液–液相分离在肝细胞癌中的研究进展
Advances in Research on Liquid-Liquid Phase Separation in Hepatocellular Carcinoma
摘要: 蛋白质、核酸等生物大分子在细胞内可通过液–液相分离,依赖多价相互作用形成动态、无膜的液体凝聚物,从而构建相对独立的功能区室,参与转录调控、信号转导等重要生命过程。近年来,越来越多的研究揭示,液–液相分离在肝细胞癌的发生、发展及转移中发挥着突出作用,它通过影响关键信号通路、重塑肿瘤微环境、介导癌相关基因的表达调控,进而驱动肿瘤的恶性进展。基于此,靶向液–液相分离过程的新兴治疗策略正逐渐浮出水面,为肝癌干预提供了潜在新靶点。因此,系统阐明液–液相分离在肝细胞癌中的具体作用机制,对于开发新型抗肿瘤策略具有重要意义。本文将从液–液相分离发生的生物物理学基础、其在肝细胞癌中的分子机制与病理功能,以及相关临床转化前景等方面展开综述,以期为肝细胞癌的精准治疗与药物研发提供新的思路和方向。
Abstract: Proteins, nucleic acids, and other biomacromolecules can undergo liquid-liquid phase separation within cells, forming dynamic, membrane-less liquid condensates through multivalent interactions. These condensates establish relatively independent functional compartments involved in critical biological processes such as transcriptional regulation and signal transduction. In recent years, growing evidence has revealed that liquid-liquid phase separation plays a prominent role in the initiation, progression, and metastasis of hepatocellular carcinoma. It drives malignant tumor progression by influencing key signaling pathways, remodeling the tumor microenvironment, and mediating the expression regulation of cancer-related genes. Consequently, emerging therapeutic strategies targeting the liquid-liquid phase separation process are gradually surfacing, offering potential novel targets for hepatocellular carcinoma intervention. Therefore, systematically elucidating the specific mechanisms of liquid-liquid phase separation in hepatocellular carcinoma holds significant importance for developing novel anti-tumor strategies. This review will summarize the biophysical basis of liquid-liquid phase separation, its molecular mechanisms and pathological functions in hepatocellular carcinoma, as well as the prospects for clinical translation, aiming to provide new insights and directions for precision therapy and drug development in hepatocellular carcinoma.
文章引用:张凯旋, 范钟辰, 程昊宇, 曹学峰, 张兴元. 液–液相分离在肝细胞癌中的研究进展[J]. 临床医学进展, 2026, 16(2): 2417-2425. https://doi.org/10.12677/acm.2026.162646

参考文献

[1] Mondal, S., Narayan, K., Botterbusch, S., Powers, I., Zheng, J., James, H.P., et al. (2022) Multivalent Interactions between Molecular Components Involved in Fast Endophilin Mediated Endocytosis Drive Protein Phase Separation. Nature Communications, 13, Article No. 5017. [Google Scholar] [CrossRef] [PubMed]
[2] Xie, Q., Cheng, J., Mei, W., Yang, D., Zhang, P. and Zeng, C. (2023) Phase Separation in Cancer at a Glance. Journal of Translational Medicine, 21, Article No. 237. [Google Scholar] [CrossRef] [PubMed]
[3] Peng, Q., Tan, S., Xia, L., Wu, N., Oyang, L., Tang, Y., et al. (2022) Phase Separation in Cancer: From the Impacts and Mechanisms to Treatment Potentials. International Journal of Biological Sciences, 18, 5103-5122. [Google Scholar] [CrossRef] [PubMed]
[4] Carrasco, J., Antón, R., Valbuena, A., Pantoja-Uceda, D., Mukhi, M., Hervás, R., et al. (2023) Metamorphism in TDP-43 Prion-Like Domain Determines Chaperone Recognition. Nature Communications, 14, Article No. 466. [Google Scholar] [CrossRef] [PubMed]
