Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges

Abstract

Biomolecular condensates are membraneless assemblies that concentrate proteins, nucleic acids, and other biomolecules into dynamic cellular compartments. Liquid-liquid phase separation (LLPS) is one important route by which such condensates form, particularly when multivalent interactions generate liquid-like, reversible assemblies. However, not every condensate or disease-associated assembly should be explained solely by LLPS. In the musculoskeletal system, condensates have been linked to transcription, signal transduction, RNA metabolism, stress responses, tissue development, homeostasis, and mechanoadaptation. Genetic mutations, altered post-translational modifications, and environmental stress can disturb these assemblies, but the evidence does not always establish whether condensates are causal drivers of disease or downstream responses to injury. This review examines how biomolecular condensates and LLPS-related mechanisms have been implicated in osteoporosis, osteoarthritis, skeletal muscle atrophy, bone and soft tissue sarcomas, and neuromusculoskeletal diseases. We focus on the strength of the available evidence, distinguish correlative observations from causal mechanisms where possible, and discuss how condensates may connect non-coding genetic variants, mechanical cues, metabolic signals, and disease phenotypes. We also assess the translational potential and limitations of condensate-based biomarkers, therapies that target pathological condensates, and phase-separation-inspired delivery systems. A central message is that biomolecular condensates offer a useful framework for musculoskeletal biology, but clinical translation will require disease-specific targets, human-relevant models, selective delivery, and rigorous tests of causality.

References

[1] Bonnevie ED, Mauck RL. Physiology and engineering of the graded interfaces of musculoskeletal junctions. Annu. Rev. Biomed. Eng., 2018, 20: 403-429

[2] La Placa G, et al. . The impact of microbiota on musculoskeletal injuries. Cells, 2025, 14: 554

[3] Livshits G, Kalinkovich A. The role of TRIM proteins in chronic inflammation-associated musculoskeletal diseases. Ageing Res. Rev., 2025, 111102837

[4] Jabre S, Hleihel W, Coirault C. Nuclear Mechanotransduction in Skeletal Muscle. Cells, 2021, 10318

[5] Espinosa A, Casas M, Jaimovich E. Energy (and reactive oxygen species generation) saving distribution of mitochondria for the activation of atp production in skeletal muscle. Antioxidants, 2023, 121624

[6] Lowe M, Barr FA. Inheritance and biogenesis of organelles in the secretory pathway. Nat. Rev. Mol. Cell Biol., 2007, 8429-439

[7] Longfield SF, et al. . Tau forms synaptic nano-biomolecular condensates controlling the dynamic clustering of recycling synaptic vesicles. Nat. Commun., 2023, 14 7277

[8] Zhao Z, et al. . Super-resolution imaging of highly curved membrane structures in giant vesicles encapsulating molecular condensates. Adv. Mater., 2022, 34 e2106633

[9] Boeynaems S, et al. . Protein phase separation: a new phase in cell biology. Trends Cell Biol., 2018, 28: 420-435

[10] Sabari BR, et al. . Coactivator condensation at super-enhancers links phase separation and gene control. Science, 2018, 361 eaar3958

[11] Boija A, et al. . Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell, 2018, 175: 1842-1855.e16

[12] Du M, Chen ZJ. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science, 2018, 361: 704-709

[13] Chen X, Wu X, Wu H, Zhang M. Phase separation at the synapse. Nat. Neurosci., 2020, 23: 301-310

[14] Zeng M, et al. . Phase transition in postsynaptic densities underlies formation of synaptic complexes and synaptic plasticity. Cell, 2016, 166: 1163-1175.e12

[15] Guo K, et al. . KANK1 shapes focal adhesions by orchestrating protein binding, mechanical force sensing, and phase separation. Cell Rep., 2023, 42: 113321

[16] Ong JY, Torres JZ. Phase separation in cell division. Mol. Cell, 2020, 809-20

[17] Yang P, et al. . G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell, 2020, 181: 325-345.e28

[18] Fu W, et al. . Multivalent interactions of Septin 6 promote the establishment of epithelial cell polarity. J. Mol. Cell Biol., 2025, 17: mjaf003

[19] Wang B, et al. . Liquid-liquid phase separation in human health and diseases. Signal Transduct. Target Ther., 2021, 6290

[20] Chen Y, et al. . Pathogenic mutation ΔK280 promotes hydrophobic interactions involving microtubule-binding domain and enhances liquid-liquid phase separation of tau. Small, 2025, 21 e2406429

