Ferroptosis plays a crucial role in lung diseases, including bronchopulmonary dysplasia (BPD), but its involvement in BPD pathogenesis and impact on pulmonary vascular development remain unclear. This study investigated ferroptosis in BPD and evaluated sodium propionate’s (SP) therapeutic potential in regulating ferroptosis and promoting pulmonary angiogenesis. Serum markers of ferroptosis and oxidative stress were measured in preterm infants (< 32 weeks) with and without BPD. BPD rats and human umbilical vein endothelial cell (HUVEC) models were established through hyperoxia induction. Sprague-Dawley rats were randomly assigned to four experimental groups: normoxia control (CON), normoxia with sodium propionate treatment (CON + SP), hyperoxia-induced BPD model (BPD), and hyperoxia with SP treatment (BPD + SP). In vitro experiments, HUVEC cells were respectively treated with hyperoxia and SP, and transfected with siRNA to detect the role of the SLC7A11/GPX4 pathway. Ferroptosis was evaluated by measuring lipid peroxidation (LPO), malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH). Angiogenesis-related genes (VEGFA, CD31) and angiogenic ability were evaluated by Western blot, RT-PCR and in vitro experiments. Serum LPO and iron levels were significantly elevated in BPD infants. SP alleviated lung injury in BPD rats. SP significantly inhibited PTGS2 expression, decreased ROS, MDA, and LPO levels, and increased GSH in BPD models. It also enhanced mRNA and protein expression of SLC7A11, GPX4, VEGFA, and CD31. Silencing SLC7A11 or GPX4 counteracted SP’s protective effects in hyperoxia-exposed HUVECs. Ferroptosis contributes to BPD pathogenesis. SP effectively inhibits ferroptosis and promotes angiogenesis in experimental BPD models, suggesting a novel avenue for potential combination therapies in BPD treatment.

BACKGROUND/AIMS:Retinitis pigmentosa (RP) is characterised by progressive photoreceptor degeneration accompanied by vascular abnormalities. We have previously demonstrated that minocycline exhibits therapeutic potential in RP. This trial aimed to evaluate its neurovascular protective effects. METHODS:Patients with RP were enrolled and administered 100 mg of minocycline once daily for 12 months. A total of 32 eyes from 16 participants were included. The primary outcomes were changes in retinal and choroidal vasculature, including vessel density, lacunarity, foveal avascular zone (FAZ) area, fluorescein angiography (FA) score and subfoveal choroidal thickness (SFCT). The secondary outcomes included changes in photoreceptor structure and function, including ellipsoid zone width, best-corrected visual acuity (BCVA), mean macular sensitivity, mean deviation (MD) and error score. Adverse events were recorded. Additionally, Rd1 mice were used to further investigate the vascular effects of minocycline. RESULTS:After 12-month minocycline treatment, RP patients exhibited increased vessel density in both the retinal superficial capillary plexus (SCP) and retinal deep capillary plexus (DCP), accompanied by reduced FAZ area and decreased lacunarity in the SCP and DCP. FA score and SFCT remained stable, as did all secondary outcomes. A total of 24 adverse events were reported in 8 patients, and all resolved spontaneously without additional intervention. Additional experiments in Rd1 mice demonstrated improved retinal vascular abnormalities and preserved blood-retinal barrier integrity, accompanied by upregulated expression of tight junction proteins. CONCLUSIONS:Oral 100 mg minocycline once daily for 12 months was beneficial to protect vascular integrity and stabilise photoreceptor structure and function with good tolerability.