[5] Chakraborty, S., Nandi, P., Mishra, J., Niharika, Roy, A., Manna, S., et al. (2024) Molecular Mechanisms in Regulation of Autophagy and Apoptosis in View of Epigenetic Regulation of Genes and Involvement of Liquid-Liquid Phase Separation. Cancer Letters, 587, Article ID: 216779. [Google Scholar] [CrossRef] [PubMed]
[6] Villegas, J.A., Heidenreich, M. and Levy, E.D. (2022) Molecular and Environmental Determinants of Biomolecular Condensate Formation. Nature Chemical Biology, 18, 1319-1329. [Google Scholar] [CrossRef] [PubMed]
[7] Lu, J., Qian, J., Xu, Z., Yin, S., Zhou, L., Zheng, S., et al. (2021) Emerging Roles of Liquid-Liquid Phase Separation in Cancer: From Protein Aggregation to Immune-Associated Signaling. Frontiers in Cell and Developmental Biology, 9, Article 631486. [Google Scholar] [CrossRef] [PubMed]
[8] Hong, K., Song, D. and Jung, Y. (2020) Behavior Control of Membrane-Less Protein Liquid Condensates with Metal Ion-Induced Phase Separation. Nature Communications, 11, Article No. 5554. [Google Scholar] [CrossRef] [PubMed]
[9] Onuchic, P.L., Milin, A.N., Alshareedah, I., Deniz, A.A. and Banerjee, P.R. (2019) Divalent Cations Can Control a Switch-Like Behavior in Heterotypic and Homotypic RNA Coacervates. Scientific Reports, 9, Article No. 12161. [Google Scholar] [CrossRef] [PubMed]
[10] Wadsworth, G.M., Srinivasan, S., Lai, L.B., Datta, M., Gopalan, V. and Banerjee, P.R. (2024) RNA-Driven Phase Transitions in Biomolecular Condensates. Molecular Cell, 84, 3692-3705. [Google Scholar] [CrossRef] [PubMed]
[11] Fu, Y. and Zhuang, X. (2020) M6a-Binding YTHDF Proteins Promote Stress Granule Formation. Nature Chemical Biology, 16, 955-963. [Google Scholar] [CrossRef] [PubMed]
[12] Matsuo, K., Asamitsu, S., Maeda, K., Suzuki, H., Kawakubo, K., Komiya, G., et al. (2024) RNA G-Quadruplexes Form Scaffolds That Promote Neuropathological α-Synuclein Aggregation. Cell, 187, 6835-6848.e20. [Google Scholar] [CrossRef] [PubMed]
[13] Liu, X., Xiong, Y., Zhang, C., Lai, R., Liu, H., Peng, R., et al. (2021) G-Quadruplex-Induced Liquid-Liquid Phase Separation in Biomimetic Protocells. Journal of the American Chemical Society, 143, 11036-11043. [Google Scholar] [CrossRef] [PubMed]
[14] Liu, Q., Li, J., Zhang, W., Xiao, C., Zhang, S., Nian, C., et al. (2021) Glycogen Accumulation and Phase Separation Drives Liver Tumor Initiation. Cell, 184, 5559-5576.e19. [Google Scholar] [CrossRef] [PubMed]
[15] Pu, X., Zhang, C., Jin, J., Jin, Y., Ren, J., Zhou, S., et al. (2025) Phase Separation of EEF1E1 Promotes Tumor Stemness via PTEN/AKT-Mediated DNA Repair in Hepatocellular Carcinoma. Cancer Letters, 613, Article ID: 217508. [Google Scholar] [CrossRef] [PubMed]
[16] Liu, Y., Zhang, J., Zhai, Z., Liu, C., Yang, S., Zhou, Y., et al. (2024) Upregulated PrPC by HBx Enhances NF-κB Signal via Liquid-Liquid Phase Separation to Advance Liver Cancer. NPJ Precision Oncology, 8, Article No. 211. [Google Scholar] [CrossRef] [PubMed]
[17] Yan, Q., Fang, X., Liu, X., Guo, S., Chen, S., Luo, M., et al. (2023) Loss of ESRP2 Activates TAK1-MAPK Signaling through the Fetal RNA-Splicing Program to Promote Hepatocellular Carcinoma Progression. Advanced Science, 11, e2305653. [Google Scholar] [CrossRef] [PubMed]
