Chen Jie, Fei Shinuan, Chan Lawrence W C, Gan Xueting, Shao Bibo, Jiang Hong, Li Sheng, Kuang Peng, Liu Xin, Yang Sijun
Department of Respiratory Medicine, Huangshi Maternity and Children's Health Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435000, PR China.
Pediatrics Department, Huangshi Maternal and Child Health Care Hospital, Affiliated Maternity and Children's Health Hospital of Hubei Polytechnic University, Huangshi Key Laboratory of Birth Defects Prevention, Huangshi, Hubei 435003, PR China.
Pharmacol Res. 2025 Jun;216:107776. doi: 10.1016/j.phrs.2025.107776. Epub 2025 May 15.
Type 2 diabetes (T2D) is a complex metabolic disorder with a growing global prevalence, and there is a linking between inflammation in pancreatic β-cell and impaired glucose homeostasis which has emerged as a key player in the pathogenesis of T2D. Recent advances in research have provided new insights into various inflammatory signaling cascades in β-cell among which we focus on Toll-like Receptor 4 (TLR4), Nuclear Factor kappa B (NF-κB), Janus Kinase-Signal Transducer and Activator of Transcription (JAK/STAT), Platelet-Derived Growth Factor Receptor α (PDGFR-α), Stimulator of Interferon Genes (STING), and the death receptor TMEM219. TLR4 activation by pathogen- or damage-associated molecular patterns initiates NF-κB and mitogen-activated protein kinase (MAPK) cascades, promoting pro-inflammatory cytokine release and β-cell apoptosis. NF-κB acts as a central hub, integrating metabolic stress signals (e.g., glucolipotoxicity, ER stress) and amplifying inflammatory responses through crosstalk with JAK/STAT and STING pathways. Meanwhile, JAK/STAT signaling exhibits dual roles in β-cell survival and inflammation, influenced by cytokine milieu and feedback regulation. PDGFR-α, traditionally linked to β-cell proliferation, paradoxically contributes to pathological hyperplasia in obesity, while STING activation by cytosolic DNA triggers β-cell senescence and ferroptosis via IRF3/NF-κB. In this review, we synthesize recent advancements of these inflammatory signaling pathways in β-cells, and current therapeutic strategies targeting TLR4/NF-κB inhibitors, JAK/STAT modulators, STING antagonists, and the death receptor TMEM219 are discussed, alongside challenges in pathway specificity and clinical translation. Understanding these inflammatory signaling pathways and their interactions in pancreatic β-cell is essential for the development of novel therapeutic strategies to prevent or treat T2D.
2型糖尿病（T2D）是一种复杂的代谢紊乱疾病，在全球范围内的患病率不断上升。胰腺β细胞炎症与葡萄糖稳态受损之间存在联系，这已成为T2D发病机制中的关键因素。近年来的研究进展为β细胞中各种炎症信号级联反应提供了新的见解，其中我们重点关注Toll样受体4（TLR4）、核因子κB（NF-κB）、Janus激酶-信号转导子和转录激活子（JAK/STAT）、血小板衍生生长因子受体α（PDGFR-α）、干扰素基因刺激物（STING）以及死亡受体TMEM219。病原体或损伤相关分子模式激活TLR4会启动NF-κB和丝裂原活化蛋白激酶（MAPK）级联反应，促进促炎细胞因子释放和β细胞凋亡。NF-κB作为一个中心枢纽，整合代谢应激信号（如糖脂毒性、内质网应激），并通过与JAK/STAT和STING途径的相互作用放大炎症反应。同时，JAK/STAT信号在β细胞存活和炎症中表现出双重作用，受细胞因子环境和反馈调节的影响。传统上与β细胞增殖相关的PDGFR-α，在肥胖中却反常地导致病理性增生，而胞质DNA激活STING会通过IRF3/NF-κB触发β细胞衰老和铁死亡。在这篇综述中，我们综合了这些β细胞炎症信号通路的最新进展，并讨论了目前针对TLR4/NF-κB抑制剂、JAK/STAT调节剂、STING拮抗剂和死亡受体TMEM219的治疗策略，以及通路特异性和临床转化方面的挑战。了解这些炎症信号通路及其在胰腺β细胞中的相互作用对于开发预防或治疗T2D的新型治疗策略至关重要。
