bims-mideyd 2025-09-21 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2025–09–21
eleven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Retinitis Pigmentosa-Associated Gene TRIM49 Regulates ULK1-Mediated Autophagy and Photoreceptor Phagocytosis by the Retinal Pigment Epithelium.
Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision.
Integrative Multiomics Identifies CD64⁺ Monocytes as Potential Contributors to Age-Related Macular Degeneration.
Specialised features of melanosomes in health and disease in the retinal pigment epithelium.
Glycolysis-Histone Lactylation Crosstalk Drives TXNIP-NLRP3-Mediated PANoptosome Assembly and PANoptosis Activation Underlying Diabetic Retinopathy Pathogenesis.
Safety and tolerability of RPESC-RPE transplantation in patients with dry age-related macular degeneration: Low-dose clinical outcomes.
Targeting RPE Senescence Via Suppressing IL-6/IL-6R Signaling for Treating Retinal Degenerative Diseases.
Role of MiR-204 in controlling metabolic functions of the subretinal microglia.
Sustained Neurotrophic Factor Co-Treatment Enhances Donor and Host Retinal Ganglion Cell Survival in Mice.
TET1 Alleviates Cigarette Smoke Induced Bronchial Epithelial Cell Apoptosis Through Upregulating Nrf2.
Succinate-mediated Ufsp2 transcription promotes high glucose-stimulated pyroptosis in rat retinal Müller cells by activating NLRP3 inflammasome.

Adv Sci (Weinh). 2025 Sep 16. e12305

Retinitis Pigmentosa-Associated Gene TRIM49 Regulates ULK1-Mediated Autophagy and Photoreceptor Phagocytosis by the Retinal Pigment Epithelium.

Zhen Yi, Chaojuan Wen, Han Du, Yingwei Wang, Shuowei Chen, Jie Liu, Shuhan Zhang, Junwen Wang, Xueshan Xiao, Shiqiang Li, Xiaoyun Jia, Yi Jiang, Jiamin Ouyang, Panfeng Wang, James Fielding Hejtmancik, Wenmin Sun, Huangxuan Shen, Qingjiong Zhang.

  Autophagy is pivotal for cellular homeostasis and photoreceptor outer segment (POS) phagocytosis by the retinal pigment epithelium (RPE) in retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa (RP). Yet, the mechanism of autophagy in the RPE remains largely unknown. RP is an inherited retinal degenerative condition, whose candidate genes provide avenues for dissecting novel autophagy factors. Here, whole exome sequencing of RP patients identified biallelic variants in TRIM49, a primate-specific gene involved in autophagy, as a novel cause of RP. Among human tissues TRIM49 is highly expressed in the RPE. In human RPE cells, deficiency of TRIM49 significantly disturbs cellular homeostasis and impairs the POS phagocytosis. Importantly, suppressed basal autophagy flux is present in TRIM49-depleted RPE cells, whereas enhanced autophagy flux is present in RPE cells overexpressing TRIM49. Variations of TRIM49 after treatment with multiple autophagy modulators indicate that TRIM49 is involved in the initiation of autophagy. TRIM49 interacts with the key regulator of autophagy initiation ULK1. Deficiency of TRIM49 down-regulates and overexpression of TRIM49 up-regulates ULK1 expression. Altogether, these findings identify TRIM49 as a critical regulator of ULK1-mediated autophagy and POS phagocytosis by the RPE, suggesting that RPE autophagy is a potential therapeutic target for retinal degenerative diseases.

Keywords:  TRIM49 ; autophagy; neurodegeneration; photoreceptor phagocytosis; retinal pigment epithelium

DOI:  https://doi.org/10.1002/advs.202512305
bioRxiv. 2025 Sep 01. pii: 2025.08.30.673239. [Epub ahead of print]

Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision.

Yuancheng Ryan Lu, James C Cameron, Yan Hu, Han Shen, Shintaro Shirahama, Alexander Tyshkovskiy, Zhaoyi Chen, Jiahe Ai, Daniel Y Zhu, Margarete M Karg, Lindsey A Chew, George W Bell, Siddhartha G Jena, Yue He, Philip Seifert, Daisy Y Shu, Mohamed A Ei-Brolosy, Qiannuo Lou, Bohan Zhang, Anna M Puszynska, Xiaojie Qiu, Xiao Tian, Meredith Gregory-Ksander, Vadim N Gladyshev, David A Sinclair, Magali Saint-Geniez, Jason D Buenrostro, Catherine Bowes Rickman, Bruce R Ksander, Jonathan S Weissman.

Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.
HIGHLIGHTS: OSK-GSTA4 provides a dynamic, Tet2-independent stress-resilience axis.Functional genomics pinpoints GSTA4 as a direct downstream effector activated by OSK.RPE aging involves progressive accumulation of 4-HNE that can be detoxified by GSTA4.Enhancing GSTA4 rejuvenates RPE cells, restores vision and is associated with lifespan-extending interventions.

DOI: https://doi.org/10.1101/2025.08.30.673239
Invest Ophthalmol Vis Sci. 2025 Sep 02. 66(12): 32

Integrative Multiomics Identifies CD64⁺ Monocytes as Potential Contributors to Age-Related Macular Degeneration.

Cunzi Li, Lan Zhou, Tianyi Luo, Hongyan Sun, Ruirui Ma, Jun Wang, Ming-Ming Yang.

Purpose: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly, characterized by chronic retinal inflammation and immune dysregulation. While myeloid cells have been increasingly implicated in AMD pathogenesis, the specific immune subsets responsible remain poorly defined. This study aimed to identify causal immune cell populations and elucidate their functional roles in AMD progression.
Methods: We employed an integrative multiomics strategy encompassing Mendelian randomization (MR) analysis using genome-wide association study summary statistics, single-cell RNA sequencing (scRNA-seq) analysis of retinal pigment epithelium (RPE)/choroid tissues from patients with AMD and healthy controls (GSE230348), and flow cytometric (FCM) validation in a sodium iodate-induced dry AMD mouse model.
Results: MR analysis identified a significant causal association between CD64 expression on CD14⁻CD16⁻ monocytes and increased AMD risk (odds ratio, 1.179; P < 0.001). scRNA-seq profiling revealed a pronounced enrichment of CD14⁻CD16⁻ monocytes in AMD tissues, with FCGR1A (CD64) expression specifically localized within this subset. Pseudotime trajectory analysis demonstrated dynamic activation and differentiation states among monocyte populations in AMD. Ligand-receptor interaction modeling identified three major signaling pathways, MIF-CD74-CXCR4, IGF1-IGF1R, and SEMA3C-PLXND1, mediating interactions between CD14⁻CD16⁻ monocytes and RPE cells. FCM analysis of retinal single-cell suspensions in AMD mice confirmed a significantly higher proportion of CD64⁺ myeloid cells compared to controls.
Conclusions: This study identifies CD64⁺CD14⁻CD16⁻ monocytes as potential contributors to AMD and reveals their putative immunomodulatory crosstalk with RPE cells. These findings highlight CD64 as a promising biomarker and therapeutic target for mitigating myeloid-driven inflammation in AMD.

DOI: https://doi.org/10.1167/iovs.66.12.32
Front Cell Dev Biol. 2025 ;13 1593840

Specialised features of melanosomes in health and disease in the retinal pigment epithelium.

Dilyana Doncheva, Emily R Eden, Clare E Futter.

  This mini-review focuses on melanosome biogenesis, positioning and function in the retinal pigment epithelium (RPE) where melanosomes absorb light scatter and protect against the harmful effects of photo-oxidation. RPE melanosomes share a common biogenesis pathway with those of skin melanocytes but are made primarily embryonically and are retained by the RPE throughout life. They do however move from the cell body into the apical processes which, in mammalian RPE, is regulated by a machinery related to that regulating melanosome distribution in skin melanocytes. Melanosomes in the RPE make extensive membrane contacts with the ER and mitochondria although their role in adult RPE remains to be fully established. Albinism is associated with multiple visual defects and reduced or absent pigmentation in melanosomes has implications for long term visual health. Age-related changes in melanosomes have been implicated in retinal degenerative disease, including age-related macular disease (AMD). The lysosomes of the RPE have an unparalleled degradative burden arising from the daily phagocytosis of the distal tips of photoreceptor outer segments, which is part of a daily process of outer segment renewal. A failure to fully process the phagocytosed outer segments leads to a build-up of the toxic ageing pigment, lipofuscin, which accumulates in all ageing RPE. Melanolipofuscin also accumulates in the RPE with age and may result from melanin-mediated degradation of lipofuscin through melanin chemiexcitation. Age-related loss of melanosome-mediated protection could be an important component of age-related visual decline.

