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Background <p>Liposarcoma (LPS) is one of the most common soft tissue sarcomas and is characterized by marked heterogeneity and a strong tendency toward recurrence. Conventional histopathologic classification mainly includes well-differentiated and dedifferentiated liposarcoma, myxoid and round cell liposarcoma, and pleomorphic liposarcoma. In recent years, molecular hallmarks, such as amplification of MDM2 and CDK4 and fusion genes including FUS::DDIT3 and CPSF6-related fusions, have become essential for accurate diagnosis and subtype assignment.</p> Main body <p>LPS development and subtype transition are driven by integrated molecular events, including 12q13–15 amplification with MDM2/CDK4 overexpression, PPARγ dysregulation, PI3K–AKT–mTOR activation, epigenetic alterations, and tumor microenvironment interactions. Together, these changes promote malignant transformation, dedifferentiation, and therapeutic heterogeneity across subtypes. Within this broader framework, the proteasome has emerged as a therapeutically relevant regulatory layer, particularly in selected contexts such as MDM2-amplified WDLS/DDLS, where protein turnover directly influences the stability of key driver proteins. Clinically, complete surgical resection remains the standard treatment when feasible, while doxorubicin plus ifosfamide is the mainstay for advanced or metastatic disease. Targeted therapies, such as palbociclib for MDM2-amplified WDLS/DDLS, as well as immunotherapy, have shown activity in some patients. Emerging investigational strategies also seek to target MDM2–p53, CDK4/6, epigenetic dysregulation, and proteostasis-related vulnerabilities.</p> Conclusion <p>This review summarizes the classification, subtype-specific characteristics, molecular mechanisms, treatment strategies, and prognosis of LPS, and further discusses how proteasome-associated mechanisms may create therapeutic vulnerabilities in selected subtypes. A better understanding of the molecular basis underlying tumor initiation, progression, and subtype transition may support the development of more precise and mechanism-based therapeutic strategies for LPS.</p>

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Molecular mechanisms underlying liposarcoma subtype transition and proteasome-associated targeted interventions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Jiahao Liu,
  • Mingke Huo,
  • Sihan Wu,
  • Zhen Wang,
  • Sanfei Peng,
  • Yang Fu

摘要

Background

Liposarcoma (LPS) is one of the most common soft tissue sarcomas and is characterized by marked heterogeneity and a strong tendency toward recurrence. Conventional histopathologic classification mainly includes well-differentiated and dedifferentiated liposarcoma, myxoid and round cell liposarcoma, and pleomorphic liposarcoma. In recent years, molecular hallmarks, such as amplification of MDM2 and CDK4 and fusion genes including FUS::DDIT3 and CPSF6-related fusions, have become essential for accurate diagnosis and subtype assignment.

Main body

LPS development and subtype transition are driven by integrated molecular events, including 12q13–15 amplification with MDM2/CDK4 overexpression, PPARγ dysregulation, PI3K–AKT–mTOR activation, epigenetic alterations, and tumor microenvironment interactions. Together, these changes promote malignant transformation, dedifferentiation, and therapeutic heterogeneity across subtypes. Within this broader framework, the proteasome has emerged as a therapeutically relevant regulatory layer, particularly in selected contexts such as MDM2-amplified WDLS/DDLS, where protein turnover directly influences the stability of key driver proteins. Clinically, complete surgical resection remains the standard treatment when feasible, while doxorubicin plus ifosfamide is the mainstay for advanced or metastatic disease. Targeted therapies, such as palbociclib for MDM2-amplified WDLS/DDLS, as well as immunotherapy, have shown activity in some patients. Emerging investigational strategies also seek to target MDM2–p53, CDK4/6, epigenetic dysregulation, and proteostasis-related vulnerabilities.

Conclusion

This review summarizes the classification, subtype-specific characteristics, molecular mechanisms, treatment strategies, and prognosis of LPS, and further discusses how proteasome-associated mechanisms may create therapeutic vulnerabilities in selected subtypes. A better understanding of the molecular basis underlying tumor initiation, progression, and subtype transition may support the development of more precise and mechanism-based therapeutic strategies for LPS.