[21] Chen C, Fu G, Guo Q, Xue S, Luo SZ. Phase separation of p53 induced by its unstructured basic region and prevented by oncogenic mutations in tetramerization domain. Int. J. Biol. Macromol., 2022, 222207-216

[22] Banani SF, Lee HO, Hyman AA, Rosen MK. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol., 2017, 18: 285-298

[23] Huai Y, et al. . HuR-positive stress granules: Potential targets for age-related osteoporosis. Aging Cell, 2024, 23 e14053

[24] Ansari MY, Haqqi TM. Interleukin-1β induced stress granules sequester COX-2 mRNA and regulates its stability and translation in human OA chondrocytes. Sci. Rep., 2016, 6 27611

[25] Ahn JH, et al. . Phase separation drives aberrant chromatin looping and cancer development. Nature, 2021, 595: 591-595

[26] Tao J, et al. . Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid-liquid phase separation implicated in myopathy. Nat. Commun., 2023, 14 8131

[27] Yang C, et al. . Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules. Autophagy, 2023, 19: 1934-1951

[28] Wilson EB. The structure of protoplasm. Science, 1899, 10: 33-45

[29] Liu Y, et al. . Mitochondria-associated endoplasmic reticulum membranes in human health and diseases. MedComm, 2025, 6 e70259

[30] Mao YS, Zhang B, Spector DL. Biogenesis and function of nuclear bodies. Trends Genet., 2011, 27: 295-306

[31] Decker CJ, Parker R. P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol., 2012, 4: a012286

[32] Handwerger KE, Cordero JA, Gall JG. Cajal bodies, nucleoli, and speckles in the Xenopus oocyte nucleus have a low-density, sponge-like structure. Mol. Biol. Cell, 2005, 16202-211

[33] Brangwynne CP, et al. . Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science, 2009, 324: 1729-1732

[34] Hyman AA, Weber CA, Jülicher F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol., 2014, 30: 39-58

[35] Basha S, Mukunda DC, Pai AR, Mahato KK. Assessing amyloid fibrils and amorphous aggregates: a review. Int. J. Biol. Macromol., 2025, 311: 143725

[36] Alberti S, Gladfelter A, Mittag T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell, 2019, 176419-434

[37] Bao L, Kang WB, Zhu BC, Xiao Y. Charge arrangement determines the sensitivity of aggregation patterns between peptide-chains to the surrounding ionic environment. J. Chem. Inf. Model., 2025, 65: 950-965

[38] Yan X, Zhang M, Wang D. Interplay between posttranslational modifications and liquid‒liquid phase separation in tumors. Cancer Lett., 2024, 584: 216614

[39] Chen Z, et al. . Liquid-liquid phase separation of biomacromolecules and its roles in metabolic diseases. Cells, 2022, 113023

[40] Rizvi A, et al. . Revealing nanoscale structure and interfaces of protein and polymer condensates via cryo-electron microscopy. Nanoscale, 2024, 1616706-16717

[41] Wang W, et al. . Engineering sequential liquid-liquid phase separation and affinity partitioning for compartmentalization and functionalization of all-aqueous emulsion drops. J. Colloid Interface Sci., 2025, 698: 138136

[42] Dubel N, Liese S, Scherz F, Seitz O. Exploring the limits of bivalency by DNA-based spatial screening. Angew. Chem. Int. Ed. Engl., 2019, 58907-911

[43] Zheng T, et al. . Molecular insights into the effect of 1,6-hexanediol on FUS phase separation. EMBO J., 2025, 44: 2725-2740

[44] Wang X, Levy Y, Iwahara J. Competition between nucleic acids and intrinsically disordered regions within proteins. Acc. Chem. Res., 2025, 58: 2415-2424

[45] Holla A, et al. . Identifying sequence effects on chain dimensions of disordered proteins by integrating experiments and simulations. JACS Au, 2024, 4: 4729-4743

[46] Xu Q, et al. . Impact of nonnative interactions on the binding kinetics of intrinsically disordered p53 with MDM2: insights from all-atom simulation and Markov state model analysis. J. Chem. Inf. Model, 2024, 64: 5219-5231

[47] Batlle C, et al. . hnRNPDL phase separation is regulated by alternative splicing and disease-causing mutations accelerate its aggregation. Cell Rep., 2020, 30: 1117-1128.e5

[48] Moses D, Ginell GM, Holehouse AS, Sukenik S. Intrinsically disordered regions are poised to act as sensors of cellular chemistry. Trends Biochem. Sci., 2023, 48: 1019-1034

