Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol

Author: Zhou, Qing ; Ye, Wei-le ; Li, Min ; Li, Yuan-yuan ; Zhang, Dong-mei ; Zhao, Man ; Zou, Jia-mi ; Yang, Si-jia ; Lin, Jiu-guo ; Liang, Li-yin ; Yang, Ping-lian ; Qiu, Wan-lu ; Liu, Pei-qing ; Li, Cheng-zhi ; Li, Zhuo-ming ; Zheng, Zhi-hua ; Wang, Jiao-jiao ; Liu, Zhi-ping

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease.Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs).However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging.Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING.STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition.Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP.In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice.By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo.We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING.These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases.A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

08 Aug 2024·ACS Medicinal Chemistry Letters

Design and Assessment of First-Generation Heterobifunctional PPARα/STING Modulators

Article

Author: Hu, Bo ; Cui, Yi ; Ma, Jian-Xing ; Duerfeldt, Adam S. ; Lee, Julia J.

Inflammatory retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) are prominent causes of blindness in industrialized countries. The complexity of these diseases, involving diverse cell types and pathways that give rise to a multifactorial pathogenesis, complicates drug discovery. As such, therapies exhibiting polypharmacology are expected to improve outcomes through broader disease stage coverage and beneficial spatiotemporal effects. We report herein the first dual modulator of PPARα and STING, two targets tied to disparate pathologies in retinal diseases. Recognizing structural similarities between a reported STING inhibitor SN-013 and our previously described PPARα agonist A229, we designed BH400, which agonizes PPARα (EC₅₀ = 1.2 μM) and inhibits STING (IC₅₀ = 8.1 μM). BH400 demonstrates superior protection over single-target PPARα or STING modulation in microglial and photoreceptor cells. These findings provide compelling evidence for the potential benefit of polypharmacology in common retinal diseases through dual PPARα/STING modulation, motivating further studies.

01 Aug 2024·Clinical and Translational Medicine

Multi‐omics integration reveals the oncogenic role of eccDNAs in diffuse large B‐cell lymphoma through STING signalling

Article

Author: Wang, Luqiao ; Leng, Jiayan ; Jin, Hui ; Li, Yongle ; Sun, Bing ; Fu, Jianxin ; Fan, Zhou ; Li, Jianyong ; Zhang, Wei ; Cao, Lei ; Jiang, Yan ; Wu, Zijuan ; Shi, Wenyu ; Zhan, Mengtao ; Jiang, Yongning

AbstractBackgroundExtrachromosomal circular DNAs (eccDNAs), a type of double‐stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B‐cell lymphoma (DLBCL) has not been reported.MethodsCircular DNA sequencing (circle‐seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK‐8 and scRNA‐seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA‐related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti‐tumour responses.ResultsEccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs‐induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS‐independent manner. Moreover, inhibition of STING exerted a synergistic anti‐tumour effect with cisplatin.ConclusionsEccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING.Highlights

EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS.

The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.

100 Deals associated with STING Inhibitor (Astellas)

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Preclinical	JP	Astellas Pharma, Inc.	21 Sep 2023
Autoimmune Diseases	Preclinical	US	Mitobridge, Inc.	21 Sep 2023
Neurodegenerative Diseases	Preclinical	JP	Astellas Pharma, Inc.	21 Sep 2023
Neurodegenerative Diseases	Preclinical	US	Mitobridge, Inc.	21 Sep 2023

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