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Abstract Short upstream open reading frames (uORFs) are the most prevalent cis -acting regulatory elements in the mammalian transcriptome which can orchestrate mRNA translation. Apart from being "passive roadblocks" that decrease expression of the main coding regions, particular uORFs can serve as specific sensors for changing conditions, thus regulating translation in response to cell stress. Here we report a novel uORF-based regulatory mechanism that is employed under conditions of hyperosmotic stress by at least two human mRNAs, coding for translation reinitiation/recycling factor eIF2D and E3 ubiquitin ligase MDM2. This novel mode of translational control selectively downregulates their expression and requires as few as one uORF. Using a set of reporter mRNAs and fleeting mRNA transfection (FLERT) technique, we provide evidence that the phenomenon does not rely on delayed reinitiation, altered AUG recognition, ribosome stalling, mRNA destabilization or other known mechanisms. Instead, it is based on events taking place at uORF stop codon or immediately downstream. Functional aspects and implications of the novel regulatory mechanism to cell physiology are discussed. Graphical abstract Image 1 Highlights • uORFs regulate translation of more than half of human mRNAs. • A novel uORF-based regulatory mechanism is employed by human MDM2 and eIF2D mRNAs. • Translation of MDM2 and eIF2D mRNAs is specifically inhibited during osmotic stress. • The inhibition is based on events occurring at uORF stop codon or downstream. • Translation repression of MDM2 mRNA contributes to stress-induced cell cycle arrest. [ABSTRACT FROM AUTHOR]