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. 2026 Mar 19;20:575342. doi: 10.2147/DDDT.S575342

Protective Effect of Idebenone Against UVB-Induced Photoaging in HaCaT Cells

Liwei Feng 1, Linjie Tian 2, Jing Guo 2, Lingling Zhang 1, Peng Wang 1,✉, Xiaolin Bu 1,✉
PMCID: PMC13007680  PMID: 41878677

Abstract

Introduction

Ultraviolet B (UVB) irradiation is a key exogenous factor contributing to skin photoaging. Idebenone (IDE), a structural analog of coenzyme Q10 (CoQ10), exhibits potent free radical scavenging capacity and is mainly employed in the treatment of neurodegenerative disorders, and in anti-aging products. However, the molecular mechanisms underlying its photoprotective effects in skin cells remain poorly understood.

Purpose

This study aims to investigate the protective effects of IDE against UVB-induced photoaging in human immortalized epidermal keratinocytes (HaCaT cells).

Methods

We applied IDE to a UVB-induced HaCaT cell photoaging model and found that it significantly ameliorated the photoaging damage caused by UVB irradiation.

Results

Specifically, cell morphology recovered from a shrinkage state toward normal, the positivity rate of senescence-associated β-galactosidase (SA-β-gal) decreased, and enhanced the impaired cell migration and proliferation capacities. Additionally, oxidative stress imbalance was alleviated, as evidenced by a significant reduction in reactive oxygen species (ROS) and malondialdehyde (MDA) levels, along with an increase in superoxide dismutase (SOD) activity. Impaired mitochondrial function was restored, reflected by the repolarization of mitochondrial membrane potential (MMP) and an increase in adenosine triphosphate (ATP) synthesis. Furthermore, the elevated secretion levels of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-8 (IL-8) were significantly reduced. Transcriptomic analysis and protein validation revealed that IDE significantly downregulated the expression of IL-3RA and effectively restored the expression of TUBA8.

Conclusion

IDE significantly improved UVB-induced photoaging damage in HaCaT cells through multiple pathways, including restoring cell viability, alleviating oxidative stress damage, reducing pro-inflammatory factor infiltration, and protecting mitochondrial function. Its mechanism of action may involve the regulation of targets such as IL-3RA and TUBA8.

Keywords: idebenone, UVB photoaging, oxidative stress, cell viability, mitochondrial function

Introduction

Skin senescence is a complex, multi-factorial biological process driven by both intrinsic and extrinsic factors.1 Intrinsic aging, also known as chronological aging, is primarily influenced by genetic factors, the passage of time, cellular metabolic dysregulation, and hormonal changes.2 This process is relatively slow and inevitable In contrast, extrinsic aging results mainly from the cumulative effects of environmental factors, involving ultraviolet (UV) irradiation, chemical exposure, and environmental pollutants. Among these, UV irradiation is widely recognized as the primary external cause of skin aging and is therefore often referred to as photoaging.3 UV exposure induces excessive production of intracellular oxygen species (ROS), upsetting the body’s oxidative-antioxidative equilibrium.4 Excessive ROS directly damages membrane lipids, mitochondrial DNA, and proteins; compromises membrane integrity; and leads to mitochondrial dysfunction and abnormal protein structure.5 Persistent oxidative stress activates inflammatory signaling pathways, induces immunosuppressive responses, and interferes with normal physiological metabolism of skin cells, ultimately accelerating skin aging.6

Idebenone (IDE) is a synthetic analog of coenzyme Q10 (CoQ 10) that acts as a robust antioxidant by scavenging free radicals, regulating mitochondrial electron transport chain function, and inhibiting lipid peroxidation. These actions collectively contribute to improving cellular energy metabolism, stabilizing the mitochondrial membrane potential, and reducing cell membrane damage caused by ROS.7 IDE is a US Food and Drug Administration-approved antioxidant8 with potential for treating neurodegenerative disorders9 such as Alzheimer’s disease,10 Parkinson’s disease,11 Leber hereditary optic neuropathy,12 vascular dementia,13 among others. Additionally, IDE is associated with regulating mitochondrial function and oxidative stress in systemic conditions like ulcerative colitis,14 systemic lupus erythematosus,15 and atherosclerosis.16 However, the precise impact of IDE on photoaging and its underlying molecular pathways remain unclear.17

UVB-induced photoaging is already well established in the literature,18,19 however, the mechanisms through which IDE exerts its protective effects against photoaging remain unclear. Therefore, our study investigated IDE’s protective impact on UVB irradiation-induced photoaging in HaCaT cells from multiple perspectives, including cell viability, oxidative stress, mitochondrial function, and inflammatory response (Figure 1). Furthermore, transcriptomic analysis is employed to preliminarily explore potential molecular targets, aiming to provide a theoretical basis and experimental foundation for the development of safe and effective novel anti-photoaging drugs.

Figure 1.

Figure 1

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Schematic Diagram of the Protective Mechanism of IDE Against UVB-induced Photoaging in HaCaT cells:A Proposed Model Based on In Vitro data. As a key exogenous factor in photoaging, UVB irradiation triggers a cascade of damaging responses in HaCaT cells. Initially, intracellular ROS levels increase sharply, inducing oxidative stress characterized by a significant decrease in SOD activity and an increase in MDA content. Excessive ROS subsequently lead to mitochondrial damage, manifested as reduced MMP and decreased ATP synthesis. Concurrently, UVB irradiation induces DNA damage, upregulates IL-3RA expression, downregulates TUBA8 expression, and activates inflammatory responses, promoting the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-8. These multiple damage mechanisms collectively result in decreased cell viability and proliferation, as well as accelerated cellular senescence. IDE effectively intervenes in this process through multiple pathways: alleviating oxidative stress, maintaining mitochondrial functional homeostasis, and inhibiting inflammatory factor infiltration, thereby significantly delaying UVB-induced photoaging in HaCaT cells. (The black arrows indicate the direction of association. The red arrows represent upregulation or increase. The blue arrows represent downregulation or decrease. The green arrows represent inhibition or suppression).

