LIN28A-dependent lncRNA NEAT1 aggravates sepsis-induced acute respiratory distress syndrome through destabilizing ACE2 mRNA by RNA methylation.

Summary

lncRNA NEAT1 worsens lung injury in sepsis-induced ARDS by destabilizing ACE2 mRNA via a methylated NEAT1–hnRNPA2B1–ACE2 complex in LPS-treated AT-II cells, with corroboration in an in vivo model. LIN28A and IGF2BP3 dynamically regulate NEAT1 stability, revealing druggable nodes in an RNA-methylation pathway.

Key Findings

• NEAT1 aggravates lung injury by suppressing ACE2 in sepsis-induced ARDS models in vitro and in vivo
• NEAT1 reduces ACE2 mRNA stability via hnRNPA2B1 and RNA methylation, forming a NEAT1/hnRNPA2B1/ACE2 complex
• LIN28A stabilizes NEAT1, whereas IGF2BP3 disrupts LIN28A–NEAT1 interaction; hnRNPA2B1 modulates this regulatory axis

Clinical Implications

Translational prospects include targeting NEAT1, hnRNPA2B1 interactions, or methylation machinery to preserve ACE2 and mitigate lung injury; biomarkers derived from this axis could stratify sepsis–ARDS risk.

Limitations

• LPS mouse model may not fully capture human sepsis–ARDS heterogeneity
• Lack of human patient tissue validation and therapeutic intervention studies

Future Directions

Validate the NEAT1–hnRNPA2B1–ACE2 axis in human ARDS samples, and test RNA-targeted or epitranscriptomic interventions in preclinical models.