[49] Conicella AE, Zerze GH, Mittal J, Fawzi NL. ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure, 2016, 24: 1537-1549

[50] Tong X, et al. . Liquid-liquid phase separation in tumor biology. Signal Transduct. Target Ther., 2022, 7: 221

[51] Wang A, et al. . A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. EMBO J., 2018, 37 e97452

[52] Kim J, Qin S, Zhou HX, Rosen MK. Surface charge can modulate phase separation of multidomain proteins. J. Am. Chem. Soc., 2024, 1463383-3395

[53] He Z, Sommer JU, Harmon TS. Impact of coiled-coil domains on the phase behavior of biomolecular condensates. ACS Macro Lett., 2025, 14: 413-419

[54] Mitrea DM, et al. . Structural polymorphism in the N-terminal oligomerization domain of NPM1. Proc. Natl. Acad. Sci. USA, 2014, 111: 4466-4471

[55] Mitrea DM, et al. . Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. Elife, 2016, 5 e13571

[56] Wang J, et al. . A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell, 2018, 174: 688-699.e16

[57] Wake N, et al. . Expanding the molecular grammar of polar residues and arginine in FUS phase separation. Nat. Chem. Biol., 2025, 21: 1076-1088

[58] Rekhi S, et al. . Expanding the molecular language of protein liquid-liquid phase separation. Nat. Chem., 2024, 16: 1113-1124

[59] Banani SF, et al. . Compositional control of phase-separated cellular bodies. Cell, 2016, 166: 651-663

[60] Ries RJ, et al. . m6A enhances the phase separation potential of mRNA. Nature, 2019, 571: 424-428

[61] Langdon EM, et al. . mRNA structure determines specificity of a polyQ-driven phase separation. Science, 2018, 360: 922-927

[62] Mahendran TS, Wadsworth GM, Singh A, Gupta R, Banerjee PR. Homotypic RNA clustering accompanies a liquid-to-solid transition inside the core of multi-component biomolecular condensates. Nat. Chem., 2025, 17: 1236-1246

[63] Henninger JE, et al. . RNA-mediated feedback control of transcriptional condensates. Cell, 2021, 184: 207-225.e24

[64] Burke KA, Janke AM, Rhine CL, Fawzi NL. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol. Cell, 2015, 60: 231-241

[65] Rippe K. Liquid-liquid phase separation in chromatin. Cold Spring Harb. Perspect. Biol., 2022, 14: a040683

[66] Yao Y, et al. . LncRNA RMG controls liquid-liquid phase separation of MEIS2 to regulate myogenesis. Int. J. Biol. Macromol., 2025, 310143309

[67] Yao Y, et al. . LncRNA-MEG3 regulates muscle mass and metabolic homeostasis by facilitating SUZ12 liquid-liquid phase separation. Adv. Sci., 2025, 12 e2417715

[68] Cheng Z, Cheng Z, Zhang Y, Zhang S. “Intrinsic disorder-protein modification-LLPS-tumor” regulatory axis: from regulatory mechanisms to precision medicine. Biochim Biophys. Acta Rev. Cancer, 2025, 1880189242

[69] Dyson HJ, Wright PE. Intrinsically unstructured proteins and their functions. Nat. Rev. Mol. Cell Biol., 2005, 6197-208

[70] Dai Z, Li G, Chen Q, Yang X. Ser392 phosphorylation modulated a switch between p53 and transcriptional condensates. Biochim. Biophys. Acta Gene Regul. Mech., 2022, 1865: 194827

[71] Yi F, et al. . Regulation of RB1CC1/FIP200 stability and autophagy function by CREBBP-mediated acetylation in an intrinsically disordered region. Autophagy, 2023, 191662-1677

[72] Ryan VH, et al. . Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol. Cell, 2018, 69: 465-479.e7

[73] Li Z, Luo A, Xie B. The complex network of ADP-ribosylation and DNA repair: emerging insights and implications for cancer therapy. Int. J. Mol. Sci., 2023, 24: 15028

[74] Sun YC, et al. . A few charged residues in galectin-3’s folded and disordered regions regulate phase separation. Adv. Sci., 2024, 11 e2402570

[75] Vakeri A, et al. . Lysozyme/alginate interactions: structural and thermodynamic Insights through ITC and SAXS. Biomacromolecules, 2025, 264859-4871

[76] Foressi NN, Cruz Rodríguez L, Wilke N, Celej MS. Cation-driven modulation of tau condensates: insights into liquid-liquid phase separation and rheological properties. Biomacromolecules, 2025, 26: 3605-3616