Keywords:  age-related macular degeneration; albinism; melanolipofuscin; melanosome; retinal pigment epithelium

DOI:  https://doi.org/10.3389/fcell.2025.1593840
MedComm (2020). 2025 Sep;6(9): e70351

Glycolysis-Histone Lactylation Crosstalk Drives TXNIP-NLRP3-Mediated PANoptosome Assembly and PANoptosis Activation Underlying Diabetic Retinopathy Pathogenesis.

Xiaoting Xi, Qianbo Chen, Jia Ma, Xuewei Wang, Yuxin Zhang, Qiuxia Xiong, Xiaolei Liu, Yuan Xia, Yan Li.

  Diabetic retinopathy (DR), a major cause of vision loss in adults, involves aberrant metabolism and inflammation. This study investigated the interplay between glycolysis, histone lactylation, and PANoptosis in DR using human retinal pigment epithelial (RPE) cells under high glucose and diabetic mouse models. Results demonstrated a positive feedback loop where enhanced glycolysis increased histone lactylation, which in turn further promoted glycolysis. This cycle activated the expression of thioredoxin interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), leading to PANoptosome formation and triggering PANoptosis, a coordinated cell death pathway contributing to DR pathology. Crucially, experiments manipulating TXNIP expression (via RNAi or overexpression) confirmed its central role in linking histone lactylation to NLRP3 activation and PANoptosome assembly. Importantly, inhibiting glycolysis or downregulating TXNIP successfully reduced histone lactylation, suppressed PANoptosome formation, and alleviated PANoptosis. These findings establish that the glycolysis-histone lactylation axis, mediated by TXNIP/NLRP3 signaling, drives PANoptosis in RPE cells through PANoptosome formation, playing a critical role in DR development. Targeting this specific pathway presents a promising new therapeutic strategy for diabetic retinopathy.

Keywords:  PANoptosis; diabetic retinopathy; glycolysis; histone lactylation; thioredoxin interacting protein

DOI:  https://doi.org/10.1002/mco2.70351
Cell Stem Cell. 2025 Sep 16. pii: S1934-5909(25)00304-2. [Epub ahead of print]

Safety and tolerability of RPESC-RPE transplantation in patients with dry age-related macular degeneration: Low-dose clinical outcomes.

Rajesh C Rao, Brigitte L Arduini, Susan Borden, Dhruv Sareen, Clive Svendsen, Paul Lee, Charles Ryan, Shilpa Kodati, Caroline Nyaiburi, Keith Wolsieffer, Eric Oh, Shuna Park, Glenna Ford, Keith Dionne, Sally Temple, Jeffrey Stern.

  Retinal pigment epithelium (RPE) cell atrophy in dry age-related macular degeneration (AMD) compromises photoreceptor cell function, leading to vision loss. Stem cell-based RPE replacement therapy aims to reverse disease progression and restore vision. RPESC-RPE-4W, a post-mitotic adult RPE stem cell-derived RPE (RPESC-RPE) progenitor cell product, exhibits consistent safety and efficacy in preclinical studies. The first-in-human clinical trial of RPESC-RPE-4W completed low-dose cohort 1 interventions (NCT04627428). Six subjects received a subretinal suspension of 50,000 RPESC-RPE-4W cells. No significant inflammation, tumor, or product-related serious adverse events were observed. Best-corrected visual acuity in the three worse-seeing group A subjects improved by an average of +21.67 letters from baseline at 12 months. Three better-seeing group B subjects improved by an average of +3.0 letters at 6 months. The positive safety and tolerability outcomes for low-dose cohort 1 enabled dose escalation to mid-dose RPESC-RPE-4W therapy for dry AMD.

Keywords:  adult stem cell; cell therapy; clinical trial; geographic atrophy; macular degeneration; retina; retinal pigment epithelium; vision

DOI:  https://doi.org/10.1016/j.stem.2025.08.012
Invest Ophthalmol Vis Sci. 2025 Sep 02. 66(12): 44

Targeting RPE Senescence Via Suppressing IL-6/IL-6R Signaling for Treating Retinal Degenerative Diseases.