Transient superficial retinal infiltrates are a recognised feature of Behçet uveitis, but their capacity to mimic infectious retinitis is under-emphasised. We describe the diagnostic pitfalls and multimodal imaging appearances of these infiltrates, and summarise practical clues for distinguishing them from infectious retinitis. Retrospective case series of five patients with Behçet uveitis who developed multiple transient superficial retinal infiltrates between May 2020 and October 2025. Assessments included visual acuity, slit-lamp examination, fundus photography, fluorescein angiography (FFA), optical coherence tomography (OCT), and in selected cases, OCT angiography (OCTA) and indocyanine green angiography (ICGA). Five patients (3 men, 2 women; aged 24–63 years) were included. The infiltrates were unilateral in all five; in one the underlying uveitis was bilateral. They were present at first presentation in three patients and developed during follow-up in two. Three had been misdiagnosed with infectious uveitis and given empirical antimicrobial therapy before referral; the median interval from first presentation to the correct diagnosis was 3.6 months (range 1.4–7.8). Retinal vascular leakage was present in all patients, was diffuse, and showed no spatial correspondence to the infiltrates. OCT showed hyperreflectivity predominantly of the inner retina with a preserved retinal pigment epithelium (RPE). Inflammatory retinal and vitreous deposits were seen in two patients, and OCTA, performed in one, showed capillary non-perfusion corresponding to the affected retina. All infiltrates resolved within days to weeks without chorioretinal scarring, and recurrences were common. Spontaneous regression with concurrent new lesion formation (Case 1) and residual inner-retinal thinning in near periphery (Case 2) were both documented on imaging. Behçet uveitis can present with transient superficial retinal infiltrates that mimic infectious retinitis. Supportive features include inflammatory retinal and vitreous deposits, resolution without chorioretinal scarring, retinal vascular leakage unrelated in distribution to the infiltrates, and inner-retinal hyperreflectivity with a preserved RPE; none excludes infection, and investigation for infectious causes remains necessary. Recurrent transient superficial retinal infiltrates, particularly when accompanied by subtle retinal vascular leakage without a classic diffuse fern-like pattern, should raise suspicion of Behçet uveitis and prompt directed questioning about recurrent oral and genital ulceration.

Background:The optimal management of patent ductus arteriosus (PDA), particularly hemodynamically significant PDA (hsPDA), in extremely preterm infants remains highly controversial. This study aimed to evaluate whether early ibuprofen for hsPDA was associated with clinically meaningful outcomes in extremely preterm infants and whether this association was modified by clinical tolerance to PDA-related hemodynamic changes. Methods:This prospective cohort study used data from the Chinese Multicenter Collaboration Platform for PDA in Extremely Preterm Infants and included infants with a gestational age ≤29+6 weeks who were admitted between November 2024 and September 2025 and diagnosed with hsPDA by echocardiography on postnatal days 3-5. A target trial emulation framework was applied, with the day of echocardiography as time zero and a 2-day grace period. Ibuprofen initiation within the grace period defined treatment. Inverse probability of treatment weighting was used to balance baseline characteristics and emulate random treatment assignment. Infants were stratified as clinically tolerant and intolerant based on respiratory and hemodynamic support at the time of echocardiography. Outcomes included mortality and major prematurity-related morbidities. Results:A total of 239 infants were included, of whom 65 received ibuprofen within the grace period and 174 did not. In the overall cohort, ibuprofen was associated with a lower, but not statistically significant, risk of mortality [risk ratio (RR), 0.51; 95% confidence interval (CI): 0.25-1.02]. In analyses stratified by clinical tolerance, ibuprofen was associated with a reduced risk of mortality only in the intolerant subgroup (RR, 0.18; 95% CI: 0.06-0.51), but not in the tolerant subgroup (RR, 0.96; 95% CI: 0.23-4.00). Conclusions:The effect of ibuprofen for hsPDA in extremely preterm infants appears heterogeneous, with differences in mortality associations observed across clinical tolerance subgroups. These findings are exploratory and warrant confirmation in future adequately powered randomized trials.