[77] Kang J, Lim L, Lu Y, Song J. A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids. PLoS Biol., 2019, 17 e3000327

[78] Liu F, Wang J. ATP acts as a hydrotrope to regulate the phase separation of NBDY clusters. JACS Au, 2023, 3: 2578-2585

[79] Dang M, Lim L, Kang J, Song J. ATP biphasically modulates LLPS of TDP-43 PLD by specifically binding arginine residues. Commun. Biol., 2021, 4: 714

[80] Aida H, Shigeta Y, Harada R. The role of ATP in solubilizing RNA-binding protein fused in sarcoma. Proteins, 2022, 901606-1612

[81] Kang J, Lim L, Song J. ATP enhances at low concentrations but dissolves at high concentrations liquid-liquid phase separation (LLPS) of ALS/FTD-causing FUS. Biochem. Biophys. Res. Commun., 2018, 504: 545-551

[82] Man J, et al. . YTHDF2 phase separation promotes arsenite-induced oxidative stress by facilitating YTHDF2-mediated PIK3R2 mRNA degradation. Int. J. Biol. Macromol., 2025, 318: 144936

[83] Guo X, et al. . N4BP1 is a nucleocytoplasmic shuttling protein and recognizes aggregates of the ubiquitin-like protein NEDD8 to protect cells under heat shock. J. Biol. Chem., 2025, 301110511

[84] Zhang X, et al. . Mechanoresponsive regulation of myogenesis by the force-sensing transcriptional regulator Tono. Curr. Biol., 2024, 344143-4159.e6

[85] Tripathi S, Miyake T, Kelebeev J, McDermott JC. TAZ exhibits phase separation properties and interacts with Smad7 and β-catenin to repress skeletal myogenesis. J. Cell Sci., 2022, 135 jcs259097

[86] Janssen A, Colmenares SU, Karpen GH. Heterochromatin: guardian of the genome. Annu. Rev. Cell Dev. Biol., 2018, 34: 265-288

[87] Pei G, Lyons H, Li P, Sabari BR. Transcription regulation by biomolecular condensates. Nat. Rev. Mol. Cell Biol., 2025, 26: 213-236

[88] Zhang Y, et al. . RUNX2 Phase separation mediates long-range regulation between osteoporosis-susceptibility variant and XCR1 to promote osteoblast differentiation. Adv. Sci., 2025, 12 e2413561

[89] Gönczi M, et al. . Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis. Nat. Commun., 2023, 14 1329

[90] Ru W, et al. . METTL3-mediated m6A modification regulates muscle development by promoting TM4SF1 mRNA degradation in P-body via YTHDF2. Int. J. Biol. Macromol., 2025, 295: 139576

[91] Wang Y, et al. . Ncl liquid-liquid phase separation and SUMOylation mediate the stabilization of HIF-1α expression and promote pyroptosis in ischemic hindlimb. Biochim. Biophys. Acta Mol. Basis Dis., 2025, 1871167706

[92] Esposito M, et al. . TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis. Nat. Cell Biol., 2021, 23257-267

[93] Xing G, et al. . Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation. Neuron, 2021, 109: 1963-1978.e5

[94] Chi Z, et al. . Gasdermin D-mediated metabolic crosstalk promotes tissue repair. Nature, 2024, 634: 1168-1177

[95] Zhong L, et al. . Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma. Sci. Adv., 2023, 9 eadi0889

[96] Ivanov P, Kedersha N, Anderson P. Stress granules and processing bodies in translational control. Cold Spring Harb. Perspect. Biol., 2019, 11: a032813

[97] Liu C, et al. . The mechanosensitive lncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention. Bone Res., 2022, 1018

[98] Lin Y, et al. . Posttranslational modification in bone homeostasis and osteoporosis. MedComm, 2025, 6 e70159

[99] Imani M, et al. . Deep learning technique for automatic segmentation of proximal hip musculoskeletal tissues from CT scan images: a MrOS study. J. Cachexia Sarcopenia Muscle, 2025, 16 e13728

[100] Nguyen A, et al. . Addressing the growing burden of musculoskeletal diseases in the ageing US population: challenges and innovations. Lancet Healthy Longev., 2025, 6100707

[101] Wang XY, et al. . An updated overview of the search for biomarkers of osteoporosis based on human proteomics. J. Orthop. Transl., 2024, 4937-48

[102] Zuo L, et al. . Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription. Nat. Commun., 2021, 12 1491

[103] Mullin BH, et al. . Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts. Genome Biol., 2020, 21 80