Materials and Methods

Cells

HaCaT cells were supplied by the Psoriasis Research Institute, Tongji University School of Medicine (Shanghai, China). The use of these cells was approved by the Medical Research Ethics Committee of Gongli Hospital of Shanghai Pudong New Area.

Methods

Cell Culture and Grouping

Cells were thawed and cultured in high-glucose DMEM (YOBIBIO Biotechnology Co., LTD, China) supplemented with 10% fetal bovine serum (Inner Mongolia Jin Yuan Kang Biotechnology Co., Ltd., China) and a 1% penicillin-streptomycin antibiotic mixture. Cells were maintained in a humidified incubator at 37°C with 5% CO2. The experimental setup divided the cells into three distinct groups: a control group grown under normal, untreated conditions; a UVB-exposed group where confluent cells were subjected to varying UVB doses after adhering; and an IDE-treated group which received serum-free media containing different IDE concentrations for 24 h following UVB irradiation. The volume of the medium was adjusted according to culture vessels: 10 mL for 100 mm dishes, 100 μL for 96-well plates, and 2 mL for 6-well plates.

Establishing HaCaT Cell Photoaging Model

HaCaT cells, during exponential growth, were plated in 96-well formats at a density of 1×104 cells/well, according to established protocols.20 Cells were subjected to PBS rinsing before UVB exposure, once they reached 80% confluence, the medium was removed. One of seven irradiation doses (0, 10, 20, 30, 60, 90, and 120 mJ/cm2) was applied, with five replicates per dose, after which the PBS was discarded. Serum-free medium was added to the cells, which were allowed to stand for 24 h. Cell viability was measured using a CCK-8 assay (YOBIBIO Biotechnology Co., LTD, China) and the UVB dose that maintained >60% viability was selected for subsequent experiments. Each experiment was conducted in triplicate.

Cellular Morphology

HaCaT cells were seeded at a concentration of 5×105 cells per well in 6-well plates and subjected to the procedures outlined in Cell Culture and Grouping. After UVB irradiation, the original culture medium was aspirated and discarded. The cells were then covered with a thin layer of PBS buffer, and the morphology of cells in each group was observed under an inverted microscope and photographed.

IDE Absorbance Analysis

IDE (Shanghai Aladdin Biochemical Technology Co., Ltd., China) powder, stored sterile, protected from light at room temperature, was dissolved in sterile DMSO (MedChemExpress LLC, America) to prepare a 1 mM stock solution. The stock solution was aliquoted, protected from light, stored at −20°C, and avoided repeated freeze-thaw cycles. On the day of the experiment, a multi-step serial dilution method was employed to ensure dosage accuracy: the stock solution was diluted 1000-fold with serum-free DMEM to a 1 μM intermediate concentration, which was then subjected to 10-fold serial dilution to obtain working solutions at 100 nM, 10 nM, and 1 nM. Subsequently, the 10 nM solution was diluted by half to 5 nM, and the 1 nM solution was diluted by half to 0.5 nM. The final concentration of DMSO in all treatment groups was controlled to below 1‰ (v/v), while the control group was treated with medium containing an equivalent amount of DMSO. Full-wavelength scanning (280–320 nm) was performed using a UV-Vis spectrophotometer (Thermo Fisher Scientific (China) Co., Ltd)., with PBS as the control. The absorption peak intensities were quantitatively analyzed, and each experiment was conducted in triplicate.

Cell Viability Assay

To test the impact of IDE on cellular viability, a CCK-8 method was applied. HaCaT cells (104 cells per well) were seeded in 96-well plates. Once they adhered, the medium was switched to serum-free medium with IDE concentrations ranging from 0 to 1000 nM (each with five trials). The cells were then incubated for 24 h, after which 10 μL of CCK-8 solution was poured into each well. The plates were then incubated in the dark for 1 hour. After one hour, absorbance was measured at 450 nm using a microplate reader (Molecular Devices (Shanghai) Co., Ltd., China). The IDE concentrations that maintained >85% cell viability were selected for the subsequent experiments.

HaCaT cells were seeded and categorized following the protocol outlined in Cell Culture and Grouping. Upon reaching 80% confluency, the cultures were rinsed with PBS and subjected to varying doses of UVB irradiation (Kernel Medical Equipment Co.,Ltd., China) (10, 20, or 30 mJ/cm2). Following a subsequent PBS rinse, cells underwent a 24-hour incubation with IDE (0.5, 1, and 5 nM) in serum-free media in a humidified incubator with 5% CO2 at 37°C. CCK-8 analysis followed the procedure outlined above; absorbance readings were taken at 450 nm.

To investigate the protective effects of IDE and CoQ10 against UVB-induced damage in HaCaT cells and to compare the difference in their protective efficacy at the same concentrations. HaCaT cells (1×104 cells/well) were seeded into 96-well plates, cultured, and grouped as described in Cells. The cells were irradiated with UVB and then treated with IDE or CoQ10 (Shanghai Aladdin Biochemical Technology Co., Ltd, China) at the same concentration and allowed to stand for 24 h. The protective impact of IDE and CoQ10 against UVB irradiation’s cellular harm was evaluated via a CCK-8 test for cell viability.

