circKIAA1462 impaires autophagy and promotes pyroptosis in retinal pigment epithelium via the miR-183-5p/HMGB1 axis in diabetic retinopathy.

Circular RNA circPSEN1 promotes neovascularization by regulating the miR-150-5p/TRIM65 axis in diabetic retinopathy

Diabetic retinopathy (DR), a major microvascular complication of diabetes, is a leading cause of vision loss. Neovascularization is a hallmark of DR, and circRNA-PSEN1 (circPSEN1) has emerged as a key regulator in its development. However, the precise molecular mechanisms by which circPSEN1 contributes to DR remain unclear. This study investigates the role of circPSEN1 in DR, focusing on its interaction with miR-150-5p and TRIM65. Human retinal microvascular endothelial cells (hRMECs) were cultured under high-glucose (HG) conditions to establish an in vitro DR model, and streptozotocin-induced DR rats were used for in vivo analysis. Lentivirus-mediated gene modulation was employed to alter expression levels. Cell viability, migration, angiogenesis, and inflammatory cytokine release were assessed using CCK-8, transwell, tube formation assays, and ELISA. Dual-luciferase reporter assays, RNA pull-down, and RNA immunoprecipitation (RIP) techniques were used to examine the interactions between circPSEN1, miR-150-5p, and TRIM65. Elevated circPSEN1 and TRIM65 levels, along with reduced miR-150-5p expression, were observed in retinal tissues from DR rats. In HG-stimulated hRMECs, circPSEN1 knockdown inhibited cell proliferation, migration, and angiogenesis, while reducing inflammatory cytokine release. These effects were reversed by miR-150-5p suppression or TRIM65 overexpression, suggesting a regulatory role of both molecules in DR. Mechanistically, circPSEN1 acts as a sponge for miR-150-5p, enhancing TRIM65 expression and contributing to DR pathogenesis. Our findings indicate that circPSEN1 may serve as a therapeutic target for DR.

CircMETTL3 Inhibits H2O2‐Induced Senescence, Oxidative Stress, and DNA Damage in ARPE‐19 Cells via miR‐100/BMPR2 Axis

Background Age‐related macular degeneration (AMD) is a common degenerative eye disease that eventually leads to irreversible vision loss. CircRNAs have received increasing attention for their regulatory role in AMD. In this study, whole transcriptome sequencing identified differentially expressed circRNA (circMETTL3) in AMD. Previous studies have unlocked the potential mechanism of circMETTL3 in cancer, but its role in AMD has not been studied. Methods ARPE‐19 cells treated with H2O2 were used as the AMD cell model. The senescence, oxidative stress, and DNA damage of ARPE‐19 cells were determined by SA‐β‐gal staining, DCFH‐DA staining, and IF assay. The levels of RPE‐specific markers or mRNA levels were assessed using western blot assay. The potential mechanism of circMETTL3 was investigated by luciferase reporting assay and RIP assay. Results CircMETTL3 was revealed to decrease in AMD cell models. The addition of circMETTL3 decreased SA‐β‐gal staining and ROS production and facilitated cell viability in H2O2‐treated ARPE‐19 cells. Moreover, γH2AX and KRT18 levels were suppressed, and TJP1, BEST1, and CTNNB1 protein levels were increased by circMETTL3 addition. In addition, circMETTL3 could bind to and negatively regulate miR‐100. Overexpression of miR‐100 exacerbated senescence, oxidative stress, and DNA damage in H2O2‐treated ARPE‐19 cells, which reversed the effects of circMETTL3. Furthermore, BMPR2 was targeted by miR‐100. Overexpression of BMPR2 inhibited H2O2‐induced cell damage in ARPE‐19 cells, which reversed the effects of miR‐100. Conclusions In sum, these findings demonstrated that the circMETTL3/miR‐100/BMPR2 axis plays a vital regulatory role in AMD development.

FOXO6 inhibits SMURF2‐mediated ubiquitination and degradation of NR4A1 to promote retinal pigment epithelial cell ferroptosis in diabetic retinopathy