[18] Li, M., Thorne, R.F., Wang, R., Cao, L., Cheng, F., Sun, X., et al. (2023) Sestrin2-Mediated Disassembly of Stress Granules Dampens Aerobic Glycolysis to Overcome Glucose Starvation. Cell Death Discovery, 9, Article No. 127. [Google Scholar] [CrossRef] [PubMed]
[19] Liu, B., Shen, H., He, J., Jin, B., Tian, Y., Li, W., et al. (2023) Cytoskeleton Remodeling Mediated by circRNA-YBX1 Phase Separation Suppresses the Metastasis of Liver Cancer. Proceedings of the National Academy of Sciences, 120, e2220296120. [Google Scholar] [CrossRef] [PubMed]
[20] Zhu, Y., Li, J., Li, S., Yang, Z., Qiao, Z., Gu, X., et al. (2024) ZMAT2 Condensates Regulate the Alternative Splicing of TRIM28 to Reduce Cellular ROS Accumulation, Thereby Promoting the Proliferation of HCC Cells. Cell Communication and Signaling, 22, Article No. 407. [Google Scholar] [CrossRef] [PubMed]
[21] Meng, J., Han, J., Wang, X., Wu, T., Zhang, H., An, H., et al. (2023) Twist1-YY1-p300 Complex Promotes the Malignant Progression of HCC through Activation of miR-9 by Forming Phase-Separated Condensates at Super-Enhancers and Relieved by Metformin. Pharmacological Research, 188, Article ID: 106661. [Google Scholar] [CrossRef] [PubMed]
[22] Sha, L., Yang, Z., An, S., Yang, W., Kim, S., Oh, H., et al. (2023) Non-Canonical MLL1 Activity Regulates Centromeric Phase Separation and Genome Stability. Nature Cell Biology, 25, 1637-1649. [Google Scholar] [CrossRef] [PubMed]
[23] Liao, Z., Zhang, H., Liu, F., Wang, W., Liu, Y., Su, C., et al. (2024) m6A-Dependent ITIH1 Regulated by TGF-Beta Acts as a Target for Hepatocellular Carcinoma Progression. Advanced Science, 11, e2401013. [Google Scholar] [CrossRef] [PubMed]
[24] Chen, S., Cao, X., Zhang, J., Wu, W., Zhang, B. and Zhao, F. (2022) circVAMP3 Drives CAPRIN1 Phase Separation and Inhibits Hepatocellular Carcinoma by Suppressing c-Myc Translation. Advanced Science, 9, e2103817. [Google Scholar] [CrossRef] [PubMed]
[25] He, Z.J., He, K., Cai, S.W., Zhang, R., Shao, Z., Wang, S., et al. (2024) Phase Separation of RNF214 Promotes the Progression of Hepatocellular Carcinoma. Cell Death & Disease, 15, Article No. 483. [Google Scholar] [CrossRef] [PubMed]
[26] Jiang, X., Liu, J., Wang, K., Sun, J., Yin, H., Jiang, Y., et al. (2025) ASPM Mediates Nuclear Entrapment of FOXM1 via Liquid-Liquid Phase Separation to Promote Progression of Hepatocarcinoma. Genome Biology, 26, Article No. 68. [Google Scholar] [CrossRef] [PubMed]
[27] Gao, Y., Tong, M., Wong, T., Ng, K., Xie, Y., Wang, Z., et al. (2023) Long Noncoding RNA URB1-Antisense RNA 1 (AS1) Suppresses Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma by Driving Ferritin Phase Separation. ACS Nano, 17, 22240-22258. [Google Scholar] [CrossRef] [PubMed]
[28] Xie, F., Zhou, X., Ran, Y., Li, R., Zou, J., Wan, S., et al. (2025) Targeting FOXM1 Condensates Reduces Breast Tumour Growth and Metastasis. Nature, 638, 1112-1121. [Google Scholar] [CrossRef] [PubMed]
[29] Lao, Y., Jin, Y., Wu, S., Fang, T., Wang, Q., Sun, L., et al. (2025) Correction: Deciphering a Profiling Based on Multiple Post-Translational Modifications Functionally Associated Regulatory Patterns and Therapeutic Opportunities in Human Hepatocellular Carcinoma. Molecular Cancer, 24, Article No. 49. [Google Scholar] [CrossRef] [PubMed]