Tian Zhou, Ziqi Yang, Biyan Ni, Hong Zhou, Yang Zhou, Huiyi Xu, Xiaojing Lin, Shiya Lin, Wei Yi, Chang He, Xialin Liu.

Purpose: Progressive dysfunction of retinal pigment epithelium (RPE) cells is a crucial factor for retinal degeneration, leading to irreversible blindness with limited therapeutic options. Cellular senescence of RPE cells and inflammation are important hallmarks for retinal degeneration, but the underlying molecular mechanisms and potential interventions remain largely unexplored. This study aims to explore whether the IL-6/ IL-6R axis establishes a senescence-inducing circuit in RPE cells, and to evaluate the therapeutic efficacy of its inhibition in rescuing senescent RPE cells and degenerative retina.
Methods: Sodium iodate (NaIO₃)-induced retinal degeneration mouse models were established and subjected to intravitreal injections of IL-6 neutralizing antibody, or an IL-6R inhibitor tocilizumab, respectively. Conditional deletion of Stat3 in RPE cells was achieved via subretinal delivery of AAV vectors. RPE cells were isolated for single-cell RNA sequencing (scRNA-seq), qPCR, Western blotting, and immunofluorescence staining. Retinal structure and function were assessed using optical coherence tomography (OCT), hematoxylin and eosin (H&E) staining, and electroretinography (ERG).
Results: RPE underwent cellular senescence in NaIO3-induced degeneration, which was dependent on activation of the IL-6/IL-6R axis. IL-6 promoted the senescence of RPE and exacerbated retinal degeneration. In contrast, inhibition of IL-6 suppressed RPE senescence and facilitated recovery of retinal structure and function. Mechanistically, STAT3 activation was essential for IL-6-mediated cellular senescence. Notably, tocilizumab effectively blocked the IL-6/IL-6R/STAT3 signaling cascade, attenuated RPE senescence, and protected against retinal degeneration, expanding the indications of tocilizumab.
Conclusions: IL-6 and IL-6R/STAT3 signaling played an essential role in RPE senescence, and tocilizumab presents a translational opportunity in treating retinal degenerative diseases.

DOI: https://doi.org/10.1167/iovs.66.12.44
Theranostics. 2025 ;15(17): 8952-8963

Role of MiR-204 in controlling metabolic functions of the subretinal microglia.

Yan Chen, Sarah E Bounds, Neloy Kundu, James Regun Karmoker, Yin Liu, Dongin Kim, Jiyang Cai.

  Rationale: MicroRNA-204 (miR-204) is one of the most abundant miRNA species in the retinal pigment epithelium (RPE) and RPE-derived extracellular vesicles (EVs). Knockout (KO) of miR-204 leads to dysfunction and degeneration of both the RPE and the retina. In addition to previously reported retinal pathologies, we observed the accumulation of lipid-laden subretinal microglia in miR-204 KO mice. This study aimed to identify potential molecular targets of miR-204 involved in microglia lipid processing and to determine whether RPE-derived EVs can improve the function of miR-204-deficient retinal microglia. Methods: Lipid accumulation in microglia was detected by staining with LipidTox, a fluorescent dye specific for neutral lipids, followed by either flow cytometry analysis or direct visualization on RPE/choroid flat mounts. MiRNA database and target prediction tools, such as miRWalk and TargetScan, were used to search for potential target genes of miR-204 in microglia. The identified target mRNA was validated with a miRNA reporter assay. RPE EVs were prepared from ex vivo cultured mice eye cups and administered via retro-orbital injection in miR-204 knockout (KO) mice. RPE integrity was assessed by ERG c-wave measurement. Results: KO of miR-204 resulted in the accumulation of neutral lipids in subretinal microglia. MiR-204 targeted the TGF-β receptor 2 gene in microglia. TGF-β markedly suppressed the expression of genes related to microglia lipid clearance. Eyes injected with RPE-derived EVs showed improved ERG c-wave responses compared to the fellow eyes injected with saline. Conclusions: This study supports that TGF-β/TGF-β receptor 2 regulates microglia lipid metabolism primarily by suppressing lipid clearance. By modulating TGF-β signaling, miR-204 in RPE-derived EVs likely enhances the lipid metabolic activities of subretinal microglia, which are crucial for the structural integrity and proper function of the outer retina and RPE. RPE-derived EVs and their delivery of miRNAs represent a potential therapeutic approach for treating retinal diseases, such as age-related macular degeneration, which involve dysregulated lipid metabolism in subretinal microglia.

