GCN1 is a conserved ribosome collision sensor that plays dual roles in translation quality control and stress response. As a primary function, GCN1 directly binds stalled ribosomes and acts as a sentinel for ribosome collisions, recruiting the E3 ligase RNF14 to promote ubiquitination and degradation of translation factors including eEF1A and eRF1 on stalled ribosomes 1. This RNF14-RNF25-dependent pathway also mediates ubiquitination of ribosomal proteins, maintaining proteostasis during translational stress 12. Mechanistically, GCN1 serves as a positive activator of the integrated stress response (ISR) by recruiting GCN2 to collided ribosomes in an amino acid starvation-dependent manner 3. GCN1-mediated GCN2 activation stimulates phosphorylation of eIF2α, attenuating global translation while promoting preferential translation of ISR-responsive mRNAs like ATF4 to reprogram amino acid biosynthesis 4. Diseases relevant to GCN1 dysfunction include acute myeloid leukemia, where GCN1/GCN2/ATF4 pathway activation mediates apoptosis following therapeutic protein degradation 5. Recent findings reveal GCN1 also regulates cell proliferation, apoptosis, and immune responses independently of GCN2, indicating broader physiological roles 67. Clinically, GCN1 represents a promising therapeutic target for cancer treatment and may be relevant in aging and neurodegenerative diseases through its regulation of ribosome-mediated proteostasis 6.