The imbalance between pathogenic Th1/Th17 cells and regulatory T cells (Tregs) is a central mechanism in central nervous system (CNS) autoimmune diseases, including autoimmune uveitis (AU) and multiple sclerosis. Tyrosine kinase 2 (TYK2) mediates signaling downstream of multiple cytokines implicated in CD4 + T cell differentiation, yet its subset-specific activation and therapeutic potential in CNS autoimmunity remain unclear. Here, we investigated the subset-specific activation of TYK2 and evaluated the therapeutic potential of selective TYK2 inhibition in CNS autoimmune diseases. TYK2 phosphorylation was examined in CD4 + T cell subsets from AU patients and from experimental autoimmune uveitis (EAU) and encephalomyelitis (EAE) models. The therapeutic effects and mechanisms of a selective TYK2 inhibitor were assessed using flow cytometry, single-cell RNA sequencing, adoptive transfer, in vitro cellular assays, and ex vivo stimulation of patient peripheral blood mononuclear cells. TYK2 phosphorylation was preferentially activated in Th1 and Th17 cells compared with Tregs in both patients and disease models. TYK2 inhibition significantly reduced clinical and histopathological scores in EAU and EAE, suppressing Th1/Th17 differentiation and production of IFN-γ and IL-17A, while Treg proportion and function remained intact. Mechanistically, IFN-α/β, IL-12, and IL-23—but not IL-2—induced TYK2 phosphorylation in CD4 + T cells. Accordingly, TYK2 blockade selectively inhibited STAT1/2/3/4 activation downstream of these cytokines without affecting IL-2-induced STAT5 phosphorylation in Tregs. These lineage-selective effects were confirmed in peripheral blood mononuclear cells from AU patients. TYK2 acts as a lineage-selective therapeutic target in CNS autoimmunity. Its inhibition suppresses pathogenic Th1/Th17 responses while preserving Treg proportion and function by targeting cytokine-specific signaling pathways, thereby rebalancing the effector–regulatory immune axis.

Neonatal respiratory distress syndrome (RDS) is a critical disease caused by pulmonary surfactant (PS) deficiency, leading to respiratory distress soon after birth. Comprehensive perinatal interventions can significantly improve outcomes. The core goal of RDS management is to maximize infant survival while minimizing lung injury. Based on the latest evidence, European neonatologists and obstetricians jointly developed the "European consensus guidelines on the management of respiratory distress syndrome: 2025". The guidelines provide evidence-based clinical recommendations for the management of RDS in preterm infants, covering the entire pathway from prenatal interventions, delivery room stabilization, surfactant administration, non-invasive and invasive respiratory support, to comprehensive supportive care. The aim is to reduce the incidence of lung injury through targeted interventions, increase survival rates, and improve long-term neurodevelopmental outcomes. This article interprets the 2025 guidelines in comparison with the 2022 version, aiming to improve the clinical competence of Chinese neonatologists in the diagnosis and treatment of RDS.

Robust mitochondrial ROS production induces extensive double-strand breaks (DSBs) in telomeric DNA of effector T cells, where the DNA repair machinery is rapidly hyper-evoked to sense and ligate DSBs during the respiratory burst. However, whether effector T cells can exploit the DNA repair system to simultaneously potentiate their functional activation remains largely unknown, especially in the context of autoimmunity. Here, we demonstrate that non-homologous end joining (NHEJ), a predominant mechanism of DNA repair, is highly activated in pathogenic T helper 17 (pTh17) cells and exerts a previously unrecognized effect on shaping the pathogenic nature of pTh17s to trigger autoimmunity. Mechanistically, the perception of DSBs by KU proteins facilitates auto-phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which stabilizes RORγt to bind to the promoters of effector-gene loci, thus initiating the pTh17 effector program to induce autoimmunity. Using mass spectrometry and transcriptome analyses, we identified IER2 as a novel NHEJ factor that potentiates DNA-PKcs kinase activity in response to IL-23R stimulation, which is necessary for shaping Th17 pathogenicity. Therefore, targeting the immuno-pattern of the NHEJ system shows potential for the treatment of autoimmune diseases.