EdU Staining for Analyzing Cell Proliferation

An EdU-488 assay (Beyotime Biotech Inc, China) evaluated the impacts of IDE on UVB-induced HaCaT cell proliferation. HaCaT cells (1×105 cells/well) were seeded into 24-well plates. The cells were irradiated with UVB, and 20 μM EdU working solution (preheated to 37 °C) was added to the control, UVB-irradiated, and IDE-treated groups, which was followed by 4 h of incubation in the dark at room temperature. Following media removal, cells underwent fixation in 4% paraformaldehyde (30 min), followed by buffer washes. EdU-labeled cells were visualized using a fluorescence microscopy (Carl Zeiss AG, German).

β-Galactosidase Staining

Commercial kit-based assessment revealed SA-β-gal (Beijing Solarbio Science & Technology Co., Ltd., China) activity to evaluate the IDE impact on UVB-mediated cell aging. After the treatment described in Cell Culture and Grouping, the samples were rinsed with PBS, followed by the addition of 1 mL of β-galactosidase staining solution, prepared as per the kit protocol. Cells were incubated at 37 °C in the absence of CO2 for 24 hours in darkness. SA-β-gal-expressing cells, characterized by blue-green stains, were photographed under a microscope. Positive cell proportions were determined from counts in six randomly selected areas.

Wound Healing Assay

Cell migration was assessed via a wound healing assay. HaCaT cells (5×105 cells/well) were seeded in 6-well plates. When cells reached 100% confluence,a scratch was made using a 200 μL pipette tip. After the treatment described in Cell Culture and Grouping, images of the identical field were taken at 0 and 24 hours with an inverted microscope. Scratch distances were measured using Image J software.

Intracellular SOD Activity and MDA Content Assays

SOD activity and MDA levels (Beyotime Biotech Inc, China) were measured to assess oxidative stress. HaCaT cells (1×106 cells/dish) were treated as described, then harvested and sonicated. The supernatant was collected after centrifugation of the cell lysate at 4 °C, and absorbance was measured at 450 nm (SOD) and 532 nm (MDA) using commercial kits. The results were quantified using standard curves.

Intracellular ROS Levels

The ROS levels were detected using a 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe (Beyotime Biotech Inc, China). HaCaT cultures (5×105 cells per well) were exposed to 10 μM of DCFH-DA at 37 °C for a duration of 30 minutes. The HaCaT cells underwent washing in PBS. DCF green fluorescence, which reflects ROS levels, was imaged using a fluorescence microscope (Olympus (China) Co., Ltd).

JC-1 Staining for MMP Detection

MMP was determined via JC-1 (Beyotime Biotech Inc, China). HaCaT cells (1×105/well) were incubated with JC-1 dye for 20 minutes, rinsed, then visualized. The red-green fluorescence ratio was quantified to assess MMP depolarization.

Mitochondrial ATP Assay

ATP concentrations were quantified via a luciferase assay (Beyotime Biotech Inc, China). HaCaT cells (5×105cells/well) were lysed on ice, and the supernatant was mixed with detection reagent. The luminescence was measured using a chemiluminescence meter, and the ATP content was calculated against a standard curve.

Proinflammatory Cytokine Assays

Cytokine concentrations (IL-1β, IL-8, TNF-α) in cell culture supernatants (centrifuged at 3000× g, 20 min) were measured using ELISA kits (Elabscience Biotechnology Co., Ltd., China).

Transcriptomic Sequencing (RNA-Seq)

HaCaT cells (5×105 cells/well) were divided into UVB and IDE treatment groups. Total RNA isolation from the cells was conducted with TRIzol, and mRNA sequencing and library preparation were performed by Shanghai Jingfang Biotechnology Co., Ltd.

Western Blot Analysis

The proteins from the candidate genes identified through RNA-seq were detected using Western blotting. The cells were lysed on ice, and the protein concentrations were quantified using a BCA assay. Following electrophoresis, the separated cell components were transferred onto membranes. Membranes were blocked with a 5% skim milk to prevent nonspecific binding. Following this, the membranes were soaked in primary antibodies targeted at IL-3RA and TUBA8 (Proteintech Group, Inc., China) overnight, both at a 1:1000 concentration. On the following day, the membranes were exposed to HRP-linked secondary antibodies, diluted to 1:10,000. The bands were then detected through enhanced chemiluminescence, and the data were analyzed using ImageJ for quantification.

Statistical Analysis

Statistical analysis was performed using GraphPad Prism 10.0 software. Data are presented as mean ± standard deviation. Normality test and homogeneity of variance test were conducted on the data. For comparison of means between two groups, an independent sample t-test was used when the data satisfied normal distribution and homogeneity of variance. For comparison of means among multiple groups, one-way analysis of variance (ANOVA) was employed when the data met the assumptions of independence, normality, and homogeneity of variance. A P-value < 0.05 was considered statistically significant. Differential gene expression analysis was performed using edgeR software. Gene expression levels were normalized using the FPKM (Fragments Per Kilobase per Million fragments) method. Genes with FDR < 0.05 and |log2FC| > 1 were identified as significantly differentially expressed between the two groups.

Results

Effects of UVB Irradiation on Morphology and Viability of HaCaT Cells

To investigate the effect of UVB irradiation on the viability of HaCaT cells, the cells were exposed to UVB irradiation at doses of 0, 10, 20, 30, 60, 90, and 120 mJ/cm2 (Figure 2A). The UVB-irradiated cells exhibited senescent phenotypes 24 h after irradiation under an inverted microscope. Compared with controls, UVB-treated cells appeared shrunken with rounded edges, widened intercellular spaces, and blurred boundaries, these effects increased in a dose-dependent manner (Figure 2B). The CCK-8 assay results showed that UVB irradiation inhibited the viability of HaCaT cells in a dose-dependent manner. Specifically, exposure to 60 mJ/cm2 UVB irradiation drastically reduced cell viability to 53.50%, whereas doses of 30 mJ/cm2 and below maintained cell viability above 60%. Therefore, UVB doses of 10, 20, and 30 mJ/cm2 were selected for subsequent experiments to ensure the reliability of the experimental results.

