Oleic acid induces lipogenesis and NLRP3 inflammasome activation in organotypic mouse meibomian gland and human meibomian gland epithelial cells.

The accumulation of oleic acid (OA) in the meibum from patients with meibomian gland dysfunction (MGD) suggests that it may contribute to meibomian gland (MG) functional disorder, as it is a potent stimulator of acne-related lipogenesis and inflammation in sebaceous gland. Therefore, we investigate whether OA induces lipogenesis and inflammasome activation in organotypic cultured mouse MG and human meibomian gland epithelial cells (HMGECs). Organotypic cultured mouse MG and HMGECs were exposed to OA or combinations with specific AMPK agonists 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Lipogenic status, ductal keratinization, squamous metaplasia, NLRP3/ASC/Caspase-1 inflammasome activation, proinflammatory cytokine IL-1ß production, and AMPK pathway phosphorylation in MG were subsequently examined by lipid staining, immunofluorescence staining, immunohistochemical staining, ELISA assay, and Western blot analyses. We found that OA significantly induced lipid accumulation, ductal keratinization, and squamous metaplasia in organotypic cultured MG, as evidenced by increased lipids deposition within acini and duct, upregulated expression of lipogenic proteins (SREBP-1 and HMGCR), and elevation of K10/Sprr1b. Additionally, OA induced NLRP3/ASC/Caspase-1 inflammasome activation, cleavage of Caspase-1, and production of downstream proinflammatory cytokine IL-1ß. The findings of lipogenesis and NLRP3-related proinflammatory response in OA-stimulated HMGECs were consistent with those in organotypic cultured MG. OA exposure downregulated phospho-AMPK in two models, while AICAR treatment alleviated lipogenesis by improving AMPK/ACC phosphorylation and SREBP-1/HMGCR expression. Furthermore, AMPK amelioration inhibited activation of the NLRP3/ASC/Caspase-1 axis and secretion of IL-1ß, thereby relieving the OA-induced proinflammatory response. These results demonstrated that OA induced lipogenic disorder and NLRP3 inflammasome activation in organotypic cultured mouse MG and HMGECs by suppressing the AMPK signaling pathway, indicating OA may play an etiological role in MGD.

Sleep Quality in Patients With Ocular Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.

OBJECTIVES: To investigate the sleep quality in patients with ocular graft-versus-host disease (oGVHD) compared with patients without oGVHD after allogeneic hematopoietic stem cell transplantation (alloHCT) and healthy controls. METHODS: This cross-sectional study analyzed 142 patients after alloHCT including 94 patients with oGVHD and 48 without. Fifty healthy controls were also enrolled. oGVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group (ICOGCG) criteria. Sleep quality was assessed by the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI). Poor sleep quality was defined as CPQSI score greater than 6. RESULTS: Patients after alloHCT demonstrated a significantly higher CPQSI score than those of controls {7.0 [interquartile range (IQR) 5.0-10.0] vs. 5.5 [IQR 4.8-7.0], P =0.002}, especially in the oGVHD subgroup (7.5 [IQR 5.0-11.0] vs. 6.0 [IQR 5.0-8.0], P =0.04) with nearly double prevalence of poor sleep quality (58 [62%] vs. 18 [37%], P =0.006). Poor sleep quality was strikingly correlated with oGVHD diagnosis (adjusted odds ratio [OR]=2.55, 95% confidence interval [CI]: 1.02-6.34, P =0.04) and systemic immunosuppressants (adjusted OR=2.61, 95% CI: 1.32-5.71, P =0.02). Among the ocular parameters, poor sleep quality was significantly associated with higher ICOGCG score (adjusted OR=1.20, 95% CI: 1.03-1.39, P =0.02) and lower tear film break-up time (adjusted OR=0.85, 95% CI: 0.74-0.99, P =0.05). CONCLUSIONS: Poor sleep quality was associated with an increased severity of oGVHD and tear film instability in the long-term alloHCT survivorship.