[30] Peng, W., Li, Y., Cheng, B., Cao, M., Liu, L., Yang, Y., et al. (2024) Liquid-Liquid Phase Separation-Related lncRNA Prognostic Signature and ZNF32-AS2 as a Novel Biomarker in Hepatocellular Carcinoma. Computers in Biology and Medicine, 169, Article ID: 107975. [Google Scholar] [CrossRef] [PubMed]
[31] Tong, X., Tang, R., Xu, J., Wang, W., Zhao, Y., Yu, X., et al. (2022) Liquid-Liquid Phase Separation in Tumor Biology. Signal Transduction and Targeted Therapy, 7, Article No. 221. [Google Scholar] [CrossRef] [PubMed]
[32] Sun, Y., Lau, S.Y., Lim, Z.W., Chang, S.C., Ghadessy, F., Partridge, A., et al. (2022) Phase-Separating Peptides for Direct Cytosolic Delivery and Redox-Activated Release of Macromolecular Therapeutics. Nature Chemistry, 14, 274-283. [Google Scholar] [CrossRef] [PubMed]
[33] Guo, R., Zhang, X., Fan, P., Song, B., Li, Z., Duan, Z., et al. (2021) In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization. Angewandte Chemie International Edition, 60, 25128-25134. [Google Scholar] [CrossRef] [PubMed]
[34] Klein, I.A., Boija, A., Afeyan, L.K., Hawken, S.W., Fan, M., Dall’Agnese, A., et al. (2020) Partitioning of Cancer Therapeutics in Nuclear Condensates. Science, 368, 1386-1392. [Google Scholar] [CrossRef] [PubMed]
[35] Liang, T., Dong, Y., Cheng, I., Wen, P., Li, F., Liu, F., et al. (2024) In Situ Formation of Biomolecular Condensates as Intracellular Drug Reservoirs for Augmenting Chemotherapy. Nature Biomedical Engineering, 8, 1469-1482. [Google Scholar] [CrossRef] [PubMed]
[36] Wen, P., Huang, H., Zhang, R., Zheng, H., Liang, T., Zhuang, C., et al. (2025) Coacervate Vesicles Assembled by Liquid-liquid Phase Separation Improve Delivery of Biopharmaceuticals. Nature Chemistry, 17, 279-288. [Google Scholar] [CrossRef] [PubMed]
[37] Hefnawy, A., Abdelhamid, A.S., Abdelaziz, M.M., Elzoghby, A.O. and Khalil, I.A. (2024) Recent Advances in Nano-Based Drug Delivery Systems for Treatment of Liver Cancer. Journal of Pharmaceutical Sciences, 113, 3145-3172. [Google Scholar] [CrossRef] [PubMed]
[38] Yu, Z., Huang, L. and Guo, J. (2024) Anti-Stromal Nanotherapeutics for Hepatocellular Carcinoma. Journal of Controlled Release, 367, 500-514. [Google Scholar] [CrossRef] [PubMed]
[39] McSwiggen, D.T., Mir, M., Darzacq, X. and Tjian, R. (2019) Evaluating Phase Separation in Live Cells: Diagnosis, Caveats, and Functional Consequences. Genes & Development, 33, 1619-1634. [Google Scholar] [CrossRef] [PubMed]
[40] Zhang, M., Zhang, Z., Niu, X., Ti, H., Zhou, Y., Gao, B., et al. (2024) Interplay between Intracellular Transport Dynamics and Liquid-Liquid Phase Separation. Advanced Science, 11, e2308338. [Google Scholar] [CrossRef] [PubMed]
[41] Zhang, Y., Jin, C., Xu, X., Guo, J. and Wang, L. (2024) The Role of Liquid-Liquid Phase Separation in the Disease Pathogenesis and Drug Development. Biomedicine & Pharmacotherapy, 180, Article ID: 117448. [Google Scholar] [CrossRef] [PubMed]
[42] Ahmad, A., Uversky, V.N. and Khan, R.H. (2022) Aberrant Liquid-Liquid Phase Separation and Amyloid Aggregation of Proteins Related to Neurodegenerative Diseases. International Journal of Biological Macromolecules, 220, 703-720. [Google Scholar] [CrossRef] [PubMed]