Limosilactobacillus reuteri (L. reuteri) FN041, a probiotic isolated from breast milk, exhibits immunomodulatory effects against allergic and immune-related diseases. However, the preventive and therapeutic potential of L. reuteri FN041 in ulcerative colitis (UC) remains unreported. This study investigates the protective effects of L. reuteri FN041 in a mouse model of colitis induced by dextran sodium sulfate (DSS). Significant alleviation of colitis symptoms was observed with L. reuteri FN041 treatment, demonstrated by decreased weight loss, reduced colon shortening, and lower Disease Activity Index and Histological Index scores. Inflammation and oxidative stress levels were reduced, as shown by lower local and systemic IL-6, elevated IL-10 and increased colonic malondialdehyde levels. The expression of tight junction proteins, indicators of intestinal mucosal permeability, increased, while serum lipopolysaccharide and D-lactate levels decreased. Fecal metagenomic analysis indicated that therapeutic effects of L. reuteri FN041 may be microbiota-dependent, demonstrated by increased beneficial gut bacteria and decreased bacteria associated with inflammation and tissue damage. Metabolomic analysis of cecal contents revealed that 1-myristoyl-sn-glycero-3-phosphocholine, 4-androsten-17-beta-ol-3-one glucosiduronate, gamma-L-glutamylputrescine, fosfomycin and alpha-cyperone were metabolite markers significantly disrupted by DSS and partially restored by probiotics. Correlation analysis among clinical colitis parameters, metagenomics, and metabolomics confirmed the interdependence of these factors. Thus, L. reuteri FN041 may alleviate colitis by reshaping the intestinal microbial flora and metabolites. In summary, L. reuteri FN041 represents a promising probiotic for UC prevention and treatment.

Food allergy is an emerging global health concern with limited treatment options. This study evaluated the efficacy of Limosilactobacillus reuteri(L. reuteri) FN041 in a cow's milk beta-lactoglobulin-induced murine model of food allergy. Daily oral administration of L. reuteri FN041 alleviated allergic symptoms, normalized body temperature, and reduced lung inflammation. L. reuteri FN041 lowered serum IgE levels, rebalanced Th1/Th2 cytokines, and expanded splenic regulatory T cells. Intestinal barrier integrity was improved, as evidenced by restored tight junction proteins and enhanced antioxidant capacity. Although the overall gut microbial alpha- and beta-diversity remained unchanged, L. reuteri FN041 selectively enriched Duncaniella muris and Muribaculum gordoncarteri, while suppressing Waltera intestinalis and Lacrimispora xylanisolvens. Metabolomic profiling revealed an upregulation of anti-inflammatory flavonoids, particularly naringenin-7-O-glucoside. Mechanistically, L. reuteri FN041 inhibited AKT/mTOR and NF-kappa B signaling. These findings suggest that L. reuteri FN041 is a promising biotherapeutic for food allergy, acting through immune modulation, gut barrier protection, microbiota remodeling, and oxidative stress mitigation.

PURPOSE:To evaluate the efficacy and safety of initial treatment combining corticosteroids and 15 mg/week methotrexate (MTX) for acute Vogt-Koyanagi-Harada disease (VKH). METHODS:A retrospective, longitudinal observational case series was conducted. Newly onset VKH patients received corticosteroids combining 15 mg/week MTX, and follow-up period ≥ 6 months were consecutively enrolled. Main outcome measures were the corticosteroid-sparing effect, improvements of visual function, changes of ophthalmic characteristics and recurrences. RESULTS:In this case series, 39 acute VKH patients (78 eyes) received corticosteroids combining oral MTX as first-line therapy. All the participants achieved corticosteroid-sparing effect and thereafter withdrew corticosteroids. At the last follow-up, 87.2% patients had managed to discontinue MTX. The median period of corticosteroids treatment was 9.2 (8.0-13.3) months, and the mean interval of MTX using was 18.0 ± 6.1 months. Eventually, 83.3% of eyes achieved visual acuity of 0.0 logMAR or better. All the eyes had retinal reattachment and the choroidal thickness significantly decreased. Sun-set glow fundus was identified in 18 eyes (23.1%). The microvascular perfusion was still defect despite the well-controlled inflammation. Recurrence occurred in five patients, with only one progressing to a chronic recurrent stage. No severe adverse event was observed. CONCLUSION:Initial treatments with corticosteroids tapered over approximately 9 months and oral methotrexate (15 mg/week) for 18 months in acute VKH patients led to favorable visual outcomes, fairly low recurrence and good safety profile. These findings support the consideration of this combined treatment for acute VKH but should be tempered by recognizing the retrospective and non-control design.

