MiR-144 regulates glucocorticoid sensitivity in acute respiratory distress syndrome via the GRβ/NF-κB axis

MicroRNA-144 (miR-144) has been implicated in inflammation and glucocorticoid (GC) receptor regulation, but its role in GC sensitivity during acute respiratory distress syndrome (ARDS) is unclear. This study aimed to investigate the impact of miR-144 on GC therapeutic efficacy, elucidate its underlying molecular mechanisms in ARDS, and validate its clinical application value.

First, we established a sepsis-induced ARDS rat model with five groups (n = 6 each): control, model, GC, GC + miR-144 mimic, or GC + miR-144 inhibitor. Body weight, inflammatory markers, lung wet/dry ratio, histopathology, and miR-144/GRα/GRβ/NF-κB mRNA were assessed after the 5-day treatment. Second, we prospectively enrolled 63 ARDS patients receiving methylprednisolone and classified them as GC-sensitive (n = 43) or GC-resistant (n = 20) based on clinical outcomes. The correlations of baseline miR-144, GRα, GRβ, and NF-κB mRNA levels in patient blood were analyzed, and the predictive value of miR-144 for GC sensitivity was evaluated.

In rats, miR-144 inhibitor enhanced GC efficacy (improved body weight recovery, reduced lung edema and inflammation), while mimic attenuated these effects. Mechanistically, in rat lung tissue, sepsis stimulation increased miR-144, GRβ, and NF-κB while reducing GRα expression; GC reversed these changes; miR-144 inhibitor further reduced GRβ/NF-κB, whereas mimic antagonized this without affecting GRα. In patients, GC-resistant individuals showed significantly higher miR-144, GRβ, and NF-κB levels than sensitive ones. Strong positive correlations were observed between miR-144 and both GRβ and NF-κB, and miR-144 effectively predicted GC resistance in ARDS.

MiR-144 regulates GC sensitivity via the GRβ/NF-κB axis in ARDS. Baseline miR-144 level is a promising biomarker for predicting GC response, providing a basis for individualized treatment.