Lactate accumulation drives hepatocellular carcinoma metastasis through facilitating tumor-derived exosome biogenesis by Rab7A lactylation.

1. Cancer Lett. 2025 Sep 1;627:217636. doi: 10.1016/j.canlet.2025.217636. Epub 2025 Mar 21. Lactate accumulation drives hepatocellular carcinoma metastasis through facilitating tumor-derived exosome biogenesis by Rab7A lactylation. Jiang C(1), He X(2), Chen X(2), Huang J(2), Liu Y(3), Zhang J(3), Chen H(4), Sui X(5), Lv X(5), Zhao X(5), Xiao C(6), Xiao J(3), Zhang J(3), Lu T(3), Chen H(3), Li H(3), Wang H(2), Lv G(3), Ye L(3), Li R(7), Zheng J(3), Yao J(3), Kang Y(8), Wang T(2), Li H(3), Wang J(9), Zhang Y(3), Chen G(3), Cai J(10), Xiang AP(11), Yang Y(12). Author information: (1)Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Centre for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, China. (2)Centre for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China. (3)Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, China. (4)Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. (5)Surgical ICU, The Third Affiliated Hospital of Sun Yat-sen University, China. (6)Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. (7)Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. (8)Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. (9)Scientific Research Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China. (10)Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, China. Electronic address: caijianyeah@163.com. (11)Centre for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China. Electronic address: xiangp@mail.sysu.edu.cn. (12)Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, China. Electronic address: yysysu@163.com. Previous studies have demonstrated that lactate accumulation, a common hallmark for metabolic deprivation in solid tumors, could actively drive tumor invasion and metastasis. However, whether lactate influences the biogenesis of tumor-derived exosomes (TDEs), the prerequisite for distant metastasis formation, remains unknown. Here, we demonstrated that extracellular lactate, after taken up by tumor cells via lactate transporter MCT1, drove the release of TDE mainly through facilitating multivesicular body (MVB) trafficking towards plasma membrane instead of lysosome. Mechanistically, lactate promoted p300-mediated Rab7A lactylation, which hereafter inhibited its GTPase activity and promoted MVB docking with plasma membrane. Moreover, lactate administration enriched integrin β4 and ECM remodeling-related proteins in TDE cargos, which promoted pulmonary pre-metastatic niche formation. Combinatorial inhibition of MCT1 and p300 significantly abrogated HCC metastasis in a clinical-relevant PDX model. In summary, we demonstrated that lactate promote TDE biogenesis and HCC pulmonary metastasis, and proposed a potential clinical strategy targeting TDEs to prevent HCC metastasis. Copyright © 2025. Published by Elsevier B.V. DOI: 10.1016/j.canlet.2025.217636 PMID: 40120799 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.