Keywords:  RPE; extracellular vesicles; inflammation; metabolism; microglia

DOI:  https://doi.org/10.7150/thno.111807
Transl Vis Sci Technol. 2025 Sep 02. 14(9): 27

Sustained Neurotrophic Factor Co-Treatment Enhances Donor and Host Retinal Ganglion Cell Survival in Mice.

Jonathan R Soucy, Julia Oswald, Emil Kriukov, Monichan Phay, John Masland, Christian Pernstich, Petr Baranov.

Purpose: Retinal ganglion cells (RGCs) lack regenerative capacity in mammals, and their degeneration in glaucoma leads to irreversible blindness. Autologous and allogeneic RGC replacement with stem cell-derived neurons is a promising strategy for vision restoration; however, low (<1%) donor cell survival in the diseased retina and optic nerve remains a major limitation. We aimed to improve initial donor RGC survival by supplementing transplants with slow-release neuroprotective factors.
Methods: Mouse and human stem cell-derived RGCs were cultured and transplanted into mouse models of optic neuropathy with or without a slow-release formulation of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). Donor RGC differentiation, survival, and function were assessed in vitro using flow cytometry, multielectrode array recordings, and neurite outgrowth analysis. Donor RGC survival and host retinal function after transplantation and BDNF/GDNF co-treatment in mice were evaluated using retinal flat mounts and electroretinography.
Results: Slow-release BDNF/GDNF significantly enhanced RGC differentiation, survival, and spontaneous neural activity in vitro. In vivo, co-treatment improved donor RGC transplantation outcomes by 2.7-fold for mouse RGCs and 15-fold for human RGCs in mice. Additionally, slow-release BDNF/GDNF preserved host RGC function, providing neuroprotection against injury-induced retinal dysfunction.
Conclusions: Engineering the retinal microenvironment with slow-release neurotrophic factors significantly enhances both donor and host neuron survival, representing a promising approach for treating glaucoma and other optic neuropathies.
Translational Relevance: This study demonstrates that sustained neurotrophic factor delivery can protect vision and improve retinal neuron transplantation outcomes, advancing the treatment of optic neuropathies at both mild and severe stages.

DOI: https://doi.org/10.1167/tvst.14.9.27
Int J Chron Obstruct Pulmon Dis. 2025 ;20 3203-3215

TET1 Alleviates Cigarette Smoke Induced Bronchial Epithelial Cell Apoptosis Through Upregulating Nrf2.

Zi-Xiao Zhang, Hao-Da Yu, Xiao-Yan Sai, Chu Qin, Yu Ding, Tao Bian.

   Introduction: Nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of oxidative stress responses, is downregulated in patients with GOLD stage III-IV chronic obstructive pulmonary disease (COPD). However, the mechanisms underlying the epigenetic regulation of Nrf2 in COPD remain poorly understood.
Methods: Protein levels of Nrf2, heme oxygenase-1 (HO-1), ten-eleven translocation methylcytosine dioxygenase 1 (TET1), and DNA methyltransferase 1 (DNMT1) were assessed by Western blotting in peripheral lung tissue and primary bronchial epithelial cells obtained from patients with COPD, never-smokers (control-NS), and smokers without COPD (control-S). CSE-treated human bronchial epithelial (HBE) cells were used as an in vitro model. Nrf2 promoter methylation was evaluated using bisulfite sequencing. Apoptosis of HBE cells was measured by flow cytometry. Chromatin immunoprecipitation (ChIP) was performed to assess the binding of TET1 to the Nrf2 promoter. Malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays were used to quantify oxidative stress and antioxidant capacity.
Results: Nrf2 and HO-1 expression was significantly reduced in both lung tissue and primary epithelial cells from patients with COPD. In vitro, CSE exposure increased Nrf2 promoter methylation in HBE cells. Overexpression of Nrf2 mitigated oxidative stress, increased SOD activity, and reduced apoptosis in response to CSE. TET1 expression was decreased in COPD lungs, and TET1 was shown to bind the Nrf2 promoter and enhance its transcription. TET1 overexpression reduced oxidative damage and apoptosis via Nrf2 upregulation.
Conclusion: Reduced Nrf2 expression in COPD may result from promoter hypermethylation. TET1 directly binds and demethylates the Nrf2 promoter, restoring its expression and attenuating CSE-induced HBE cells apoptosis. These findings identify a potential epigenetic mechanism contributing to COPD pathogenesis and suggest TET1 as a novel therapeutic target.