Bronchopulmonary dysplasia (BPD) involves macrophage-driven immunoinflammation, while macrophage-derived exosomes act as key extracellular vehicles linking macrophage-driven inflammation with tissue injury. Emerging evidence suggests that Lipoxin A4 (LXA4) modulates macrophage immune responses. However, the precise role of LXA4 in regulating macrophage function in BPD and its underlying mechanisms remains unclear. Neonatal rats were exposed to 85% hyperoxia to establish a BPD model. LXA4 or M2-polarized macrophage-derived exosomes (M2-exo) were injected intraperitoneally, and pulmonary inflammation, macrophage polarization and pyroptosis were examined. M2-exo were co-cultured with type II alveolar epithelial cells (AT2) to further validate the animal experimental findings and explore underlying mechanisms. Here, we find that monocyte-derived macrophages were activated in BPD. LXA4 significantly ameliorated lung tissue injury and pyroptosis by promoting M2-exos release. Single-cell transcriptomic profiling revealed altered macrophage-epithelial cell interactions in BPD lungs. Mechanistic studies demonstrated that M2-exo-derived miR-25-5p alleviated AT2 pyroptosis, which targeted nuclear receptor binding protein 2 (NRBP2) and downregulated the PI3K/AKT pathway. Additionally, PI3K inhibition (LY294002) or miR-25-5p knockdown reversed these protective effects. This study proved that LXA4 promotes M2 macrophage polarization and enhances exosomal miR-25-5p release, thereby inhibiting pyroptosis via the NRBP2/PI3K/AKT axis and ameliorating BPD lung injury. These findings elucidate the lung-protective mechanism of LXA4 and highlight a novel macrophage-AT2 cross-talk in BPD, providing new therapeutic strategies for BPD-related lung injury.

Neonatal acute kidney injury (AKI) is associated with poor clinical outcomes. Consequently, this study was designed to explore the prenatal and postnatal risk factors in Chinese extremely low gestational age neonates (ELGANs). This retrospective study included all ELGANs (born between 23—0/7 and 27—6/7 weeks of gestation) hospitalized from January 2019 to December 2022. These premature babies were divided into the AKI group (n = 39) and the non-AKI group (n = 76) according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. AKI most frequently occurred in the first 10 days of life (median: 8th day, quartile range: 6th – 10th day). Most infants (61.54

Autoimmune uveitis (AU) is a sight-threatening ocular autoimmune disorder that often manifests as retinal vasculitis. Increased neutrophil infiltration around retinal vessels has been reported during the progression of AU, while how they function is not fully recognized. Neutrophil extracellular traps (NETs), produced by activated neutrophils, have been suggested to be detrimental in autoimmune diseases. Here, we found that NETs were elevated in patients with active AU, and this was verified in an experimental AU (EAU) mouse model. Depletion of neutrophils or degradation of NETs with deoxyribonuclease-I (DNase I) could decrease CD4+ effector T cell (Teff) infiltration in retina and spleen to alleviate EAU. Moreover, we found that the expression of adhesion molecules, selectin, and antigen-presenting molecules was elevated in EAU retina and in retinal microvascular endothelial cells (RMECs) cocultured with NETs. The stimulated RMECs further facilitated CD4+ T cell adhesion, activation, and differentiation into Teffs. Mechanistically, NETs trigger RMEC activation by hastening cell senescence through the cyclic GMPAMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Slowing down senescence or inhibiting the cGAS/STING pathway in RMECs reduces the activation and differentiation of CD4+ T cells. These results suggest a deleterious role of NETs in AU. Targeting NETs would offer an effective therapeutic method.