Figure 2.

Figure 2

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Effects of IDE on the Viability and Morphology of UVB-induced HaCaT cells. (A) Effects of different doses of UVB irradiation (10, 20, 30, 60, 90, and 120 mJ/cm2) on the viability of HaCaT cells, detected by CCK-8 assay (n=3). (B) Representative photomicrographs (original magnification, ×20) of HaCaT cells 24 h after exposure to UVB irradiation at doses of 10, 20, 30, 60, 90, and 120 mJ/cm2, captured under an inverted microscope. (C) Viability of HaCaT cells treated with different concentrations of IDE (0.1, 1, 10, 100, and 1000 nM) for 24 h, detected by CCK-8 assay (n=3). (D–F) Cell viability of HaCaT cells co-treated with UVB irradiation (10, 20, and 30 mJ/cm2) and IDE (0.5, 1, and 5 nM) for 24 h, detected by CCK-8 assay (n=3). (G) Chemical structure of IDE. (H) Absorbance of IDE at concentrations of 0.5, 1, and 5 nM across different wavelengths (280, 290, 300, 310, and 320 nm), measured by UV spectrophotometry (n=3). (*P < 0.05, **P < 0.01, ns: no significant difference compared with the UVB-exposed or control group).

IDE Therapy Recovered UVB-Exposed HaCaT Cell Viability

To screen for the optimal concentration of IDE in promoting the viability of HaCaT cells, the cells were treated with 0.1–1000 nM IDE for 24 h. The CCK-8 assay results showed that after 24 h of IDE treatment, concentrations ranging from 0.1 to 100 nM significantly enhanced the viability of HaCaT cells, with all differences being statistically significant (P < 0.05). Compared with the control group, cell viability dropped below 85% at IDE concentration exceeded 100 nM (Figure 2C), however, the difference did not reach statistical significance (ns). To further determine the protective effect of IDE on the viability of HaCaT cells following UVB irradiation, cells were exposed to UVB at doses of 10, 20, and 30 mJ/cm2 and subsequently treated with 0.1, 0.5, 1, and 5 nM IDE for 24 h. At UVB irradiation doses of 10 and 20 mJ/cm2, treatment with 0.5, 1, and 5 nM IDE significantly restored the viability of HaCaT cells (P < 0.05). At a UVB irradiation dose of 30 mJ/cm2, 0.5 nM IDE exhibited a significant protective effect, whereas 1 nM IDE showed an improving trend, although it did not reach statistical significance. Based on these findings, IDE concentrations of 0.5, 1, and 5 nM were selected for subsequent experiments (Figure 2D–F).

IDE Did Not Directly Absorb UVB

To evaluate the UVB absorption capacity of IDE, the absorbance of 0.5, 1, and 5 nM IDE at different wavelengths (280, 290, 300, 310, and 320 nm) was measured. The results of UV-Vis spectrophotometry showed that the UVB absorbance did not significantly differ between IDE (0.5–5 nM) and distilled water at 280–320 nm (P > 0.05), indicating that IDE did not directly absorb UVB (Figure 2G and H).

IDE Enhanced the Migration Ability of HaCaT Cells Following UVB Irradiation

To investigate the promoting effect of IDE on the migration ability of UVB-induced HaCaT cells, a wound healing assay was performed. As shown in Figure 3A–D, compared with the control group, UVB irradiation significantly increased apoptosis and reduced the migratory capacity of HaCaT cells. Following IDE treatment, the wound healing rate was enhanced in a concentration-dependent manner, with statistically significant differences (P < 0.05). Among the tested concentrations, the 0.5 nM IDE treatment group exhibited the most pronounced effect.

Figure 3.

Figure 3

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Effects of IDE on Proliferation, Migration, and Senescence of UVB-induced HaCaT cells. (A) Wound healing assay detecting the effect of IDE on the migration ability of HaCaT cells after UVB irradiation. Cells were exposed to 30 mJ/cm2 UVB, immediately scratched, and treated with 0.5, 1, and 5 nM IDE for 24 h. Wound healing was observed and photographed under an inverted microscope at 0 h and 24 h. (B) EdU staining detecting the effect of IDE on the proliferation of HaCaT cells after UVB irradiation. Cells were exposed to 30 mJ/cm2 UVB, treated with 0.5, 1, and 5 nM IDE for 24 h, and labeled with Hoechst 33342 and EdU. EdU-positive cells were observed and counted under a fluorescence microscope. (C) SA-β-gal staining detecting the effect of IDE on the senescence of HaCaT cells after UVB irradiation. Cells were exposed to 30 mJ/cm2 UVB, treated with 0.5, 1, and 5 nM IDE for 24 h, and stained with β-galactosidase. Blue-stained cells indicate senescent cells. (D) Quantitative analysis of wound healing area. The wound healing area was measured using ImageJ software, and the percentage of healing area relative to the initial wound area was calculated for each group (n=3). (E) Statistical analysis of EdU-positive cell ratio. The percentage of EdU-positive cells relative to the total number of Hoechst-stained nuclei was calculated using ImageJ software (n=3). (F) Statistical analysis of senescent cell ratio. The percentage of blue-stained positive cells relative to the total number of cells was calculated (n=3). (*P < 0.05, **P < 0.01, ns: no significant difference compared with the UVB-exposed group).