Vision-specific and cancer-specific quality of life in ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

PURPOSE: To compare the vision-specific and cancer-specific quality of life (QOL) between patients with and without ocular graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplantation (alloHCT). METHODS: This cross-sectional observational study analyzed 142 patients after alloHCT including 94 patients with oGVHD and 48 without. oGVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group (ICOGCG) criteria. QOL was assessed by using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). RESULTS: Compared with non-oGVHD patients, patients with oGVHD had worse vision-specific (NEI VFQ-25: 64.3 ± 20.3 vs. 77.6 ± 19.3, P < 0.001) and cancer-specific (EORTC QLQ-C30: 59.9 ± 20.3 vs. 67.4 ± 17.5, P = 0.03) QOL, as well as impaired cognitive function (72.7 ± 22.1 vs. 82.3 ± 19.0, P = 0.01). The vision-specific QOL was significantly correlated with ICOGCG score (ß = - 1.88, 95%CI: - 3.35 to - 0.41, P = 0.01) and post-alloHCT medical expense (ß = - 5.70, 95%CI: - 10.35 to - 1.05, P = 0.02), while cancer-specific QOL was strikingly correlated with post-alloHCT medical expense (ß = - 9.91, 95%CI: - 14.43 to - 5.39, P < 0.001), frequency of ophthalmic medication (ß = - 0.93, 95%CI: - 1.64 to - 0.21, P = 0.01), education (ß = - 6.97, 95%CI: - 13.31 to - 0.62, P = 0.03), and peripheral blood stem cell use (ß = - 6.42, 95%CI: - 12.59 to - 0.25, P = 0.04). CONCLUSIONS: Patients with oGVHD experienced significant impairment in both vision-specific and cancer-specific QOL including cognitive function when compared with those without after alloHCT. Multidimensional QOL assessment should be included in the long-term alloHCT survivorship care.

Quantitative evaluation of lipid layer thickness and blinking in children with allergic conjunctivitis.

PURPOSE: To quantitatively evaluate the lipid layer thickness (LLT) and blinking in children with or without allergic conjunctivitis (AC), and to compare those between the different types of AC. METHODS: For this case-control study, 81 children with symptomatic AC with an average age of 9.62 ± 2.67 years were enrolled and subdivided according to the subtypes of AC, including seasonal/perennial allergic conjunctivitis group and vernal keratoconjunctivitis (VKC)/atopic keratoconjunctivitis (AKC) group. Another 82 age-matched healthy children were enrolled as control group. All subjects underwent routine eye examination and measurements of LLT, the number of incomplete or total blinking, partial blinking rate by the LipiView interferometer over a 10-s period. Other ocular surface assessment included fluorescein tear breakup time (TBUT), lower tear meniscus height, meibomian gland loss (MGL), meibum expressibility and quality. RESULTS: Pediatric patients with AC had significant thinner LLT, shorter TBUT, decreased total blinking but increased partial blinking rate, especially in those with VKC/AKC (all P < 0.05). A significant deterioration of meibomian gland parameters was observed in AC group when compared with control subjects, demonstrated by severe upper and lower MGL, lid margin abnormalities, decreased meibum expressibility, and abnormal meibum quality, all of which were worse in the severe type of AC (all P < 0.05). Thinner LLT was significantly correlated with decreased TBUT (ß = 3.666, P < 0.001) and severity of upper MGL (ß = - 7.701, P = 0.002). CONCLUSION: Decreased LLT and blinking disorders in pediatric patients with AC may contribute to lipid layer deficiency in the long run, which should be considered and appropriately diagnosed for a more precise treatment.

Subconjunctival injection of tumor necrosis factor-α pre-stimulated bone marrow-derived mesenchymal stem cells enhances anti-inflammation and anti-fibrosis in ocular alkali burns.

PURPOSE: To investigate the therapeutic effect of subconjunctival injection of tumor necrosis factor-α (TNF-α) pre-stimulated bone marrow-derived mesenchymal stem cells (BMMSCs) on ocular alkali burns in a rat model. METHODS: After applying a 6 mm filter paper soaking in 1 N NaOH on the cornea of rats, the suspension of TNF-α pre-stimulated BMMSCs, BMMSCs and PBS were given subconjunctivally and respectively. Corneal epithelial defect, corneal opacity, inflammation as well as PTGS2 and TSG-6 expression on day 7 and fibrosis on day 14 were compared. RESULTS: TNF-α pre-stimulated BMMSCs group had a more predominate effect on promoting corneal epithelial repairing, decreasing corneal opacity, reducing inflammatory cells and CD68 + macrophages on day 7 and suppressing fibrosis on day 14 compared to BMMSCs group. Besides, it had significant increased expressions of PTGS2 and TSG-6 in vitro. Pre-treated with Indomethacin revealed a reverse effect on above-mentioned changes. CONCLUSION: Subconjunctival injection of TNF-α pre-stimulated BMMSCs enhanced anti-inflammatory and anti-fibrotic effect in ocular alkali burns, which was possibly though up regulation of PTGS2 and TSG-6 expression.