Keywords:  DNA methylation; Nrf2; TET1; chronic obstructive pulmonary disease

DOI:  https://doi.org/10.2147/COPD.S524465
Biochem Biophys Res Commun. 2025 Sep 09. pii: S0006-291X(25)01330-0. [Epub ahead of print]783 152614

Succinate-mediated Ufsp2 transcription promotes high glucose-stimulated pyroptosis in rat retinal Müller cells by activating NLRP3 inflammasome.

Shuzhi Zhao, Yili Zhang, Chenxin Li, Zhi Zheng, Mingming Ma.

  The pyroptosis of retinal Müller cells is intricately linked to the pathogenesis of diabetic retinopathy (DR). Ubiquitin-fold modifier 1 (UFM1)-mediated UFMylation plays an important role in insulin and diabetes mellitus metabolism and regulates cell death such as apoptosis and pyroptosis. UFM1-specific protease 2 (UFSP2) mediates the maturation of the UFM1 precursor and thus affects UFMylation reaction. However, its role in DR remains unknown. The aim of our study was to determine the mechanism and upstream regulation of UFSP2 on the pyroptosis of rat retinal Müller cells. Pathological changes, UFSP2 expression and succinate accumulation were determined in retinal tissues of db/db diabetic mice via Hematoxylin and eosin and immunofluorescence staining and biochemical analysis. High glucose (HG) was used to construct a DR cell model using rat retinal Müller cells (rMC-1). Ufsp2 RNA interference and overexpression plasmids were constructed to determine the effects of UFSP2. Pyroptosis and reactive oxygen species (ROS) levels were assessed via flow cytometry. Inflammatory cytokine (IL-1β and IL-18) levels and key molecular markers related to pyroptosis (NLRP3, ASC, Caspase-1p20, GSDMD-N) were measured by enzyme linked immunosorbent assay and Western blot, respectively. Succinate-mediated H3K3me3 enrichment in Ufsp2 promoter region was measured by chromatin immunoprecipitation. In vivo experiments revealed that the UFSP2 expression and succinate levels were increased in retinal tissues of db/db diabetic mice with thinning of retinal thickness. Moreover, in vitro experiments showed that The mRNA and protein levels of Ufsp2 exhibited a time-dependent increase under HG conditions. Upon Ufsp2 knockdown, the elevated oxidative stress, inflammatory responses, and pyroptosis stimulated by HG were significantly suppressed. The effect of Ufsp2 overexpression on pyroptosis and inflammatory responses was consistent with the HG stimulation, whereas the UFSP2-induced heightened levels of pyroptosis as well as the inflammatory state were significantly reversed when co-administered with NLRP3 inhibitor or ROS inhibitor. Further activating NLRP3 inflammasome using LPS + ATP stimulation revealed that the knockdown of Ufsp2 resulted in inhibited pyroptosis levels and inflammatory responses, while the Ufsp2 overexpression markedly increased pyroptosis and inflammatory responses. Lastly, succinate was demonstrated to influence Ufsp2 transcription, as well as the expression of H3K3me3 and its enrichment in the Ufsp2 promoter region, ultimately affecting pyroptosis and inflammatory responses. Succinate-mediated Ufsp2 transcription promotes pyroptosis in rMC-1 cells by activating NLRP3 inflammasome and oxidative stress.

Keywords:  Diabetic retinopathy; NLRP3 inflammasome; Pyroptosis; Succinate; UFSP2

DOI:  https://doi.org/10.1016/j.bbrc.2025.152614