing tissue regeneration through autophagy and apoptosis modulation, offering new insights into peptide regulatory mechanism and clinical development of peptide-based drugs.

Vaginal mucosa repair is influenced by multiple factors, including mechanical trauma, infection, and hormonal deficiency [46]. Persistent inflammation, suppressed angiogenesis, and microbiome dysbiosis constitute key barriers to this healing process [47]. Current therapeutic strategies mainly employ biomaterials (e.g., hyaluronic acid, collagen hydrogels) to rebuild physical barriers and maintain hydration for epithelial regeneration; growth factors (e.g., EGF, bFGF) to stimulate cellular proliferation and angiogenesis [48]; antimicrobial agents (e.g., erythromycin ointment) targeting infectious complications in atrophic vaginitis [49]; and anti-inflammatory/antioxidant compounds (e.g., vitamin E, curcumin derivatives) mitigating oxidative stress. Although existing therapies alleviate symptoms and promote repair, they exhibit limitations including insufficient long-term efficacy [20,50,51], significant interindividual variability, and limited efficacy against multifactorial etiologies. Consequently, developing novel therapeutic agents with superior target specificity and biocompatibility is imperative. Amphibian-derived peptides represent promising candidates for novel targeted therapeutics due to their high biocompatibility, target specificity, bioactivity, and selectivity [31,52]. However, peptide-based therapeutics remain largely unexplored for vaginal mucosal repair. Here, we demonstrate that the amphibian-derived peptide RL-QN15 significantly suppresses excessive inflammation and promotes mucosal regeneration, thereby accelerating the repair of vaginal mucosal injury and confirming its promising therapeutic efficacy. Notably, RL-QN15 exhibits dual functionality (promoting mucosal regeneration and suppressing inflammation), whereas erythromycin ointment is solely anti-inflammatory. In all, utilizing amphibian-derived peptides (e.g., RL-QN15) as molecular probes to elucidate their therapeutic mechanisms in vaginal mucosal repair will advance understanding of pathological molecular bases and accelerate discovery of novel therapeutic targets and clinical drug development.

The balance between autophagy and apoptosis is essential for vaginal mucosal repair [28,53]. Under physiological conditions, moderate autophagy promotes epithelial cell survival and regeneration by clearing damaged organelles, supplying energy substrates (including ATP), and reducing oxidative stress [54,55]. For instance, in estrogen-deficient (e.g., postmenopausal atrophy) or infection-induced injury models, autophagy enhancers (e.g., rapamycin) accelerate barrier repair by upregulating LC3-II/Beclin-1 expression, inhibiting mTOR signaling, and reducing epithelial apoptosis [56,57]. Conversely, excessive apoptosis-observed in radiation injury or chronic inflammation-disrupts mucosal integrity through caspase-3 activation, elevated Bax/Bcl-2 ratio, and PARP cleavage, thereby impeding re-epithelialization. Our study demonstrates that RL-QN15 significantly promotes vaginal epithelial proliferation and regeneration. At cellular level, RL-QN15 alleviated LPS-induced dysregulation of autophagy (increased LC3-II/LC3-I ratio, p62 accumulation) and suppressed excessive apoptosis (caspase-3/Bax pathway). Notably, we identify RL-QN15 as the first amphibian peptide shown to mitigate inflammatory damage by modulating autophagy and apoptosis. In vivo validation further confirmed RL-QN15's dual regulation of autophagy (p62/LC3 axis) and apoptosis inhibition (Bcl-2/caspase-3 pathway). These findings suggest RL-QN15 modulates ER stress or upstream kinases (e.g., AMPK/mTOR), warranting further mechanistic investigation.

Collectively, our study identifies the amphibian peptide RL-QN15 as a novel therapy for vaginal mucosal repair, advancing translational development of peptide-based interventions. We demonstrate that RL-QN15 outperforms conventional therapies (e.g., erythromycin ointment) by mediating three regenerative mechanisms: ameliorating pathological inflammation, restoring autophagy-apoptosis balance, and enhancing epithelial proliferation. Its efficacy in mitigating LPS-induced dysregulation (autophagy impairment and caspase-3/Bax-mediated apoptosis) and in vivo validation of p62/LC3 axis modulation and Bcl-2/caspase-3 pathway suppression highlight RL-QN15's unique capacity to target multifactorial etiology. As the first documented amphibian peptide to modulate vaginal mucosal autophagy, apoptosis and inflammation, RL-QN15 establishes a blueprint for multitargeted biologics development while revealing novel mechanistic targets (e.g., ER stress, AMPK/mTOR kinases), thereby advancing peptide therapeutics toward clinical translation for complex mucosal pathogenesis.

5. Conclusion

This study demonstrates that the amphibian-derived peptide RL-QN15 effectively treats vaginal mucosal injuries in rats by mitigating LPS-induced inflammation, restoring autophagy (increased LC3-II/LC3-I, decreased p62), and inhibiting apoptosis (regulated Bax/Bcl-2, Caspase-3). Superior to erythromycin ointment, RL-QN15 promotes mucosal regeneration, revealing a novel mechanism for peptide-based therapeutics.

Funding

This work was supported by the Scientific Research Fund Project of Yunnan Provincial Department of Education (2024J0250) and the innovative research team of Yunnan Province (Grant no.:202305AS350020).

CRediT authorship contribution statement

Yue Jia: Data curation, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. Yuying Pang: Data curation, Software, Writing – original draft. Ying Liu: Formal analysis, Investigation, Methodology. Zhiling Yan: Investigation. Youqin Ruan: Validation. Jinwei Liu: Data curation, Methodology, Supervision. Yuye Li: Data curation, Investigation. Die Li: Resources, Supervision, Validation. Linlin Yang: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. Yan Hu: Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing.

Declaration of competing interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work.

Acknowledgments

Not applicable.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbrep.2026.102704.

Contributor Information

Linlin Yang, Email: YLL194900@sina.com.

Yan Hu, Email: huyansmile@126.com.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.docx (5.5MB, docx)

Data availability

Data will be made available on request.

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Associated Data

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Supplementary Materials

Multimedia component 1
mmc1.docx (5.5MB, docx)

Data Availability Statement

Data will be made available on request.

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