Prevalence of Ocular Demodex Infestation in Children: An Epidemiological Survey in South China.

OBJECTIVES: To investigate the prevalence of and risk factors for Demodex mite infestation of the eyelashes in Chinese children. METHODS: A total of 1,575 children were surveyed from June 2017 to January 2019 and stratified into two age groups: 3 to 6 and 7 to 14 years. All subjects underwent routine eye examination and lash epilation for Demodex mite identification and counting using microscopy. Demographic data and lifestyle habits were also recorded. RESULTS: Demodex mites were detected in 189 of 1,575 (12.0%) children, including Demodex folliculorum (D. folliculorum) in 180 (11.4%), Demodex brevis (D. brevis) in 11 (0.7%), and both mites in 2 (0.1%). The median number of D. folliculorum mites was 1 (interquartile range [IQR], 1-2) and that of D. brevis was 1 (IQR, 1-1). Children with Demodex infestation did not exhibit more ocular discomfort than those without (21.2% vs. 23.1%; P=0.56). However, lash abnormalities, including trichiasis, cylindrical dandruff, or scaly discharge at the lash root, were more prevalent in children with Demodex infestation (24.9% vs. 12.8%; P<0.001) and in the 7 to 14-year subgroup (33.7% vs. 12.8%; P<0.001). Multiple logistic regression revealed that autumn-winter was associated with a higher detection rate of Demodex infestation (all P<0.05). In the 3-6-year subgroup, children residing in rural regions exhibited a higher prevalence of Demodex infestation (P=0.03). CONCLUSIONS: Ocular Demodex infestation, with a low Demodex mite count, was found in healthy Chinese children aged 3 to 14 years.

A New Perspective on Dry Eye Classification: Proposal by the Asia Dry Eye Society.

The 2017 consensus report of the Asia Dry Eye Society (ADES) on the definition and diagnosis of dry eyes described dry eye disease as "Dry eye is a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage." The report emphasized the instability of tear film and the importance of visual dysfunction in association with dry eyes, highlighting the importance of the evaluation of tear film stability. This report also discussed the concept of tear film-oriented therapy, which stemmed from the definition, and which is centered on provision of insufficient components in each tear film layer and ocular surface epithelium. The current ADES report proposes a simple classification of dry eyes based on the concept of tear film-oriented diagnosis and suggests that there are three types of dry eye: aqueous-deficient, decreased wettability, and increased evaporation. It is suggested that these three types respectively coincide with the problems of each layer: aqueous, membrane-associated mucins, and lipid/secretory mucin. Although each component cannot be quantitatively evaluated with the current technology, a practical diagnosis based on the patterns of fluorescein breakup is recommended. The Asia Dry Eye Society classification report suggests that for a practical use of the definition, diagnostic criteria and classification system should be integrated and be simple to use. The classification system proposed by ADES is a straightforward tool and simple to use, only through use of fluorescein, which is available even to non-dry eye specialists, and which is believed to contribute to an effective diagnosis and treatment of dry eyes.

Defining Dry Eye from a Clinical Perspective.

Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: "Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities." The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.

[Rethinking clinical significance of tear osmolarity measurement for dry eye diagnosis and therapeutic efficacy evaluation].

Increased tear osmolarity is one of the core mechanisms of dry eye and has been considered as an important diagnostic criterion, if not"gold standard", of dry eye. However, recent studies showed the limitations of tear osmolarity measurement not only in the diagnosis, but also in the therapeutic efficacy evaluation of dry eye. The clinical significance of tear osmolarity measurement has become a hot topic of argument. Herein, we review the publications on this topic and try to find the underlying causes of such argument.

Urban Particulate Matter Triggers Meibomian Gland Dysfunction.