[104] Zheng K, et al. . Plectin promotes bone formation via phase separation and sequestering annexin A2. Biochem. Pharm., 2025, 242: 117403

[105] Zhao X, Zhao D, Geng B, Yaobin W, Xia Y. A novel ceRNA regulatory network involving the long noncoding NEAT1, miRNA-466f-3p and its mRNA target in osteoblast autophagy and osteoporosis. J. Mol. Med., 2022, 1001629-1646

[106] Zhang Y, et al. . lncRNA Neat1 stimulates osteoclastogenesis via sponging miR-7. J. Bone Min. Res., 2020, 35: 1772-1781

[107] Hisaoka S, et al. . Subcellular distribution of bone morphogenetic protein 2-inducible kinase (BMP2K): Regulation by liquid-liquid phase separation and nucleocytoplasmic shuttling. Biochem. Biophys. Res. Commun., 2023, 649: 16-24

[108] Glyn-Jones S, et al. . Osteoarthritis. Lancet, 2015, 386: 376-387

[109] Chen Z, et al. . Intelligent nanomaterials design for osteoarthritis managements. Small Methods, 2025, 9 e2402263

[110] Li Y, Dong B. Exploring liquid-liquid phase separation-related diagnostic biomarkers in osteoarthritis based on machine learning algorithms and experiment. Immunobiology, 2024, 229: 152825

[111] Huang Y, et al. . TAR DNA-binding protein 43 inhibits inflammatory response and protects chondrocyte function by modulating RACK1 expression in osteoarthritis. Biomed. Pharmacother., 2017, 85362-371

[112] Hata K, et al. . Paraspeckle protein p54nrb links Sox9-mediated transcription with RNA processing during chondrogenesis in mice. J. Clin. Investig., 2008, 118: 3098-3108

[113] Mensah MA, et al. . Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 2023, 614: 564-571

[114] Gu X, et al. . Targeting cancer-induced skeletal damage: a holistic approach to understanding pathophysiology, mechanisms, and management solutions. Am. J. Cancer Res., 2025, 15: 1494-1516

[115] Mesny E, et al. . State-of-the-art of multidisciplinary approach of bone metastasis-directed therapy: review and challenging questions for preparation of a GEMO practice guidelines. Cancer Metastasis Rev., 2025, 44: 45

[116] Merchant MS, et al. . Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin. Cancer Res., 2016, 221364-1370

[117] Tawbi HA, et al. . Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol., 2017, 18: 1493-1501

[118] Kager L, et al. . Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J. Clin. Oncol., 2003, 21: 2011-2018

[119] Ullah K, Zubia E, Narayan M, Yang J, Xu G. Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset. FEBS J., 2019, 286: 2018-2034

[120] Lu B, et al. . Pharmacological inhibition of core regulatory circuitry liquid-liquid phase separation suppresses metastasis and chemoresistance in osteosarcoma. Adv. Sci., 2021, 8 e2101895

[121] Li M, et al. . WDR3 undergoes phase separation to mediate the therapeutic mechanism of Nilotinib against osteosarcoma. J. Exp. Clin. Cancer Res., 2025, 44: 201

[122] Selig EE, et al. . Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain. Proc. Natl. Acad. Sci. USA, 2025, 122 e2221823122

[123] Hou C, Tsodikov OV. Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites. Nucleic Acids Res., 2025, 53gkaf205

[124] Shorter J. Prion-like domains program Ewing’s Sarcoma. Cell, 2017, 17130-31

[125] Kim YR, et al. . Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma. Nat. Commun., 2024, 15 6569

[126] Sohn EJ, Libich DS. Hijacking the BAF complex: the mechanistic interplay of ARID1A and EWS::FLI1 in Ewing sarcoma. Mol. Oncol., 2025, 19: 961-964

[127] Johnson CN, et al. . Insights into molecular diversity within the FUS/EWS/TAF15 protein family: unraveling phase separation of the N-terminal low-complexity domain from RNA-binding protein EWS. J. Am. Chem. Soc., 2024, 146: 8071-8085

[128] Wang Y, et al. . Dissolution of oncofusion transcription factor condensates for cancer therapy. Nat. Chem. Biol., 2023, 19: 1223-1234

[129] Fornetti J, Welm AL, Stewart SA. Understanding the Bone in Cancer Metastasis. J. Bone Miner. Res., 2018, 33: 2099-2113

[130] Jaffe N, Puri A, Gelderblom H. Osteosarcoma: evolution of treatment paradigms. Sarcoma, 2013, 2013: 203531

