Dysregulated alveolar type 2 epithelial cell proteostasis promotes fibrogenic macrophage migration inhibitory factor-CD74 signaling.

Summary

Using multiple models, the authors demonstrate that disrupting the ubiquitin–proteasome system in AEC2s drives profibrotic macrophage signaling via MIF family proteins and CD74. The work implicates epithelial proteostasis as an upstream regulator of MIF–CD74 crosstalk in IPF pathogenesis and highlights this axis as a potential therapeutic target.

Key Findings

• AEC2-specific disruption of the ubiquitin–proteasome system amplifies profibrotic signaling toward macrophages.
• Macrophage migration inhibitory factor (MIF) family proteins and CD74 mediate the epithelial–macrophage crosstalk.
• Findings were consistent across several experimental models, supporting a generalizable mechanism.

Clinical Implications

Targeting MIF–CD74 signaling or restoring epithelial proteostasis in AEC2s may attenuate macrophage-driven fibrosis, offering new avenues for IPF treatment beyond current antifibrotic agents.

Limitations

• Abstract does not detail human validation or therapeutic intervention data.
• Specifics of the AEC2 cullin 3 model and downstream effectors beyond MIF–CD74 are truncated in the abstract.

Future Directions

Validate MIF–CD74 dependency in human IPF tissues and test pharmacologic modulation of MIF–CD74 or epithelial UPS pathways in preclinical models moving toward translational trials.