IDE Restored the Proliferative Capacity of HaCaT Cells Following UVB Irradiation

To determine the effect of IDE on the proliferation of HaCaT cells after UVB exposure, an EdU staining assay was performed. The results showed that IDE effectively reversed the inhibition of cell proliferation induced by UVB irradiation (Figure 3B–E). Compared with the UVB group, IDE treatment significantly increased both proliferation and the proportion of EdU-positive cells, with statistically significant differences (P < 0.05).

IDE Ameliorated UVB-Induced Senescence in HaCaT Cells

To investigate the effect of IDE on UVB-induced senescence in HaCaT cells, SA-β-gal staining was performed. As shown in Figure 3C–F, compared with the control group, exposure to 30 mJ/cm2 UVB irradiation successfully induced a cellular senescence model (P < 0.05). In contrast with the UVB irradiation group, IDE treatment effectively ameliorated UVB-induced cellular senescence. Specifically, treatment with 0.5, 1, and 5 nM IDE for 24 h significantly reduced the percentage of SA-β-gal-positive cells, with statistically significant differences (P < 0.05).

IDE Provided Stronger Photoprotection Than CoQ10

To investigate the protective effects of IDE and CoQ10 against UVB-induced damage in HaCaT cells and to compare the differences in their efficacy at equal concentrations, HaCaT cells were exposed to UVB irradiation followed by treatment with 0.5, 1, and 5 nM IDE or CoQ10 for 24 h. CCK-8 results showed that following UVB irradiation at 10 and 20 mJ/cm2, treatment with 0.5 and 1 nM IDE/CoQ10 significantly enhanced cell viability, with statistically significant differences between the two groups (P < 0.05). After treatment with 5 nM IDE/CoQ10, although no statistically significant difference was observed, the protective effect of IDE was numerically superior to that of CoQ10. When the UVB irradiation dose was increased to 30 mJ/cm2, IDE/CoQ10 at all three concentrations of significantly enhanced cell viability, with statistically significant differences between the two groups (P < 0.05). These findings indicate that, at the same concentration, IDE exhibits a stronger protective effect than CoQ10 against the impairment of HaCaT cell viability induced by certain doses of UVB irradiation. (Figure 4A–C).

Figure 4.

Figure 4

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Effects of IDE on Oxidative Stress in UVB-induced HaCaT cells. (A–C) Protective effects of IDE and CoQ10 on the viability of HaCaT cells under different UVB irradiation doses, detected by CCK-8 assay. Cells were exposed to 10, 20, and 30 mJ/cm2 UVB, respectively, and treated with 0.5, 1, and 5 nM IDE or CoQ10 (positive control) for 24 h. Cell viability was then measured (n=3). (D–F) SOD activity in each group after corresponding treatments (n=3). (G–I) MDA content in each group after corresponding treatments (n=3). (*P < 0.05, **P < 0.01, ***P < 0.001, ns: no significant difference compared with the UVB-exposed group).

IDE Treatment Alleviated UVB-Related Oxidative Stress in HaCaT Cells

To investigate the effects of different doses of UVB irradiation on the oxidative stress levels in HaCaT cells and to verify the reparative effect of IDE on UVB-induced oxidative damage in HaCaT cells, this study analyzed antioxidant enzyme activity and lipid peroxidation levels. The results showed that, compared with the control group, exposure to 10, 20, and 30 mJ/cm2 UVB irradiation induced a significant oxidative stress response in HaCaT cells, manifested as a marked decrease in SOD activity (Figure 4D–F) and a significant increase in MDA content (Figure 4G–I), which correlated positively with the UVB dose. Some of these differences were statistically significant (P < 0.05). Following treatment with 0.5, 1, and 5 nM IDE for 24 h in UVB-irradiated HaCaT cells, SOD activity was restored and MDA content was reduced. Moreover, the recovery of SOD activity showed a significant positive correlation with IDE concentration, with some differences reaching statistical significance (P < 0.05), while the reduction in MDA levels did not exhibit a clear concentration-dependent trend. These findings suggested that IDE could effectively alleviate UVB-induced oxidative damage in cells.

IDE Treatment Protected Mitochondrial Function in UVB-Irradiated HaCaT Cells

To elucidate the repair effect of IDE on UVB-induced mitochondrial damage in HaCaT cells, this study integrated quantitative analysis of reactive oxygen species (ROS), ATP synthesis level measurement, mitochondrial membrane potential monitoring, and transmission electron microscopy observation to investigate the protective effect of IDE on mitochondrial function. Following exposure to 30 mJ/cm2 UVB irradiation, HaCaT cells exhibited significant mitochondrial dysfunction: mitochondrial swelling and disruption of cristae structure were observed, along with a significant increase in ROS (Figure 5A and B), depolarization of mitochondrial membrane potential (Figure 5C and D), and a marked decrease in ATP synthesis (Figure 5E), all with statistically significant differences (P < 0.05). After treatment with 0.5, 1, and 5 nM IDE, the degree of mitochondrial swelling was alleviated, membrane structural integrity improved, intracellular ROS levels were significantly reduced, and both ATP content and mitochondrial membrane potential levels were significantly restored, with some differences reaching statistical significance (P<0.05). These findings indicated that IDE could effectively ameliorate UVB-induced mitochondrial dysfunction in HaCaT cells. The results of mitochondrial function evaluation experiments showed that when the UVB irradiation dose was below 30 mJ/cm2, JC-1 staining indicated that the mitochondrial membrane potential (MMP) maintenance rate exceeded 90%, and there were no significant differences in intracellular ATP and ROS levels compared with the UVB-free control group (P > 0.05). This indicated that 30 mJ/cm2 UVB irradiation serves as the threshold for mitochondrial damage while maintaining cell viability above 60%. Therefore, 30 mJ/cm2 was adopted as the UVB irradiation dose for all subsequent mitochondrial evaluation experiments.

