The findings on melatonin’s regulation of PER2 and CRY2 and its therapeutic potential for RA-ILD are intriguing. I was particularly interested in the interplay between macrophagic infiltration and epithelial–mesenchymal transition (EMT). Could the authors elaborate on whether the identified chemokine suppression (e.g., CCL2, CCL3, CCL4) was linked to specific macrophage subtypes (e.g., M1 vs. M2 polarization)? This could provide more clarity on the immune modulatory pathways involved.
Additionally, while the study highlights melatonin’s influence on CCGs, the underlying mechanisms connecting circadian rhythm restoration with reduced EMT are less explored. Could future studies investigate whether PER2 and CRY2 directly regulate EMT-related transcription factors, such as Snail or Twist, to establish a more mechanistic link?
Lastly, given the therapeutic implications, how do the authors envision translating these findings into clinical applications? For example, would melatonin supplementation or clock gene modulators be considered as adjunct therapies for RA-ILD, and what challenges might arise in terms of dosing or timing to synchronize with circadian cycles?