Internal ribosome entry sites (IRESs) are found in some eukaryotic mRNAs and allow translation initiation without the need for the 5' cap structure. Unlike the canonical scanning mechanism, which relies on the 5' cap and eIF4E to recruit ribosomes, IRESs enable initiation directly at internal sites within the mRNA. This mechanism is particularly useful under physiological conditions such as mitosis, apoptosis, hypoxia, and viral infections, where most mRNAs are repressed. The canonical scanning mechanism involves the 43S complex, which includes eIF2-GTP/Met-tRNA, eIF1A, and eIF3, binding to the 5' cap of the mRNA. This complex scans the mRNA until it finds an appropriate start codon, after which the 60S subunit joins to form an 80S ribosome. However, IRESs bypass this process by allowing ribosomes to bind directly to the mRNA at internal sites, often in the 5' nontranslated region (NTR). IRESs are found in viral and some cellular mRNAs. They are highly structured and contain multiple AUG triplets that can act as barriers to scanning ribosomes. However, certain IRESs, such as those in picornaviruses, can mediate translation without the need for the 5' cap or eIF4E. This is achieved through mechanisms like ribosomal shunting and internal initiation. Ribosomal shunting allows ribosomes to bypass stable RNA structures by shunting to a downstream landing site, while internal initiation enables ribosomes to bind directly to the mRNA at internal sites. These mechanisms are crucial for the efficient translation of mRNAs under conditions where the canonical scanning mechanism is not effective. The HCV IRES is a well-studied example of an IRES that allows translation initiation without the need for eIF4E, eIF4A, eIF4B, or eIF4F. It binds directly to the 40S subunit, placing the initiation codon in the ribosomal decoding region. This allows for efficient translation even in the absence of the usual initiation factors. In addition to viral IRESs, some cellular mRNAs also contain IRESs, which can be regulated by specific factors. These IRESs are often involved in the translation of regulatory proteins and can be influenced by cellular conditions such as the availability of amino acids or the presence of specific RNA-binding proteins. The study of IRESs has provided important insights into the diversity of translation initiation mechanisms in eukaryotic cells. These mechanisms are essential for the efficient translation of mRNAs under various physiological conditions and highlight the complexity of the translation process in eukaryotic cells.Internal ribosome entry sites (IRESs) are found in some eukaryotic mRNAs and allow translation initiation without the need for the 5' cap structure. Unlike the canonical scanning mechanism, which relies on the 5' cap and eIF4E to recruit ribosomes, IRESs enable initiation directly at internal sites within the mRNA. This mechanism is particularly useful under physiological conditions such as mitosis, apoptosis, hypoxia, and viral infections, where most mRNAs are repressed. The canonical scanning mechanism involves the 43S complex, which includes eIF2-GTP/Met-tRNA, eIF1A, and eIF3, binding to the 5' cap of the mRNA. This complex scans the mRNA until it finds an appropriate start codon, after which the 60S subunit joins to form an 80S ribosome. However, IRESs bypass this process by allowing ribosomes to bind directly to the mRNA at internal sites, often in the 5' nontranslated region (NTR). IRESs are found in viral and some cellular mRNAs. They are highly structured and contain multiple AUG triplets that can act as barriers to scanning ribosomes. However, certain IRESs, such as those in picornaviruses, can mediate translation without the need for the 5' cap or eIF4E. This is achieved through mechanisms like ribosomal shunting and internal initiation. Ribosomal shunting allows ribosomes to bypass stable RNA structures by shunting to a downstream landing site, while internal initiation enables ribosomes to bind directly to the mRNA at internal sites. These mechanisms are crucial for the efficient translation of mRNAs under conditions where the canonical scanning mechanism is not effective. The HCV IRES is a well-studied example of an IRES that allows translation initiation without the need for eIF4E, eIF4A, eIF4B, or eIF4F. It binds directly to the 40S subunit, placing the initiation codon in the ribosomal decoding region. This allows for efficient translation even in the absence of the usual initiation factors. In addition to viral IRESs, some cellular mRNAs also contain IRESs, which can be regulated by specific factors. These IRESs are often involved in the translation of regulatory proteins and can be influenced by cellular conditions such as the availability of amino acids or the presence of specific RNA-binding proteins. The study of IRESs has provided important insights into the diversity of translation initiation mechanisms in eukaryotic cells. These mechanisms are essential for the efficient translation of mRNAs under various physiological conditions and highlight the complexity of the translation process in eukaryotic cells.