MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to target mRNAs, leading to reduced protein production. A study using ribosome profiling shows that miRNAs primarily decrease mRNA levels rather than translational efficiency. The research found that for both ectopic and endogenous miRNA interactions, mRNA destabilization accounts for most of the reduced protein output, with over 84% of the effect attributed to decreased mRNA levels. This suggests that miRNAs mainly function by destabilizing their target mRNAs, rather than by inhibiting translation. The study also found that miRNAs have a consistent effect on mRNA levels regardless of the expression level of the target genes. While some miRNAs may have a minor effect on translational efficiency, the majority of miRNA-mediated repression is due to mRNA destabilization. The findings support the "mRNA-destabilization" scenario, which contrasts with the previously proposed "translational-repression" scenario. The study also showed that mRNA levels and ribosome profiling data are closely correlated, indicating that mRNA destabilization is a major factor in miRNA-mediated gene regulation. The results suggest that miRNAs predominantly act to reduce mRNA levels of nearly all targets, with only a small fraction of repression attributed to translational efficiency. The study provides evidence that miRNA-mediated mRNA destabilization is a widespread and dominant mechanism of gene regulation.MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to target mRNAs, leading to reduced protein production. A study using ribosome profiling shows that miRNAs primarily decrease mRNA levels rather than translational efficiency. The research found that for both ectopic and endogenous miRNA interactions, mRNA destabilization accounts for most of the reduced protein output, with over 84% of the effect attributed to decreased mRNA levels. This suggests that miRNAs mainly function by destabilizing their target mRNAs, rather than by inhibiting translation. The study also found that miRNAs have a consistent effect on mRNA levels regardless of the expression level of the target genes. While some miRNAs may have a minor effect on translational efficiency, the majority of miRNA-mediated repression is due to mRNA destabilization. The findings support the "mRNA-destabilization" scenario, which contrasts with the previously proposed "translational-repression" scenario. The study also showed that mRNA levels and ribosome profiling data are closely correlated, indicating that mRNA destabilization is a major factor in miRNA-mediated gene regulation. The results suggest that miRNAs predominantly act to reduce mRNA levels of nearly all targets, with only a small fraction of repression attributed to translational efficiency. The study provides evidence that miRNA-mediated mRNA destabilization is a widespread and dominant mechanism of gene regulation.