[131] Sturge J, Caley MP, Waxman J. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat. Rev. Clin. Oncol., 2011, 8357-368

[132] Xin Z, et al. . Immune mediated support of metastasis: implication for bone invasion. Cancer Commun., 2024, 44: 967-991

[133] Bartkowiak K, et al. . Disseminated tumor cells persist in the bone marrow of breast cancer patients through sustained activation of the unfolded protein response. Cancer Res., 2015, 75: 5367-5377

[134] Zhang L, et al. . EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation. Nat. Commun., 2022, 13 2543

[135] Shinde A, et al. . Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer. Cancer Res., 2019, 79: 1831-1843

[136] Ji K, Mayernik L, Moin K, Sloane BF. Acidosis and proteolysis in the tumor microenvironment. Cancer Metastasis Rev., 2019, 38: 103-112

[137] Alsamraae M, Cook LM. Emerging roles for myeloid immune cells in bone metastasis. Cancer Metastasis Rev., 2021, 40: 413-425

[138] Gamboa AC, Gronchi A, Cardona K. Soft-tissue sarcoma in adults: an update on the current state of histiotype-specific management in an era of personalized medicine. CA Cancer J. Clin., 2020, 70: 200-229

[139] Crompton JG, Ogura K, Bernthal NM, Kawai A, Eilber FC. Local control of soft tissue and bone sarcomas. J. Clin. Oncol., 2018, 36: 111-117

[140] Smith HG, et al. . Patterns of disease relapse in primary extremity soft-tissue sarcoma. Br. J. Surg., 2016, 103: 1487-1496

[141] Geramizadeh B, Zare Z, Dehghanian AR, Bolandparvaz S, Marzban M. Huge mesenteric low-grade fibromyxoid sarcoma: a case report and review of the literature. Rare Tumors, 2018, 10: 2036361318777031

[142] Panagopoulos I, et al. . The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer, 2004, 40218-228

[143] Matsuyama A, et al. . Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens. Am. J. Surg. Pathol., 2006, 30: 1077-1084

[144] Wang X, et al. . Aberrant phase separation drives membranous organelle remodeling and tumorigenesis. Mol. Cell, 2025, 85: 1852-1867.e10

[145] Möller E, et al. . FUS-CREB3L2/L1-positive sarcomas show a specific gene expression profile with upregulation of CD24 and FOXL1. Clin. Cancer Res., 2011, 17: 2646-2656

[146] Toro JR, et al. . Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases. Int. J. Cancer, 2006, 119: 2922-2930

[147] Mastrangelo G, et al. . Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. Cancer, 2012, 118: 5339-5348

[148] Gazendam AM, et al. . Synovial sarcoma: a clinical review. Curr. Oncol., 2021, 28: 1909-1920

[149] de Necochea-Campion R, et al. . Metastatic biomarkers in synovial sarcoma. Biomark. Res., 2017, 5 4

[150] Orbach D, et al. . Regional lymph node invasion in pediatric non-rhabdomyosarcoma soft tissue sarcoma: an international cohort study from the International Soft Tissue Sarcoma Consortium. EClinicalMedicine, 2025, 87: 103409

[151] Ren C, Liu J, Hornicek FJ, Yue B, Duan Z. Advances of SS18-SSX fusion gene in synovial sarcoma: emerging novel functions and therapeutic potentials. Biochim. Biophys. Acta Rev. Cancer, 2024, 1879189215

[152] Cheng Y, et al. . Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas. Nat. Commun., 2022, 13 2724

[153] McBride MJ, et al. . The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell, 2018, 331128-1141.e7

[154] Anchondo GM, Parker K, Bruce A, Cortez E, Su LE. The SS18-SSX fusion oncoprotein: friend and foe in targeted therapy for synovial sarcoma. Oncol. Res, 2025, 33: 1001-1005

[155] Tornin J, et al. . FUS-CHOP promotes invasion in myxoid liposarcoma through a SRC/FAK/RHO/ROCK-dependent pathway. Neoplasia, 2018, 20: 44-56

[156] Owen I, et al. . The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation. J. Cell Sci., 2021, 134: jcs258578

[157] Li X, et al. . Targeting drug delivery system to skeletal muscles: a comprehensive review of different approaches. J. Cachexia Sarcopenia Muscle, 2025, 16 e13691

[158] Wen ZQ, et al. . Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases. Mil. Med. Res., 2023, 1054

[159] Julien A, et al. . Direct contribution of skeletal muscle mesenchymal progenitors to bone repair. Nat. Commun., 2021, 12 2860

