肝细胞癌（HCC）是最常见的肝癌，预后较差。用于晚期 HCC 的可用药物有限，仍然迫切需要包括新药和新联合疗法在内的重大治疗进展。在这项研究中，我们发现罗伊氏乳杆菌（L. reuteri）的主要代谢产物罗伊氏菌素表现出巨大的抗肝癌潜力，并有助于索拉非尼的治疗。罗伊氏菌治疗会损害线粒体自噬，导致线粒体核苷异常聚集，从而阻断线粒体 DNA (mtDNA) 复制和线粒体裂变，从而促进 mtDNA 渗漏和随后 HCC 细胞中的 STING 激活。 STING 可以激活细胞焦亡和坏死性凋亡，而罗伊素处理还可以通过裂解 HCC 细胞中的 RIPK3 来诱导 caspase 8 表达，从而抑制坏死性凋亡。因此，焦亡是罗伊氏菌处理的 HCC 细胞的主要死亡形式，STING 抑制显着挽救了罗伊菌素的生长抑制作用，同时敲低 caspase 8 协同抑制焦亡的诱导。总之，我们的研究解释了罗伊素抗肿瘤作用的详细分子机制，并揭示了其作为 HCC 治疗组合药物的潜力。版权所有 © 2024。由 Elsevier B.V. 出版。

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.Copyright © 2024. Published by Elsevier B.V.