中华放射医学与防护杂志

宋星,邵英杰,孙锐,等.Kupffer细胞来源IL-6激活STAT3/CCNG1通路加剧放射性肝损伤[J].中华放射医学与防护杂志,2026,46(9):826-835.Song Xing,Shao Yingjie,Sun Rui,et al.Kupffer cell-derived interleukin-6 aggravating radiation-induced liver disease by activating the STAT3/CCNG1 pathway[J].Chin J Radiol Med Prot,2026,46(9):826-835

Kupffer细胞来源IL-6激活STAT3/CCNG1通路加剧放射性肝损伤

Kupffer cell-derived interleukin-6 aggravating radiation-induced liver disease by activating the STAT3/CCNG1 pathway

投稿时间：2025-12-22

DOI：10.3760/cma.j.cn112271-20251222-00441

中文关键词: 放射性肝损伤 Kupffer细胞白细胞介素6 细胞周期蛋白G1 STAT3信号通路

英文关键词:Radiation-induced liver disease Kupffer cell Interleukin-6 Cyclin G1 STAT3 signaling pathway

基金项目:常州市科技计划项目(CJ20243011)

作者	单位	E-mail
宋星	苏州大学附属第三医院肿瘤放射治疗科, 常州 213003
邵英杰	苏州大学附属第三医院肿瘤放射治疗科, 常州 213003
孙锐	苏州大学附属第三医院肿瘤放射治疗科, 常州 213003
蒋文杰	苏州大学附属第三医院肿瘤放射治疗科, 常州 213003
陈远	苏州大学附属第三医院肿瘤放射治疗科, 常州 213003
顾文栋	苏州大学附属第三医院肿瘤放射治疗科, 常州 213003	guwendong1415@czfph.com

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中文摘要:

目的探讨Kupffer细胞来源白细胞介素6 (IL-6)在放射性肝损伤(RILD)中的作用及分子机制，筛选潜在治疗靶点。方法选取6~8周龄雄性SD大鼠45只，按照射剂量分为0、15、30 Gy 3个组别，按照射后观察时间分为0 d、3 d、1 周、2 周、4 周、8 周6个组别，每组各5只。采用9 MeV电子线对大鼠右上腹行单次30 Gy照射，建立RILD模型。检测血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)及肝组织病理变化；通过单细胞RNA测序(scRNA-seq)解析肝组织细胞异质性，筛选差异基因；采用Anti-IL-6抗体、sgp130Fc、JAK抑制剂鲁索替尼/托法替尼体内干预，验证IL-6信号通路功能；采用染色质免疫沉淀测序(ChIP-seq)、流式细胞术及Western blot，解析IL-6/STAT3/CCNG1/TP53信号轴的调控机制。结果 30 Gy照后，与 0 d组ALT(128.58±0.88) ng/ml、AST(25.05±0.37) ng/ml相比，大鼠血清ALT、AST在2周时达峰值分别为(207.91±4.02) 、(42.63±0.47) ng/ml (q=63.56、97.24，P<0.05)，肝细胞脂肪变性、CD45+免疫细胞浸润显著增加(q=9.85，P<0.05)。scRNA-seq显示，30 Gy照后2周Kupffer细胞占比由17.9%升至42.4% (t=3.15，P<0.05)，其中Kupffer_0亚群(占比29.9%)高表达IL6。照后血清及肝组织IL-6浓度显著升高(t=69.00、65.57，P<0.001)。Anti-IL-6抗体可显著降低血清ALT/AST (q=24.81、15.14，P<0.05)，并抑制肝窦内皮细胞凋亡(q=9.46，P<0.05)；JAK抑制剂可抑制STAT3磷酸化(q=12.87、13.83，P<0.05)、减少肝细胞凋亡(q=12.82、10.81，P<0.05)。ChIP-seq鉴定STAT3靶基因Ccng1，敲低Ccng1可缓解IL-6诱导的肝细胞凋亡(q=10.72，P<0.05)，并抑制IL-6诱导的γH2AX水平上调；IL-6通过CCNG1招募PP2A，催化MDM2与TP53结合，进而下调TP53表达(q=5.24，P<0.05)，形成IL-6/STAT3/CCNG1/PP2A/MDM2/TP53致病轴，阻断JAK/STAT通路可逆转该效应。结论 Kupffer细胞(尤其是Kupffer_0亚群)分泌IL-6通过激活STAT3/CCNG1/TP53通路加剧RILD，Anti-IL-6抗体或JAK抑制剂可通过阻断该通路减轻肝损伤，为RILD防治提供新靶点。