Bruton’s tyrosine kinase (BTK), a key regulator of immune responses, has been extensively studied in B cells and innate immunocytes. Small-molecule BTK inhibitors (BTKi) have shown remarkable efficacy in multiple preclinical and clinical studies for autoimmune diseases via mediating the activation of B cells and innate immunocytes. Recent studies have demonstrated functional BTK expression in T cells, contributing to T cell activation and the pathogenesis of aplastic anemia. Whether BTK is involved in uveitis, the CD4+ T cell-mediated autoimmune disease, and whether it could be a therapeutic target remain unclear. We assessed BTK expression and phosphorylation levels in CD4+ T cells from Autoimmune uveitis (AU) patients and experimental autoimmune uveitis (EAU) mice. By administering BTKi to EAU mice, we evaluated its effects on ocular and systemic inflammation levels through fundus photography, histopathology, qPCR, and flow cytometry. In vitro, we assessed its impact on the Th1/Th17/Treg differentiation, and the pathogenicity of CD4+ T cells. Transcriptomic sequencing and flow cytometry were employed to explore the potential mechanism by which BTK regulates CD4+ T cells. BTK expression and activation were upregulated in CD4+ T cells from AU patients and EAU mice. BTK inhibition suppressed the polarization of Th17 and Th1 cells, but not Treg differentiation. BTK inhibition upregulated the PPAR-γ signaling, alleviating oxidative stress and inflammatory responses in CD4+ T cells, thereby reducing ocular and systemic inflammation in EAU mice. Additionally, BTKi exhibited significant anti-inflammatory effects in CD4+ T cells from AU patients. This study demonstrates the critical role of BTK in CD4+ T cell-driven AU. BTK inhibition ameliorates oxidative stress and inflammatory responses via PPAR-γ involved signaling in CD4+ T cells and suppresses their differentiation to Th1/Th17 to restore immune homeostasis, thereby mitigating AU. These findings identify BTK as a potential therapeutic target and provide a theoretical foundation for the clinical application of BTKi in AU.

Background and aim:Bronchopulmonary dysplasia (BPD) is one of the most important complications of very preterm infants. This study was to investigate changes in the intestinal microbiota of very preterm infants with BPD. Methods:We enrolled 50 very preterm infants at the gestational age of 24+0-31+6 weeks, categorizing them into the BPD group and control group, and fecal samples were collected on days 1, 7, 14, 21, and 28, respectively. Finally, 30 preterm infants were left after excluding 20 preterm infants. We tested and analyzed 16S rDNA of bacteria and short-chain fatty acids (SCFAs) within the feces. Results:The BPD group possessed a higher abundance of Ureaplasma urealyticum (UU) and a lower abundance of Bacteroidota than the control on day 1. The differences in intestinal microbiota were reduced on days 7 and 14, and no difference in SCFAs existed on day 14. New differences emerged over time, with a significant decrease of Veillonella dispar in the BPD group than in the control group on day 28, which showed a continuous decline in the BPD group over time. Conclusion:Intestinal microbiota dysbiosis existed in very preterm infants with BPD. The increased abundance of UU on day 1 and the decrease of Veillonella dispar on day 28 might increase the risk of BPD.

