Protein degradation is crucial for maintaining protein homeostasis, and the ubiquitin-proteasome system (UPS) and autophagy-lysosome system are the primary pathways responsible for this process. In colorectal cancer (CRC), these pathways play dual roles in both initiation and progression. The UPS is critical in managing the excessive protein load caused by cancer cell hyperproliferation, while the autophagy-lysosome system is involved in degrading long-lived proteins, insoluble aggregates, and damaged organelles. The interplay between these pathways is complex and bidirectional, with mutual compensation mechanisms. The UPS involves six components: ubiquitin, E1, E2, E3, the proteasome, and a deubiquitinating enzyme (DUB). Protein degradation through the UPS involves ubiquitination, followed by degradation by the 26S proteasome. E3 ligases play a key role in substrate specificity, influencing cell cycle, gene transcription, DNA repair, and apoptosis. Dysregulation of UPS components, such as E1, E2, and E3, can lead to CRC progression. For example, UBE2J1 and UBE2V1 promote CRC by facilitating protein degradation, while RNF6 and FBXL6 promote cell growth and invasion by degrading specific proteins. The autophagy-lysosome system includes macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Autophagy regulates cell cycle, oncogenic signaling pathways, and lysosomal homeostasis. It also influences metastasis, genomic stability, cancer stemness, immune response, and chemotherapy resistance. For instance, RSL1D1 inhibits autophagy to promote CRC metastasis, while ATG9B increases the risk of metastasis through autophagy-independent mechanisms. The UPS and autophagy-lysosome system are interconnected, with ubiquitin molecules linking them. Autophagy receptors like p62/SQSTM1 target ubiquitinated proteins for lysosomal degradation. E2 and E3 enzymes can affect autophagy by modifying proteins involved in autophagy activation or inhibition. For example, UBE2V1 suppresses autophagy genes, while RNF186 binds to EPHB2 to promote autophagy. Inhibition of the autophagy-lysosomal process can enhance proteasome activity, leading to increased protein degradation and cancer cell death. Conversely, inhibition of the UPS can activate autophagy, promoting tumor growth and resistance to chemotherapy. This bidirectional relationship highlights the potential for combined targeting of both pathways to improve treatment efficacy against CRC. Further research is needed to fully understand these mechanisms and their therapeutic implications.Protein degradation is crucial for maintaining protein homeostasis, and the ubiquitin-proteasome system (UPS) and autophagy-lysosome system are the primary pathways responsible for this process. In colorectal cancer (CRC), these pathways play dual roles in both initiation and progression. The UPS is critical in managing the excessive protein load caused by cancer cell hyperproliferation, while the autophagy-lysosome system is involved in degrading long-lived proteins, insoluble aggregates, and damaged organelles. The interplay between these pathways is complex and bidirectional, with mutual compensation mechanisms. The UPS involves six components: ubiquitin, E1, E2, E3, the proteasome, and a deubiquitinating enzyme (DUB). Protein degradation through the UPS involves ubiquitination, followed by degradation by the 26S proteasome. E3 ligases play a key role in substrate specificity, influencing cell cycle, gene transcription, DNA repair, and apoptosis. Dysregulation of UPS components, such as E1, E2, and E3, can lead to CRC progression. For example, UBE2J1 and UBE2V1 promote CRC by facilitating protein degradation, while RNF6 and FBXL6 promote cell growth and invasion by degrading specific proteins. The autophagy-lysosome system includes macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Autophagy regulates cell cycle, oncogenic signaling pathways, and lysosomal homeostasis. It also influences metastasis, genomic stability, cancer stemness, immune response, and chemotherapy resistance. For instance, RSL1D1 inhibits autophagy to promote CRC metastasis, while ATG9B increases the risk of metastasis through autophagy-independent mechanisms. The UPS and autophagy-lysosome system are interconnected, with ubiquitin molecules linking them. Autophagy receptors like p62/SQSTM1 target ubiquitinated proteins for lysosomal degradation. E2 and E3 enzymes can affect autophagy by modifying proteins involved in autophagy activation or inhibition. For example, UBE2V1 suppresses autophagy genes, while RNF186 binds to EPHB2 to promote autophagy. Inhibition of the autophagy-lysosomal process can enhance proteasome activity, leading to increased protein degradation and cancer cell death. Conversely, inhibition of the UPS can activate autophagy, promoting tumor growth and resistance to chemotherapy. This bidirectional relationship highlights the potential for combined targeting of both pathways to improve treatment efficacy against CRC. Further research is needed to fully understand these mechanisms and their therapeutic implications.