Figure 5.

Figure 5

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Effects of IDE on Mitochondrial Function and Inflammatory Factors in UVB-induced HaCaT cells. (A) Detection of intracellular ROS levels using the DCFH-DA fluorescent probe. Cells were exposed to 30 mJ/cm2 UVB and treated with 0.5, 1, and 5 nM IDE for 24 h. DCFH-DA enters cells and is oxidized by ROS to form fluorescent DCF. Representative images were captured under a fluorescence microscope at 488 nm excitation wavelength. (B) Quantitative analysis of relative intracellular ROS levels. Fluorescence intensity in each group was calculated using ImageJ software as fold change relative to the control group, and statistical analysis was performed using GraphPad Prism software (n=3). (C) Detection of MMP changes using the JC-1 probe. Cells were exposed to 30 mJ/cm2 UVB and treated with 0.5, 1, and 5 nM IDE for 24 h, followed by JC-1 staining. In normal cells, JC-1 aggregates in mitochondria emitting red fluorescence, whereas in cells with decreased MMP, JC-1 exists as monomers emitting green fluorescence. Representative images were captured using a fluorescence microscope (20× objective). (D) Quantitative analysis of MMP. The proportion of JC-1 red fluorescence-positive cells was calculated using ImageJ software, presented as a percentage, and compared between groups (n=3). (E) ATP content assay. After exposure to 30 mJ/cm2 UVB and treatment with 0.5, 1, and 5 nM IDE for 24 h, intracellular ATP levels were detected using a chemiluminescence method. ATP was converted into a light signal using an ATP assay kit, and chemiluminescence intensity was measured with a multifunction microplate reader (n=3). (F–H) Detection of inflammatory factor levels. The levels of TNF-α, IL-1β, and IL-8 in the cell supernatant of each group were measured using ELISA (n=3). (*P < 0.05, **P < 0.01, ns: no significant difference compared with the UVB-exposed group).

IDE Treatment Suppressed UVB-Induced Inflammation in HaCaT Cells

To clarify the reparative effect of different concentrations of IDE on UVB-induced inflammatory damage in HaCaT cells and its underlying molecular mechanism, this study employed ELISA for detection. The results showed that following exposure to 30 mJ/cm2 UVB irradiation, the levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-8 in HaCaT cells were significantly increased compared with the control group, with all differences reaching statistical significance (P < 0.05). After treatment with 0.5, 1, and 5 nM IDE for 24 h, the levels of the aforementioned inflammatory cytokines decreased in a concentration-dependent manner, with some differences achieving statistical significance (P < 0.05). These findings suggested that IDE could alleviate UVB-induced inflammatory damage in cells (Figure 5F–H).

Involvement of IL-3RA and TUBA8 in IDE-Mediated Photoprotection

To elucidate the regulatory mechanism of IDE in cells damaged by UVB irradiation, this study compared the gene expression profiles between IDE treatment group and UVB irradiation group using transcriptome sequencing (Figure 6A–F). The results identified 347 differentially expressed genes (DEGs) between the two groups, of which 221 were significantly upregulated and 126 were significantly downregulated. GO enrichment analysis revealed that these DEGs are widely involved in various biological processes, with significant enrichment in oxidative stress, cell-cell junctions, and mitochondrial metabolic regulation. KEGG pathway analysis identified 18 key signaling pathways, including Apoptosis, Oxidative phosphorylation, and the PI3K-Akt signaling pathway, suggesting that IDE may alleviate UVB-induced oxidative stress damage through a multi-target regulatory mechanism.

Figure 6.

Figure 6

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Transcriptomic Analysis of the Molecular Characteristics of UVB-induced HaCaT cells Treated with IDE. (A) Volcano plot of differentially expressed genes (DEGs). With log2(FC) as the x-axis and -log10(P-value) as the y-axis, the distribution of gene expression differences after IDE intervention in UVB-induced cells is displayed. Red and blue represent significantly upregulated (|log2(FC)| > 1, P < 0.05) and downregulated genes, respectively. (B) Principal component analysis (PCA) plot. Dimensionality reduction via PCA shows the distribution of samples in each group (UVB group, IDE group). Ellipses represent 95% confidence intervals, reflecting the overall transcriptomic differences between IDE-treated samples and the UVB-induced group. (C) Sample correlation heatmap. Pearson correlation coefficients were calculated based on gene expression levels, with red and blue representing positive and negative correlations, respectively. This illustrates the correlation of gene expression patterns between different treatment groups, reflecting sample reproducibility and inter-group differences. (D) KEGG pathway enrichment analysis of DEGs. The x-axis represents the gene ratio (the number of DEGs in the pathway relative to the total number of DEGs), the y-axis shows significantly enriched pathway names, and colors represent P-values. Core signaling pathways involved in IDE treatment (such as apoptosis and oxidative phosphorylation) are displayed. (E) Clustering heatmap of DEG expression. Hierarchical clustering was performed on significantly DEGs, with rows representing genes and columns representing samples. Red and blue indicate upregulated and downregulated gene expression, respectively, showing the grouping characteristics and regulatory patterns of gene expression after UVB induction and IDE treatment. (F) GO functional enrichment bar plot of DEGs. Categorized by biological process (BP), molecular function (MF), and cellular component (CC) (represented by blue, green, and red, respectively). The x-axis represents the enrichment factor (the ratio of DEGs to background genes in the GO term), and the y-axis shows significantly enriched GO terms, revealing the key biological functions regulated by IDE. (A total of six samples were included in this transcriptome sequencing analysis: UVB1-3 represented three biological replicates of the 30 mJ/cm2 UVB irradiation group, and IDE1-3 represented three biological replicates of the 30 mJ/cm2 UVB irradiation combined with 5 nM IDE treatment group. All samples were processed in a single batch: cell passaging, culture, and drug interventions were performed simultaneously on the same experimental day to ensure consistency in cell passage number, culture conditions, and treatment timing. Subsequently, total RNA from all six samples was extracted concurrently using the same batch of reagents and extraction kits, and library construction was completed in a single experimental run using the same batch of adapters and enzymes. Finally, all samples were sequenced on the same flow cell lane of the Novaseq platform to eliminate technical variability across different lanes. The enrichment analysis results are predicted based on transcriptomic data and require further validation through functional experiments.).