Purpose: The meibomian gland (MG), as the largest modified sebaceous gland, is potentially damaged by urban particulate matter (UPM) based on epidemiological evidence, but the specific experimental mechanisms remain unknown. This study investigated the effects of UPM on MG dysfunction (MGD) in rodent models. Methods: Female C57BL/6J mice received eye drops containing UPM suspension or PBS for 14 days. The proliferative capacity and progenitor of MG were evaluated by immunofluorescence. Cell apoptosis was confirmed by TUNEL assay, along with the analysis of caspase family expression. Lipid accumulation was visualized by Oil Red O staining and LipidTox staining. Ductal hyperkeratinization, neutrophil infiltration, and pyroptosis activation were detected through immunostaining. The relative gene expression and signaling pathway activation were determined by Western blot analysis. Results: Administration of UPM caused MGD-like clinical signs, manifested as distinct corneal epithelial erosion, increased MG orifice occlusion, and glandular dropout. UPM exposure significantly induced progenitor loss, cellular apoptosis, and lipogenic disorder in MG, by reducing P63/Lrig1 expression and increasing cleaved caspase-8, -9, and -3 and meibum lipogenic protein (HMGCR/SREBP-1) expression. UPM-treated mice exhibited ductal hyperkeratinization and neutrophil recruitment. Simultaneously, pyroptosis was motivated, as indicated by the heightened expression of NLRP3 and the cleavage of caspase-1 and -4 and gasdermin D, as well as the increase in IL-1ß and IL-18 downstream. The underlying pathological mechanisms of UPM involve the phosphorylation of mitogen-activated protein kinase and nuclear factor-κB. Conclusions: These results provided direct evidence for the toxicity of UPM in MG. UPM-induced activation of pyroptosis and mitogen-activated protein kinase/nuclear factor-κB signaling pathway might account for the inflammatory MGD.

Anterior Segment Optical Coherence Tomography Imaging of the Lacrimal Gland in Patients With Chronic Ocular Graft-Vs-Host Disease.

PURPOSE: The purpose of this study was to explore the image characteristics of the palpebral lobe of the lacrimal gland in patients with chronic ocular graft-vs-host disease (coGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) using anterior segment optical coherence tomography (AS-OCT). METHODS: This comparative cross-sectional study included 32 patients with coGVHD, 21 patients with severe aqueous tear deficiency dry eye, and 20 healthy control subjects. All subjects underwent an AS-OCT examination on the palpebral lobe of the lacrimal gland. The main outcomes are the number of visible gland lobules, ducts, and blood vessels and the proportions of mille crêpe-like structures in the AS-OCT images. RESULTS: Compared with the other 2 groups, patients with coGVHD had significantly more blood vessels and slightly less visible lobules and ducts (all P <0.05) in the palpebral lacrimal gland. Mille crêpe-like structures were observed only in the coGVHD group. Number of blood vessels was positively correlated with time after allo-HSCT (ß: 0.14, 95% confidence interval [CI], 0.01-0.26). Mille crêpe-like structure was positively correlated with coGVHD severity (odds ratio: 9.07, 95% CI, 1.75-16.38) and time after allo-HSCT (odds ratio: 0.13, 95% CI, 0.03-0.23). CONCLUSIONS: We reported the AS-OCT characteristics of the palpebral lacrimal gland in coGVHD and found an increased number of blood vessels and mille crêpe-like structures. AS-OCT has the potential in the disease monitoring of coGVHD.

Delayed diagnosis of ocular graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

