A549 cells with glucocorticoid treatment

Processing bodies (P-bodies) are cytoplasmic, membraneless organelles that play a key role in regulating RNA translation. To identify new pathways controlling their formation, we conducted a Food and Drug Administration (FDA)-approved drug screen. We found that glucocorticoids, among the most prescribed medicines, significantly increase P-body numbers across diverse epithelial cell types. This effect was fully reversible after glucocorticoid withdrawal, illustrating the adaptive dynamics of P-bodies. Using genetic invalidation and rescue approaches, we demonstrated that this accumulation requires the Glucocorticoid Receptor alpha isoform. P-body accumulation was associated with selective post-transcriptional regulation of P-body-associated mRNAs rather than global inhibition of translation. This selectivity was driven by intrinsic transcript features, including nucleotide composition and codon usage: AU-rich transcripts with low Codon Adaptation Index (CAI) were preferentially accumulated and translationally repressed, whereas GC-rich transcripts with higher CAI displayed enhanced protein output under glucocorticoid treatment. Furthermore, we associated the decrease of LSM14B, a negative regulator of P-bodies, under glucocorticoid treatment to P-body reshaping. Our results reveal that, beyond their known transcriptional activity, prolonged exposure to glucocorticoids influences mRNA post-transcription and translation through a nucleotide composition-based mechanism.