Abstract Diabetic retinopathy (DR) is the main cause of vision loss, with retinal pigment epithelial (RPE) cell dysfunction as a key contributor. Ferroptosis is implicated in RPE injury under hyperglycemia; however, its upstream regulatory mechanisms remain unclear. High glucose (HG)‐induced human RPE ARPE‐19 cells and a diabetic mouse model were used. Ferroptosis was assessed through biochemical assays, Western blot, fluorescence probes, and histological staining. Protein interactions and transcriptional regulation were examined using Co‐IP, glutathione S‐transferase pull‐down, ChIP, and luciferase reporter assays. Immunofluorescence staining was used as key indicator expression in retinal tissues. Nuclear receptor 4A1 (NR4A1) expression was upregulated under HG‐induced ARPE‐19 cells. NR4A1 knockdown alleviated HG‐induced iron accumulation, lipid peroxidation, and ferroptosis marker changes. Mechanistically, SMAD‐specific E3 ubiquitin protein ligase 2 (SMURF2) interacted with NR4A1 and promoted its ubiquitination and degradation. Forkhead box O6 (FOXO6) was upregulated by HG and repressed SMURF2 transcription. SMURF2 overexpression mitigated HG‐induced ARPE‐19 ferroptosis and retinal injury in DR mice, an effect reversed by NR4A1 co‐overexpression. SMURF2 knockdown reversed the effect of FOXO6 knockdown on HG‐induced ferroptosis in ARPE‐19 cells and retinal injury in DR mice. The FOXO6–SMURF2–NR4A1 axis critically regulates ferroptosis in RPE cells during DR.

circGAB1 Activates Autophagy to Promote Sepsis-Associated Acute Kidney Injury by Interacting with ELAVL1 to Activate the HMGB3/β-catenin Signaling Pathway​.

Lactylation at H3K18 drives pathological angiogenesis via metabolic-epigenetic crosstalk in ischemic retinopathy

Ocular neovascular disease, characterized by aberrant angiogenesis in the eye, is a primary cause of global vision impairment and blindness. As the primary barrier exposed to hypoxia-related blood metabolites, endothelial cells (ECs) undergo metabolic reprogramming that drives pathological angiogenesis. However, the epigenetic mechanisms that link EC metabolic dysfunction to retinal vasculopathy remain elusive. Methods: Using western blotting and immunofluorescence analysis of retinal sections/whole-mounts, we confirmed increased histone 3 lactylation at lysine 18 (H3K18la). We subsequently identified downstream target genes through integrated CUT&Tag and RNA sequencing (RNA-seq), assessed their angiogenic regulatory functions using siRNA, and validated the mechanisms in vivo employing adeno-associated virus (AAV)-based gene transfer. Results: Our data indicated that histone lactylation levels were elevated in retinal vascular ECs under hypoxic conditions both in vivo and in vitro . In oxygen-induced retinopathy (OIR) retinal vascular ECs, H3K18la was the most prominent modification. Pharmacological inhibition of glycolysis suppressed H3K18la levels, concurrently abrogating EC activation and neovascularization. Combined CUT&Tag and RNA-seq analyses revealed that ETS1 was a direct transcriptional target governed by H3K18la in retinal ECs. Silencing ETS1 substantially inhibited hypoxia-induced proliferation, migration, sprouting, and tube formation in human retinal microvascular endothelial cells (HRMECs). Crucially, in vivo rescue experiments confirmed that ETS1 overexpression reversed the suppression of pathological neovascularization in OIR mice treated with AAV-Pfkfb3-RNAi. Conclusions: Collectively, this study revealed a lactate-driven epigenetic cascade wherein H3K18la licenses ETS1-dependent pathological angiogenesis, providing a promising therapeutic avenue for ischemic retinal diseases.

circRNA_013145-miR-185-5p-RhoA axis: A novel mechanism in the pathophysiology of diabetes-induced erectile dysfunction

Diabetes mellitus-induced erectile dysfunction (DMED) is a common diabetic complication characterized by endothelial dysfunction and corpus cavernosum (CC) remodeling. Although circular RNAs (circRNAs) have been implicated in diabetic vascular diseases, their roles in DMED remain largely unknown. The present study investigated the biological function and underlying mechanism of circRNA_013145 in DMED. CircRNA microarray analysis identified circRNA_013145 as a significantly upregulated circRNA in penile tissue from DMED rats. Its biological function was evaluated using loss-of-function and rescue experiments in high glucose (HG)-treated CC smooth muscle cells (CCSMCs), human umbilical vein endothelial cells (HUVECs) and a DMED rat model. circRNA_013145 expression was markedly increased in DMED penile tissue and HG-treated cells. circRNA_013145 knockdown attenuated HG-induced oxidative stress, inflammation, apoptosis, autophagy and phenotypic transformation, while improving endothelial function and cell viability. Mechanistically, circRNA_013145 served as a molecular sponge for miR-185-5p, thereby positively regulating RhoA expression. Rescue experiments demonstrated that inhibition of miR-185-5p partially abolished the protective effects of circRNA_013145 knockdown. Furthermore, adenovirus-mediated knockdown of circRNA_013145 significantly improved erectile function and alleviated cavernosal pathological injury in DMED rats, as evidenced by an increased intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio, enhanced CD31 expression and reduced collagen deposition. In conclusion, circRNA_013145 promotes the progression of DMED through the miR-185-5p/RhoA axis. Targeting circRNA_013145 may represent a potential therapeutic strategy for DMED.