PURPOSE: To investigate the delayed diagnosis of chronic ocular graft-versus-host disease (coGVHD) after allogeneic hematopoietic stem cell transplantation (alloHCT), and further analyze potential confounding factors. METHODS: This cross-sectional study included 118 patients newly diagnosed as coGVHD after alloHCT at Zhongshan Ophthalmic Center, Sun Yat-sen University. All participants finished the flow path of medical history taking, detailed ophthalmological examination and questionnaire-based survey. coGVHD was diagnosed and graded by International Chronic Ocular GVHD Consensus Group (ICOGCG) criteria. Lag time of diagnosis was defined as interval between noting of ocular symptoms and confirmed diagnosis of coGVHD (TN-D). We further compared the clinical parameters between groups categorized by the median TN-D as medium and long delay groups. RESULTS: The median TN-D was 6.3 [IQR 2.8-14.5] months. Most coGVHD patients underwent delayed diagnosis of coGVHD longer than 3 months (70 %, 83 of 118), with 90 of 118 diagnosed as severe coGVHD (76 %). The long delay group exhibited higher ICOGCG scores (10 [IQR 9-10.5] vs. 9 [IQR 8-10], P = 0.039) and more pronounced ocular signs, including conjunctival injection, meibomian gland loss, fibrotic tarsal conjunctiva, symblepharon, and corneal complications (all P < 0.05). Delayed diagnosis was strikingly correlated with seeking ophthalmic medical care twice or more prior to diagnosis (adjusted OR = 5.42, 95%CI: 1.40-21.06, P = 0.015) and accurate knowledge of ocular discomfort symptoms in coGVHD (adjusted OR = 0.29, 95%CI: 0.08-1.00, P = 0.050). CONCLUSIONS: Delayed diagnosis of coGVHD, associated with disease severity, was common among alloHCT recipients in southern China. Improving patient education and the awareness of ophthalmologists may facilitate early diagnosis of coGVHD.

Effect of laughter exercise versus 0.1% sodium hyaluronic acid on ocular surface discomfort in dry eye disease: non-inferiority randomised controlled trial.

OBJECTIVE: To assess efficacy and safety of laughter exercise in patients with symptomatic dry eye disease. DESIGN: Non-inferiority randomised controlled trial. SETTING: Recruitment was from clinics and community and the trial took place at Zhongshan Ophthalmic Center, Sun Yat-sen University, the largest ophthalmic centre in China, between 18 June 2020 to 8 January 2021. PARTICIPANTS: People with symptomatic dry eye disease aged 18-45 years with ocular surface disease index scores ranging from 18 to 80 and tear film break-up time of eight seconds or less. INTERVENTIONS: Participants were randomised 1:1 to receive laughter exercise or artificial tears (0.1% sodium hyaluronic acid eyedrop, control group) four times daily for eight weeks. The laughter exercise group viewed an instructional video and participants were requested to vocalise the phrases "Hee hee hee, hah hah hah, cheese cheese cheese, cheek cheek cheek, hah hah hah hah hah hah" 30 times per five minute session. Investigators assessing study outcomes were masked to group assignment but participants were unmasked for practical reasons. MAIN OUTCOME MEASURES: The primary outcome was the mean change in the ocular surface disease index (0-100, higher scores indicating worse ocular surface discomfort) from baseline to eight weeks in the per protocol population. The non-inferiority margin was 6 points of this index score. Main secondary outcomes included the proportion of patients with a decrease from baseline in ocular surface disease index score of at least 10 points and changes in dry eye disease signs, for example, non-invasive tear break up time at eight weeks. RESULTS: 299 participants (mean age 28.9 years; 74% female) were randomly assigned to receive laughter exercise (n=149) or 0.1% sodium hyaluronic acid (n=150). 283 (95%) completed the trial. The mean change in ocular surface disease index score at eight weeks was -10.5 points (95% confidence interval (CI) -13.1 to -7.82) in the laughter exercise group and -8.83 (-11.7 to -6.02) in the control group. The upper boundary of the CI for difference in change between groups was lower than the non-inferiority margin (mean difference -1.45 points (95% CI -5.08 to 2.19); P=0.43), supporting non-inferiority. Among secondary outcomes, the laughter exercise was better in improving non-invasive tear break up time (mean difference 2.30 seconds (95% CI 1.30 to 3.30), P<0.001); other secondary outcomes showed no significant difference. No adverse events were noted in either study group. CONCLUSIONS: The laughter exercise was non-inferior to 0.1% sodium hyaluronic acid in relieving subjective symptoms in patients with dry eye disease with limited corneal staining over eight weeks intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04421300.

Comparative single-cell transcriptomic analysis across tissues of aging primates reveals specific autologous activation of ZNF281 to mitigate oxidative stress in cornea.

