Panobinostat suppresses cGAS-STING pathway activation and ameliorates DSS-induced colitis in mice

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-10-10 DOI:10.1016/j.intimp.2025.115637

Meizhen Qin , Zijiao Liu , Meng Wang , Wanqing Yang , Zihua Zhou , Mengfei Xue , Fan Xia , Chunyong Ding , Ao Zhang , Zhenliang Sun

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Abstract

Abnormal or excessive activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in natural immunity nucleic acid sensing causing the overproduction of cytokines, triggering inflammatory tissue damage, immune pathology, or autoimmune diseases closely associated with the release of type I interferons. Inhibiting aberrant cGAS activation represents a promising therapeutic strategy for clinical development. Through screening a library of epigenetic drugs, we identified that the histone deacetylase inhibitor panobinostat significantly suppresses the cGAS-STING pathway, reducing both the mRNA expression and protein phosphorylation levels of downstream inflammatory mediators, as well as decreasing the secretion of inflammatory factors. Furthermore, we found that panobinostat alleviates symptoms of dextran sulfate sodium-induced colitis in mice, offering new insights into the prevention and treatment of inflammatory diseases.

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Panobinostat抑制cGAS-STING通路激活并改善dss诱导的小鼠结肠炎

天然免疫核酸感应中环GMP-AMP合成酶(cGAS)-干扰素基因刺激因子（STING）通路异常或过度激活，导致细胞因子过量产生，引发炎性组织损伤、免疫病理或与I型干扰素释放密切相关的自身免疫性疾病。抑制异常的cGAS激活是一种很有前景的临床治疗策略。通过筛选表观遗传药物文库，我们发现组蛋白去乙酰化酶抑制剂panobinostat显著抑制cGAS-STING通路，降低下游炎症介质mRNA表达和蛋白磷酸化水平，减少炎症因子的分泌。此外，我们发现帕比司他可缓解葡聚糖硫酸钠诱导的小鼠结肠炎的症状，为炎症性疾病的预防和治疗提供了新的见解。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.