2. Academic Validation
  3. Lipid-induced granules in hepatocytes alleviate liver fibrosis

Lipid-induced granules in hepatocytes alleviate liver fibrosis

  • Cell Metab. 2026 Jan 9:S1550-4131(25)00546-7. doi: 10.1016/j.cmet.2025.12.015.
Yunhui Li 1,  Ting Lei 1,  Wen Nie 1,  Mingrui Ma 1,  Wei Zhao 1,  Ye Zhou 1,  Yanfang Liu 1,  Minjun Wang 1,  Kaiwei Jia 1,  Shanrong Liu 1,  Yuanyuan Wang 1,  Yiwen Fan 1,  Long Chen 1,  Xing He 1,  Jihang Yuan 1,  Xuetao Cao 2,  Jin Hou 3
Affiliations

Affiliations

  • 1 National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai 200433, China.
  • 2 National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai 200433, China; Center for Immunotherapy, Chinese Academy of Medical Sciences, Beijing 100005, China.
  • 3 National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai 200433, China. Electronic address: [email protected].
PMID: 41519131 DOI: 10.1016/j.cmet.2025.12.015
Abstract

Intracellular membraneless organelles, including granules, bodies, speckles, etc., play critical roles in physiological and pathological processes. The discovery of new membraneless organelles has generated significant attention. DEAD-box helicase (DDX) family members possess the potential to undergo liquid-liquid phase separation (LLPS), the foundation for the assembly of membraneless organelles. Here, to identify new granules assembled in steatotic hepatocytes, we screened DDX family members and found that lipids, especially arachidonic acid (AA) metabolites, induced LLPS of DDX49 in hepatocytes, forming an assembled granule named as lipid-induced granule (LIG). The assembled LIGs by DDX49 feedback restrained metabolic dysfunction-associated steatotic liver disease (MASLD)-associated fibrosis. Mechanistically, C5-methylcytosine (m5C)-modified mRNA of pro-fibrotic hepatokine tissue inhibitor of metalloproteinase 2 (Timp2) and its reader Y-box binding protein 1 (YBX1) were recruited into LIGs, thereby inhibiting Timp2 mRNA translation and consequently feedback suppressing liver fibrosis. Moreover, LIGs were identified in human MASLD livers and exhibited reverse correlation with fibrosis progression. Therefore, we identified a new granule in steatotic hepatocytes and elucidated its role in restraining liver fibrosis.

Keywords

C5-methylcytosine; DEAD-box helicase 49; liquid-liquid phase separation; membraneless organelle; metabolic dysfunction-associated steatotic liver disease.

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