biostudies-literatureLi MFundamental Research Funds for the Central UniversitiesChina Postdoctoral Science FoundationNational Natural Science Foundation of China102682https://www.ebi.ac.uk/biostudies/studies/S-EPMC12790727biostudies-literatureUnknown20(11)Long noncoding RNAs in gene desert regions remain largely uncharacterized despite their potential regulatory roles in cell differentiation. Here, we identify LINC01612 as a crucial modulator of human definitive endoderm differentiation. LINC01612 exhibits stage-specific expression and lacks protein-coding potential during endoderm differentiation. Depletion of LINC01612, through either short hairpin RNA (shRNA)-mediated knockdown or promoter deletion, severely impairs human endoderm differentiation. Mechanistically, LINC01612 interacts with DVL2, a WNT regulator essential for early development, and enhances DVL2 protein stability by reducing its ubiquitination. Loss of LINC01612 or DVL2 impairs WNT signaling, while both WNT activation and DVL2 overexpression can rescue endoderm differentiaStem cell reportsThe LINC01612-DVL2-WNT axis promotes human endoderm differentiation.PMC12790727GZC20251853324006722042022dx00032025M77280732270857Yang JYang YJiang WYan CLu PLi MfalseThe LINC01612-DVL2-WNT axis promotes human endoderm differentiation.Long noncoding RNAs in gene desert regions remain largely uncharacterized despite their potential regulatory roles in cell differentiation. Here, we identify LINC01612 as a crucial modulator of human definitive endoderm differentiation. LINC01612 exhibits stage-specific expression and lacks protein-coding potential during endoderm differentiation. Depletion of LINC01612, through either short hairpin RNA (shRNA)-mediated knockdown or promoter deletion, severely impairs human endoderm differentiation. Mechanistically, LINC01612 interacts with DVL2, a WNT regulator essential for early development, and enhances DVL2 protein stability by reducing its ubiquitination. Loss of LINC01612 or DVL2 impairs WNT signaling, while both WNT activation and DVL2 overexpression can rescue endoderm differentia2025-01-01T00:00:00Z2025 Nov2026-06-11T05:57:30.269Z2026-06-11T03:12:02.177ZS-EPMC127907274113552810.1016/j.stemcr.2025.102682