Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1β (IL-1β)– and IL-1β–dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal–mediated pore. We found that IL-33 was highly induced in senescent HSCs in an IL-1β–dependent manner in the tumor microenvironment. The release of both IL-33 and IL-1β was triggered by lipoteichoic acid (LTA), a cell wall component of gut microbiota that was transferred and accumulated in the liver tissue of high-fat diet–fed mice, and the release of these factors was mediated through cell membrane pores formed by the GSDMD amino terminus, which was cleaved by LTA-induced caspase-11. We demonstrated that IL-33 release from HSCs promoted HCC development via the activation of ST2-positive T reg cells in the liver tumor microenvironment. The accumulation of GSDMD amino terminus was also detected in HSCs from human NASH-associated HCC patients, suggesting that similar mechanism could be involved in a certain type of human HCC. These results uncover a release mechanism for SASP factors from sensitized senescent HSCs in the tumor microenvironment, thereby facilitating obesity-associated HCC progression. Furthermore, our findings highlight the therapeutic potential of inhibitors of GSDMD-mediated pore formation for HCC treatment.

中文翻译：

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Gasdermin D 介导的衰老肝星状细胞释放 IL-33 促进肥胖相关肝细胞癌

长期衰老细胞表现出称为衰老相关分泌表型 (SASP) 的分泌组。尽管已经深入研究了 SASP 因子诱导的机制，但其释放机制以及 SASP 因子如何影响生物学背景下的肿瘤发生仍不清楚。在这项研究中，我们使用肥胖诱导的肝细胞癌 (HCC) 小鼠模型，确定了 SASP 因子的释放机制，包括白细胞介素 1β (IL-1β) 和 IL-1β 依赖性 IL-33，从衰老肝星状细胞 (HSC) 通过 gasdermin D (GSDMD) 氨基末端介导的孔。我们发现在肿瘤微环境中以 IL-1β 依赖性方式在衰老的 HSC 中高度诱导 IL-33。IL-33 和 IL-1β 的释放均由脂磷壁酸 (LTA) 触发，一种肠道微生物群的细胞壁成分，它在高脂饮食喂养的小鼠的肝组织中转移和积累，这些因子的释放是通过 GSDMD 氨基末端形成的细胞膜孔介导的，它被 LTA-裂解诱导的 caspase-11。我们证明了从 HSC 释放的 IL-33 通过激活 ST2 阳性 T 促进了 HCC 的发展。注册肝肿瘤微环境中的细胞。在来自人类 NASH 相关 HCC 患者的 HSC 中也检测到 GSDMD 氨基末端的积累，这表明类似的机制可能涉及某种类型的人类 HCC。这些结果揭示了肿瘤微环境中致敏的衰老 HSC 释放 SASP 因子的机制，从而促进肥胖相关的 HCC 进展。此外，我们的研究结果强调了 GSDMD 介导的孔形成抑制剂在 HCC 治疗中的治疗潜力。