Subsequently, Western blot analysis was employed to validate the protein levels of IL-3RA and TUBA8, which exhibited the most significant differential expression in the transcriptomic analysis. The results showed that compared to the control group, UVB irradiation significantly downregulated the protein expression of TUBA8 and significantly upregulated the expression of IL-3RA in HaCaT cells, with both differences being statistically significant (P < 0.05). Following treatment with 0.5, 1, and 5 nM IDE, the protein expression levels of TUBA8 were significantly restored compared to the UVB irradiation group, with statistically significant differences (P < 0.05) (Figure 7B–D). IL-3RA expression was significantly reduced in the 0.5 and 1 nM IDE treatment groups (P < 0.05), while the 5 nM IDE treatment group showed a decreasing trend, although the difference did not reach statistical significance (Figure 7A–C). The supplementary figures containing the Western blot data could be found in Supplementary Figure S1. These findings suggested that IL-3RA and TUBA8 might serve as potential molecular targets through which IDE exerts its anti-photoaging effects.

Figure 7.

Figure 7

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Effects of IDE on the Protein Expression of IL-3RA and TUBA8 in UVB-induced HaCaT cells. (A and B) Western blot detection of IL-3RA and TUBA8 protein expression. Cells were exposed to 30 mJ/cm2 UVB and treated with 0.5, 1, and 5 nM IDE for 24 h. The expression levels of IL-3RA (A) and TUBA8 (B) were detected by Western blot, and representative band images are shown. (C) Statistical analysis of relative IL-3RA protein expression. Using β-actin as an internal reference, band grayscale values were quantitatively analyzed with ImageJ software. Relative changes in IL-3RA protein expression levels in each group were calculated and compared between groups (n=3). (D) Statistical analysis of relative TUBA8 protein expression. Using GAPDH as an internal reference, quantitative analysis of TUBA8 protein band grayscale values was performed using the same method as in (C). Relative expression levels were calculated and compared between groups (n=4). (*P < 0.05, **P < 0.01, ns: no significant difference compared with the UVB-exposed group).

Discussion

The skin, the body’s largest organ, acts as the main barrier between internal systems and the outside world.21 UV irradiation is a predominant exogenous driver of skin aging among the environmental insults experienced by the skin. Photoaging is a specific subtype of skin aging: a pathological condition triggered by the chronic exposure to UV irradiation and other environmental light sources. Photoaging is clinically characterized by hallmark features such as pronounced wrinkling, skin elasticity loss, and aberrant pigmentation.22 Over 80% of observable skin aging phenotypes are attributable to ultraviolet irradiation.23 UV irradiation is classified into UVA (320–400 nm), UVB (280–320 nm), and UVC (100–280 nm) segments according to their wavelengths.24 UVC rays are blocked by the ozone layer, preventing them from reaching Earth’s surface.25 UVA more deeply penetrates the dermis, inducing the generation of ROS, triggering oxidative stress, and degrading collagen and elastin fibers.26 UVB primarily affects the epidermis due to its limited penetration depth; however, UVB photon energy is nearly 1000 times higher than UVA. UVB directly damages epidermal keratinocyte DNA, activates intracellular proinflammatory signaling cascades, and accelerates cellular senescence.27 Chronic UVB exposure impairs skin barrier function, increasing transepidermal water loss, sensitivity, and the risk of skin cancer.28

IDE is structurally highly similar to CoQ10; however, the molecular weight of IDE is approximately 40% lower than CoQ10.29 The compact benzoquinone ring structure enables the high transmembrane permeability of IDE, which is approximately 2.3 times more efficient at penetrating the stratum corneum and mitochondrial membranes than CoQ10. This structure allows IDE to rapidly reach free radical-generating sites (such as mitochondrial complexes I and II) to scavenge excess ROS.30 IDE more efficiently blocks oxidative chain reactions and inhibits skin photoaging compared with traditional antioxidants such as CoQ10, ascorbic acid,31 and green tea extract.32

UVB-induced oxidative stress is the core mechanism underlying skin photodamage.33 The body’s intrinsic antioxidant system includes both enzymatic and nonenzymatic components. The enzymatic antioxidants include SOD and catalase, whereas nonenzymatic substances such as glutathione and thioredoxin work together to maintain redox homeostasis.34 We found that UVB exposure suppressed SOD activity and increased the level of the lipid peroxidation product, MDA, in HaCaT cells compared with those of the control cells, disrupting the redox balance and inducing cellular damage. IDE treatment reversed this process, restoring SOD activity and reducing the MDA content. These effects of IDE may be attributed to the unique redox properties of the benzoquinone ring structure of IDE, which can switch between reduced and oxidized forms. The ketone bond on the ring can be reduced to form a transient semiquinone intermediate, which can be further reduced to dihydroubiquinone,35 efficiently mitigating UVB-related oxidative stress within HaCaT cells, thus sustaining intracellular redox homeostasis.