英文摘要:

Objective To determine the role and molecular mechanisms of Kupffer cell-derived interleukin-6 (IL-6) in radiation-induced liver disease (RILD), aiming to select potential therapeutic targets.Methods A total of 45 male Sprague-Dawley (SD) rats aged 6-8 weeks were selected. These rats were divided into three groups based on irradiation dose (0, 15, and 30 Gy) and six groups based on post-irradiation observation time point (0, 3 d, 1 week, 2 weeks, 4 weeks, and 8 weeks), with five rats in each group. A RILD model was established by delivering a 30 Gy dose of single irradiation to the right upper abdomen of rats using 9 MeV electron beams. The alanine aminotransferase (ALT) and aspartate transaminase (AST) levels in serum, as well as pathological changes in liver tissues, were detected. Differentially expressed genes were selected by analyzing the cellular heterogeneity in liver tissues using single-cell RNA sequencing (scRNA-seq) The function of the IL-6 signaling pathway was verified through in vivo intervention experiments with anti-IL-6 antibody, inhibitor sgp130Fc, and JAK inhibitors ruxolitinib and tofacitinib. The regulatory mechanism of the IL-6/STAT3/CCNG1/TP53 signaling axis was analyzed using method including chromatin immunoprecipitation sequencing (ChIP-seq), flow cytometry, and Western blot.Results After 30 Gy irradiation, the ALT and AST levels in rat serum peaked at (207.91±4.02) ng/ml and (42.63±0.47) ng/ml, respectively at 2 weeks post-irradiation, significantly higher than those the 0-day group [ALT: (128.58±0.88) ng/ml; AST: (25.05±0.37) ng/ml] (q= 63.56, 97.24, P < 0.05). Meanwhile, hepatocyte steatosis and the infiltration of CD45+ immune cells increased significantly in liver tissues (q= 9.85, P < 0.05). scRNA-seq revealed that the proportion of Kupffer cells increased from 17.9% to 42.4% at 2 weeks after 30 Gy irradiation (t= 3.15, P < 0.05). Concurrently, the Kupffer_0 subset (29.9% of Kupffer cells) exhibited highly expressed IL-6, with the IL-6 concentrations in serum and liver tissues increased significantly post-irradiation (t=69.00, 65.57, P<0.05). The anti-IL-6 antibody significantly reduced the ALT and AST levels in serum (q= 24.81, 15.14, P < 0.05). And inhibited the apoptosis of hepatic sinusoidal endothelial cells (q=9.46, P<0.05). The JAK inhibitors inhibited STAT3 phosphorylation (q=12.87, 13.83, P<0.05). and reduced hepatocyte apoptosis (q=12.82, 10.81, P<0.05). CCNG1, a STAT3 target gene, was identified by ChIP-seq, and CCNG1 knockdown alleviated IL-6-induced hepatocyte apoptosis (q=10.72, P<0.05) and suppressed the IL-6-induced upregulation of γH2AX levels. IL-6 recruited PP2A via CCNG1, catalyzed the binding of MDM2 to TP53, and further downregulated TP53 expression (q=5.24, P<0.05), leading to the formation of the IL-6/STAT3/CCNG1/PP2A/MDM2/TP53 pathogenic axis. This effect can be reversed by blocking the JAK/STAT pathway.Conclusions Kupffer cells, especially the Kupffer_0 subset, secrete IL-6, which exacerbates RILD by activating the STAT3/CCNG1/TP53 pathway. In contrast, the anti-IL-6 antibody or JAK inhibitors can reduce liver injury by blocking this pathway. This study provides new targets for RILD prevention and treatment.

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