[160] Yin L, et al. . Skeletal muscle atrophy: from mechanisms to treatments. Pharm. Res., 2021, 172105807

[161] Zammit PS. Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis. Semin. Cell Dev. Biol., 2017, 7219-32

[162] Pérez-Schindler J, et al. . RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates. Proc. Natl. Acad. Sci. USA, 2021, 118 e2105951118

[163] Liu X, et al. . RPS27L enhances myogenesis and muscle mass by targeting IGF1 through liquid-liquid phase separation. Adv. Sci., 2025, 12 e12354

[164] Wang Y, Chen LL. Organization and function of paraspeckles. Essays Biochem, 2020, 64: 875-882

[165] Zhang M, et al. . SRRM2 phase separation drives assembly of nuclear speckle subcompartments. Cell Rep., 2024, 43: 113827

[166] Sunwoo H, et al. . MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res., 2009, 19347-359

[167] Evangelisti C, et al. . Subnuclear localization and differentiation-dependent increased expression of DGK-zeta in C2C12 mouse myoblasts. J. Cell Physiol., 2006, 209: 370-378

[168] Mercuri E, Bönnemann CG, Muntoni F. Muscular dystrophies. Lancet, 2019, 394: 2025-2038

[169] Mezzell AT, Zhang Y, Perez AM, Vest KE. Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics. PLoS Genet., 2026, 22: e1011743

[170] Bengoechea R, et al. . Nuclear speckles are involved in nuclear aggregation of PABPN1 and in the pathophysiology of oculopharyngeal muscular dystrophy. Neurobiol. Dis., 2012, 46118-129

[171] Banerjee A, Vest KE, Pavlath GK, Corbett AH. Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing. Nucleic Acids Res., 2017, 45: 10706-10725

[172] Peng S, et al. . The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation. Cell Death Differ., 2025, 32: 2111-2125

[173] Zibold J, et al. . The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis. Brain, 2024, 147: 1768-1783

[174] Lee Y, et al. . TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations. J. Clin. Invest., 2018, 128: 1164-1177

[175] Kwan HR, et al. . Nerve-independent formation of membrane infoldings at topologically complex postsynaptic apparatus by caveolin-3. Sci. Adv., 2023, 9 eadg0183

[176] Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat. Rev. Neurol., 2013, 9: 617-628

[177] Suk TR, Rousseaux MWC. The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol. Neurodegener., 2020, 15: 45

[178] Yan X, et al. . Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates. Cell, 2025, 1884123-4140.e18

[179] Sun H, et al. . Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms. Nat. Nanotechnol., 2024, 19: 1354-1365

[180] Gao C, et al. . Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus. Cell Rep., 2022, 40: 111086

[181] Carlozzi NE, et al. . How different aspects of motor dysfunction influence day-to-day function in Huntington’s disease. Mov. Disord., 2019, 341910-1914

[182] Yang J, Chen X, Xu H. SQSTM1/p62 droplet -mediated autophagosome formation: insights into Huntington disease. Autophagy, 2021, 17: 3256-3259

[183] De Virgilio A, et al. . Parkinson’s disease: autoimmunity and neuroinflammation. Autoimmun. Rev., 2016, 15: 1005-1011

[184] Stocchi F, Bravi D, Emmi A, Antonini A. Parkinson disease therapy: current strategies and future research priorities. Nat. Rev. Neurol., 2024, 20: 695-707

[185] Dickson, D. W. Neuropathology of Parkinson’s disease and parkinsonism. Cold Spring Harb. Perspect. Med. a041610 (2025).

[186] Ray S, et al. . Synuclein aggregation nucleates through liquid-liquid phase separation. Nat. Chem., 2020, 12: 705-716

[187] Ikenoue T, et al. . De novo peptides that induce the liquid-liquid phase separation of α-synuclein. J. Am. Chem. Soc., 2025, 147: 24113-24126

[188] Xu B, et al. . β-synuclein blocks α-synuclein condensate fusion to disrupt the maturation of phase separation. Cell Rep., 2025, 44: 115761

[189] Han W, Wei M, Xu F, Niu Z. Aggregation and phase separation of α-synuclein in Parkinson’s disease. Chem. Commun., 2024, 606581-6590

[190] Xu B, et al. . Distinct effects of familial Parkinson’s disease-associated mutations on α-synuclein phase separation and amyloid aggregation. Biomolecules, 2023, 13: 726