Purpose:The purpose of this study was to explore the underlying mechanism that Th17-like T follicular helper cells (Tfh) orchestrated by STING signaling have a pathogenic role in experimental autoimmune uveitis (EAU). Methods:The differences of transcriptome and gene ontology (GO) pathway of Tfh between EAU and control mice were analyzed by single-cell RNA sequence (scRNA-seq) and bulk RNA sequence. Additionally, draining lymph nodes (DLNs) were extracted to verify the expression of IL-17A and IFN-γ in Tfh from EAU and control mice by flow cytometry. Then, the scRNA-seq and flow cytometry were used to explore the different proportion of Tfh between STING deficiency (Sting-/-) mice and wild type (WT) mice. In vitro, naïve CD4+ T cells were isolated from Sting-/- mice and WT mice to induce the Tfh under the induction condition. In addition, flow cytometry was used to detect the different induction ratio and the IL-17A expression between 2 groups of naïve CD4+ T cells. Results:Compared with control mice, marked increase of Tfh was observed in EAU, accompanied by elevated levels of Th1 and Th17 cells. Moreover, Th17-related genes, such as Rorc, Il22, Il23r, Il17a, and Il17f, and the corresponding GO pathways were upregulated in Tfh from EAU. The scRNA-seq showed that a higher proportion of Tfh was observed in the DLNs from Sting-/- mice than WT mice, which was verified by flow cytometry. When STING was knocked out, the Tfh was characterized with upregulated Th17-related phenotype in vivo, and there was a higher induction ratio of Tfh whose IL-17A expression was significantly increased in vitro. Notably, the STING expression of CD4+ T cells was downregulated in the EAU. STING-deficient EAU mice displayed more severe retinal inflammation, characterized by massive infiltration of CD4+ T cells, including Th1 and Th17 subsets. Importantly, treatment with a STING agonist alleviated inflammation of EAU. Conclusions:Th17-like Tfh cells play a pathogenic role in the EAU. STING deficiency promotes the differentiation and phenotypic transformation of Th17-like Tfh cells, exacerbating the inflammatory response in EAU. These findings highlight the potential of targeting STING to modulate Tfh cells as a therapeutic strategy for uveitis.

BACKGROUND:Autoimmune uveitis is a sight-threatening inflammatory disease of the retina. MicroRNA-142 (miR-142) has been implicated in its pathogenesis. This study aimed to elucidate the role of miR-142 in uveitis and its underlying mechanisms. METHODS:The expression of miR-142-3p was analyzed in peripheral blood mononuclear cells from uveitis patients and in experimental autoimmune uveitis (EAU) models. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the retinal inflammation. To investigate the effects of miR-142 deficiency on uveitis development, the miR-142 knockout (miR-142-/-) mouse model was used. The miR-142-/- T cell phenotype and function were characterized using flow cytometry and single-cell sequencing for both in vivo and in vitro experiments. The Seahorse Analyzer, mitochondrial staining and electron microscope analysis were conducted to reveal the mitochondrial function and morphology. And then Luciferase Assays and Western-Blot analysis were used to explore the target of miR-142. RESULTS:We found that miR-142-3p was significantly up-regulated in uveitis and that its deletion in mice prevented EAU development. The T cell isolated from miR-142-/- mice lose its uveitogenic nature. T cell lacking miR-142 exhibited reduced numbers and attenuated pathogenicity in uveitis, characterized by decreased proliferation, increased apoptosis, and abnormal differentiation. Single-cell sequencing, energy metabolism analysis and flow cytometry analysis unveiled metabolic reprogramming in miR-142-/- T cells, with a distinct shift toward glycolysis and restrained oxidative phosphorylation. Further investigation revealed mitochondrial fission regulator 1 (MTFR1) as a direct target of miR-142. The over-expressed protein of MTFR1 in CD4+ T cells was found in miR-142-/- mice. CONCLUSIONS:Our findings highlight the indispensable role of miR-142 in maintaining T cell mitochondrial function. By modulating MTFR1, miR-142 orchestrates mitochondrial homeostasis, metabolic alterations, apoptosis susceptibility, and proliferation capacity in T cells, thereby influencing susceptibility to autoimmune uveitis.

Circadian rhythm plays a critical role in the progression of autoimmune diseases. While our previous study demonstrated the therapeutic effects of melatonin in experimental autoimmune uveitis, the involvement of circadian rhythm remained unclear. Using a light-induced circadian rhythm disruption model, we showed that disrupted circadian rhythms exacerbate autoimmune uveitis by impairing the stability and function of Treg cells. Mechanistically, we identified the core clock gene Per1, which is significantly reduced under circadian disruption, is essential for Treg cell metabolism and immunoregulatory function. This study underscores the pivotal role of circadian rhythm-related Treg cells in autoimmune disease progression.