Oxidative stress often leads to mitochondrial dysfunction.36 IDE treatment effectively antagonized the UVB-induced mitochondrial damage in HaCaT cells, maintained MMP stability, and prevented ATP depletion. Acting as an electron shuttle, IDE could potentially boost ATP production by facilitating the electron handoff from complexes I and II to complex III, ultimately enhancing oxidative phosphorylation.37 Furthermore, IDE safeguards against membrane potential decline and inhibits cytochrome C’s release, suppresses the apoptotic cascade, sustains cellular energy metabolism, and enhances cell resistance to damage by reducing ROS production and inhibiting the abnormal opening of mitochondrial permeability transition pores.38

The release of proinflammatory cytokines is a key link in the adaptive immune response to inflammatory stimulation, with IL-1β and TNF-α serving as core proinflammatory mediators.39 TNF-α is a pleiotropic cytokine and early initiator of the inflammatory response that activates immune cells and induces apoptosis.40 IL-1β is a regulator of inflammatory intensity, participating in immune responses through regulating T-cell function and playing critical roles in phagocytosis, antigen presentation, and modulating inflammatory processes.41 UVB radiation can induce keratinocytes to release inflammatory factors such as TNF-α, IL-1β, and IL-8. These inflammatory factors can act on dermal vascular endothelial cells in vivo, leading to increased vascular permeability and inflammatory cell infiltration, which clinically manifest as erythema and edema.42 IDE treatment substantially reduced the levels of inflammatory cytokines in HaCaT cells after UVB irradiation, confirming that IDE effectively inhibits UVB-induced inflammatory responses and alleviates the UVB-related inflammatory damage to the epidermal cells.

The results of this study indicated that UVB irradiation upregulated IL-3RA expression and downregulates TUBA8 expression in HaCaT cells. Treatment with IDE effectively reduced IL-3RA expression and restored TUBA8 expression. As a key subunit of the IL-3 receptor, IL-3RA is widely distributed on immune and epithelial cells. Previous studies have shown that UVB-induced DNA damage can disrupt IL-3RA function, leading to immune imbalance, inhibition of keratinocyte proliferation, and dysfunction of dendritic cells, thereby exacerbating skin photodamage. We hypothesize that IDE may repair photodamage by modulating immunity and cell proliferation via IL-3RA.43 TUBA8 belongs to the alpha-tubulin family and is a core component of the cytoskeletal microtubule network,44 playing a crucial role in cytoskeletal structure, cell junctions, and mitochondrial respiratory chain function. Numerous studies have demonstrated that UVB irradiation can disrupt tubulin polymerization status through the induction of oxidative stress and DNA damage,45 leading to cytoskeletal remodeling and functional abnormalities.46,47 Our findings were consistent with the literature. Therefore, it is speculated that UVB may lead to tubulin depolymerization and inhibit TUBA8 expression, thereby interfering with the cell cycle and disrupting epidermal integrity. The restoration of TUBA8 expression following IDE treatment suggests that IDE may promote the proliferation and migration of damaged keratinocytes by preserving the integrity of the microtubule cytoskeleton, thereby accelerating epidermal repair.

This study has several limitations. Firstly, the conclusions are primarily derived from in vitro experiments. Although these findings provided a crucial theoretical basis for elucidating the photoprotective mechanism of IDE, they were obtained within a simplified culture system. Therefore, whether these conclusions can be extrapolated to more complex physiological environments remains to be verified. Future studies should employ 3D reconstructed skin models or in vivo animal experiments to confirm their applicability beyond the cellular system. Secondly, despite the significant anti-aging efficacy demonstrated by IDE, its clinical application faces challenges. Previous studies found that IDE exhibited poor chemical stability; when stored at 40°C and 75% humidity for 45 days, its degradation rate reached 60%, accompanied by a 30% reduction in antioxidant activity.48,49 This significantly limits its long-term storage and practical application. Furthermore, the potential risk of inducing allergic contact dermatitis in clinical use should be concerned.50 Future research should focus on developing novel delivery systems, such as nanostructured lipid carriers, to enhance its stability, and on conducting in-depth investigations into its sensitization mechanism.51 This approach aims to ensure the safety of its use while fully leveraging its therapeutic efficacy.

Conclusion

IDE effectively ameliorated the UVB-induced photoaging process in HaCaT cells. Its protective effects were not only manifested in restoring cell viability, alleviating oxidative stress, maintaining mitochondrial function, and reducing inflammatory factor infiltration but might also be associated with the regulation of IL-3RA and TUBA8. This study has laid the foundation for further in-depth research on IDE against UVB-induced photoaging and has provided new insights for the development of anti-photoaging drugs.

Acknowledgments

The abstract of this paper was presented at the SID 2025 Annual Meeting as a poster. The poster’s abstract was published in “Poster Abstracts” in The Journal of Investigative Dermatology: https://www.jidonline.org/article/S0022-202X(25)01096-6/pdf

Funding Statement

The Healthcare Talents Elite Program of Shanghai Pudong New Area (2025PDWSYCBJ-11); Laser and Medical Innovation Capability Enhancement Program of Shanghai Pudong Gongli Hospital (JGYX2024A-06); The Leading Talent Development Program of Gongli Hospital of Shanghai Pudong New Area (2025-GLSHLH-01).

Abbreviations

UV, ultraviolet; IDE, idebenone; CoQ10, coenzyme Q10; HaCaT human immortalized epidermal keratinocytes; SA-β-gal, senescence-associated β-galactosidase; ROS, reactive oxygen species; MDA, malondialdehyde; MMP, mitochondrial membrane potential; PBS, phosphate-buffered saline; BCA, bicinchoninic acid; SOD, superoxide dismutase.

Data Sharing Statement

Data is available from the corresponding author upon request.

Author Contributions

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

Disclosure

The authors have no conflicts of interest to declare for this work.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data is available from the corresponding author upon request.

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