[191] Wang S, et al. . A novel liquid-liquid phase separation-related gene signature for predicting prognosis in colon cancer. Front. Immunol., 2024, 151514613

[192] Peng W, et al. . Liquid-liquid phase separation-related lncRNA prognostic signature and ZNF32-AS2 as a novel biomarker in hepatocellular carcinoma. Comput Biol. Med., 2024, 169107975

[193] Qiu Y, Pan M, Chen X. A liquid-liquid phase separation-related gene signature as prognostic biomarker for epithelial ovarian cancer. Front. Oncol., 2021, 11671892

[194] Sun L, et al. . Identification of molecular subtypes based on liquid-liquid phase separation and cross-talk with immunological phenotype in bladder cancer. Front. Immunol., 2022, 131059568

[195] Tao B, Wang F, Zhu L. Liquid-liquid phase separation-related signature predicts prognosis and therapeutic response in esophageal adenocarcinoma. Anal. Chim. Acta, 2024, 1330343202

[196] Xie F, et al. . Targeting FOXM1 condensates reduces breast tumour growth and metastasis. Nature, 2025, 6381112-1121

[197] Liu J, et al. . Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma. Nat. Commun., 2021, 12 1022

[198] Chen Y, Xiang H, Li X, Chen Y, Zhang J. Near-infrared laser-switching DNA phase separation nanoinducer for glioma therapy. ACS Nano, 2024, 18: 24426-24440

[199] Chen H, et al. . Cell surface engineering by phase-separated coacervates for antibody display and targeted cancer cell therapy. Angew. Chem. Int. Ed. Engl., 2024, 63 e202410566

[200] Nakamura T, et al. . Phase separation of FSP1 promotes ferroptosis. Nature, 2023, 619: 371-377

[201] Doll S, et al. . FSP1 is a glutathione-independent ferroptosis suppressor. Nature, 2019, 575: 693-698

[202] Li M, et al. . BiFC and FACS-based CRISPR screening revealed that QKI promotes PABPN1 LLPS in colorectal cancer cells. Protein Cell, 2025, 16: 557-574

[203] Wen P, et al. . Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals. Nat. Chem., 2025, 17: 279-288

[204] Sun Y, et al. . Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics. Nat. Chem., 2022, 14: 274-283

[205] Sun Y, et al. . Phase-separating peptide coacervates with programmable material properties for universal intracellular delivery of macromolecules. Nat. Commun., 2024, 15 10094

[206] Bao Y, et al. . Photo-responsive phase-separating fluorescent molecules for intracellular protein delivery. Angew. Chem. Int Ed. Engl., 2023, 62 e202307045

[207] Duan G, et al. . Drug molecule recruitment empowered by phase separation on cell membranes in vivo. JACS Au, 2025, 5: 2567-2579

[208] Guo RC, et al. . In vivo self-assembly induced cell membrane phase separation for improved peptide drug internalization. Angew. Chem. Int. Ed. Engl., 2021, 60: 25128-25134

[209] Fortin AG, et al. . Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence. Acta Biomater., 2025, 200: 313-325

[210] Huang K, et al. . Cartilage-penetrating framework nucleic acid nanoparticles ameliorate osteoarthritis by promoting drug delivery and chondrocyte uptake. Adv. Sci., 2025, 12 e2502661

[211] Zhou Z, et al. . Programmed drug delivering Janus hydrogel adapted to the spatio-temporal therapeutic window for Achilles tendon repair. Acta Biomater., 2025, 201: 139-155

[212] Torrino S, et al. . Mechano-dependent sorbitol accumulation supports biomolecular condensate. Cell, 2025, 188: 447-464.e20

[213] Dupont S, et al. . Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474: 179-183

[214] Zhu F, et al. . Cell-reprogramming-inspired dynamically responsive hydrogel boosts the induction of pluripotency via phase-separated biomolecular condensates. Adv. Mater., 2024, 36 e2211609

[215] Tan K, et al. . Elastic modulus of hydrogel regulates osteogenic differentiation via liquid-liquid phase separation of YAP. J. Biomed. Mater. Res. A, 2023, 111: 1781-1797

[216] Sun X, et al. . Biomolecular condensates decipher molecular codes of cell fate: from biophysical fundamentals to therapeutic practices. Int. J. Mol. Sci., 2024, 254127

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82572835)

Young Scientists Project of the National Key R&D Program (2025YFA1309700) Fundamental Research Funds for the Central Universities (2042025kf0029) Hubei Provincial Health and Health Technology Program (WJ2025Q021)

RIGHTS & PERMISSIONS

The Author(s)