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

Summary

NEAT1 exacerbates lung injury in sepsis-induced ARDS by destabilizing ACE2 mRNA through an hnRNPA2B1-dependent RNA methylation complex, validated in LPS-treated AT-II cells and mouse models. The LIN28A–IGF2BP3–hnRNPA2B1 axis reciprocally controls NEAT1 stability, highlighting multiple potential intervention points.

Key Findings

• NEAT1 suppresses ACE2 and aggravates lung injury in sepsis-induced ARDS models in vitro and in vivo.
• NEAT1 destabilizes ACE2 mRNA via an hnRNPA2B1-dependent, RNA methylation–mediated complex (NEAT1/hnRNPA2B1/ACE2 mRNA) in LPS-treated AT-II cells.
• LIN28A stabilizes NEAT1, whereas IGF2BP3 promotes NEAT1 destabilization by disrupting LIN28A–NEAT1 binding; hnRNPA2B1 counters by stabilizing NEAT1.

Clinical Implications

While preclinical, the work suggests that targeting NEAT1 or its interacting proteins (hnRNPA2B1, LIN28A, IGF2BP3) could ameliorate lung injury in sepsis-induced ARDS; it also cautions that ACE2-modulating strategies may have complex upstream regulatory layers.

Limitations

• LPS-induced models may not capture full clinical heterogeneity of human sepsis-induced ARDS
• No therapeutic knockdown/antagonist studies demonstrating reversal of injury in clinically relevant models

Future Directions

Validate NEAT1/hnRNPA2B1–ACE2 axis in human sepsis-ARDS lung tissues; test antisense oligonucleotides or small-molecule inhibitors targeting NEAT1 or its interactors in clinically relevant models.