Reactive oxygen species (ROS) and oxidative stress accelerate cellular aging, but their impact on different tissues varies. The cornea, known for its robust antioxidant defense systems, is relatively resistant to age-related diseases like cancer. However, the precise mechanisms by which the cornea maintains ROS homeostasis during aging remain unclear. Through comparative single-cell transcriptomic analysis of the cornea and other tissues in young and old nonhuman primates, we identified that a ZNF281 coding transcriptomic program is specifically activated in cornea during aging. Further investigation revealed that ZNF281 forms a positive feedback loop with FOXO3 to sense elevated levels of ROS and mitigate their effects potentially by regulating the mitochondrial respiratory chain and superoxide dismutase (SOD) expression. Importantly, we observed that overexpression of ZNF281 in MSCs prevented cellular senescence. In summary, these findings open up possibilities for understanding tissue-specific aging and developing new therapies targeting ROS damage.

Plasmonic Au-MoS2 Nanohybrids Using Pulsed Laser-Induced Photolysis Synthesis for Enhanced Visible-Light Photocatalytic Dye Degradation.

The Au-MoS2 nanocomposites (NCPs) exhibit excellent visible-light photocatalytic activity and potential applications in the photocatalytic degradation of organic dyes. In this study, an Au-MoS2 heterojunction structure with Au nanoparticles (NPs) deposited on MoS2 nanosheets was synthesized via the pulsed laser-induced photolysis method. The influence of Au content on the photocatalytic performance was systematically investigated, and the working mechanism under visible light excitation was elucidated. The optimal Au-MoS2 NCPs exhibited efficient degradation of methylene blue (MB) dye, mainly attributed to the plasmon resonance effect of Au NPs which facilitated the visible light harvesting and hot electron injection. The Au/MoS2 interface promoted the separation and transfer of photogenerated charge carriers. The electrostatic adsorption between positively charged MB molecules and the negatively charged MoS2 surface favored the affinity toward active sites. Furthermore, the photogenerated electrons and holes participated in generating reactive oxygen species such as superoxide and hydroxyl radicals, which initiated the oxidative degradation of MB. The PLIP-introduced Au NPs not only endowed the material with excellent visible light responsivity but also possibly modulated the electronic structure and photocatalytic active sites of MoS2 through an intrinsic effect, providing new insights for further enhancing the photocatalytic performance of Au-MoS2 NCPs.

Cytarabine chemotherapy induces meibomian gland dysfunction.

PURPOSE: Cytarabine (Ara-C) chemotherapy causes symptoms resembling meibomian gland dysfunction (MGD), suggesting potential associations between Ara-C and MGD. In this study, the pathological effects of Ara-C on MGD were investigated in a rodent model. METHODS: Mice received Ara-C with or without rosiglitazone (PPARγ agonist) for 7 consecutive days. Slit-lamp biomicroscope was used for ocular examinations. Immunofluorescence detected acinar cell proliferation, differentiation, and ductal keratinization in the meibomian gland (MG). Lipid accumulation was evaluated by Oil Red O and LipidTox staining. Lipogenic status, FoxO1/FoxO3a cellular localization, and oxidative stress were visualized via immunohistochemistry. Western blotting assessed relative protein expression and AKT/FoxO1/FoxO3a pathway phosphorylation. RESULTS: Ara-C (50 mg/kg) did not affect mouse survival but induced damage to ocular surface microenvironment, including corneal epithelial defects, MG orifice plugging and acinar dropout, and lacrimal gland (LG) dysfunction. Ara-C intervention inhibited proliferation and caused progenitor loss in the MG, as evidenced by reduced PCNA + labeling and P63+/Lrig1+ basal cell numbers. The MG ducts of Ara-C-treated mice exhibited marked dilatation, lipid deposition, and hyperkeratinization (K1/K10 overexpression). Ara-C disrupted MG lipid metabolism by downregulating PPARγ and its downstream lipogenic targets AWAT2/SOAT1/ELOVL4 and upregulating HMGCR. Dephosphorylation of AKT and the subsequent nuclear translocation of FoxO1/FoxO3a contributed to Ara-C-induced PPARγ downregulation. Ara-C triggered oxidative stress with increases in 4-HNE and 8-OHdG and Keap1/Nrf2/HO-1/SOD1 axis dysregulation. Rosiglitazone treatment ameliorated MGD-associated pathological manifestations, LG function, MG lipid metabolism, and oxidative stress in Ara-C-exposed mice. CONCLUSIONS: Systemic Ara-C chemotherapy exerted topical cytotoxic effects on the ocular surface, and PPARγ restoration by rosiglitazone mitigated Ara-C-induced MGD alterations.