Lipid-induced granules in hepatocytes alleviate liver fibrosis

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.