The Keap1-Nrf2 signaling pathway is crucial for cellular defense against oxidative stress. Keap1, a key regulator in this pathway, controls Nrf2 activity through various post-translational modifications (PTMs), such as alkylation, glycosylation, glutathioneylation, S-sulfhydration, and others. These modifications affect the binding affinity between Keap1 and Nrf2, leading to Nrf2 accumulation and nuclear translocation, which activates downstream antioxidant genes. Understanding these PTMs is essential for identifying novel drug targets and biomarkers, as the Keap1-Nrf2 pathway is linked to diseases like cancer, neurodegenerative disorders, and diabetes. Keap1 is a protein with a complex structure, consisting of five domains, including the BTB/POZ and Kelch domains. These domains regulate oxidative stress by modulating Nrf2 activity. The Kelch domain interacts with Nrf2, influencing its stability and the expression of antioxidant response genes. PTMs of Keap1, such as ubiquitination, glutathionylation, alkylation, glycosylation, phosphorylation, S-sulfhydration, and SUMOylation, play critical roles in regulating Nrf2 activity and the antioxidant response. These modifications can either enhance or inhibit Nrf2 function, affecting cellular defense against oxidative stress. Various PTMs of Keap1 have been identified, including ubiquitination, which regulates Nrf2 stability and degradation; glutathionylation, which affects Nrf2 nuclear translocation and antioxidant gene expression; alkylation, which disrupts Keap1-Nrf2 interaction and promotes Nrf2 activation; glycosylation, which influences Keap1-CUL3 interaction and Nrf2 ubiquitination; phosphorylation, which modulates Keap1-Nrf2 binding; S-sulfhydration, which enhances Nrf2 nuclear translocation and antioxidant gene expression; and SUMOylation, which affects Keap1 stability and Nrf2 regulation. These PTMs are crucial for maintaining cellular redox balance and protecting against oxidative stress-related diseases. Understanding the mechanisms of these modifications provides insights into the molecular basis of oxidative stress and offers potential therapeutic strategies for diseases associated with oxidative damage. The study of Keap1 PTMs is essential for developing new treatments and interventions targeting oxidative stress-related conditions.The Keap1-Nrf2 signaling pathway is crucial for cellular defense against oxidative stress. Keap1, a key regulator in this pathway, controls Nrf2 activity through various post-translational modifications (PTMs), such as alkylation, glycosylation, glutathioneylation, S-sulfhydration, and others. These modifications affect the binding affinity between Keap1 and Nrf2, leading to Nrf2 accumulation and nuclear translocation, which activates downstream antioxidant genes. Understanding these PTMs is essential for identifying novel drug targets and biomarkers, as the Keap1-Nrf2 pathway is linked to diseases like cancer, neurodegenerative disorders, and diabetes. Keap1 is a protein with a complex structure, consisting of five domains, including the BTB/POZ and Kelch domains. These domains regulate oxidative stress by modulating Nrf2 activity. The Kelch domain interacts with Nrf2, influencing its stability and the expression of antioxidant response genes. PTMs of Keap1, such as ubiquitination, glutathionylation, alkylation, glycosylation, phosphorylation, S-sulfhydration, and SUMOylation, play critical roles in regulating Nrf2 activity and the antioxidant response. These modifications can either enhance or inhibit Nrf2 function, affecting cellular defense against oxidative stress. Various PTMs of Keap1 have been identified, including ubiquitination, which regulates Nrf2 stability and degradation; glutathionylation, which affects Nrf2 nuclear translocation and antioxidant gene expression; alkylation, which disrupts Keap1-Nrf2 interaction and promotes Nrf2 activation; glycosylation, which influences Keap1-CUL3 interaction and Nrf2 ubiquitination; phosphorylation, which modulates Keap1-Nrf2 binding; S-sulfhydration, which enhances Nrf2 nuclear translocation and antioxidant gene expression; and SUMOylation, which affects Keap1 stability and Nrf2 regulation. These PTMs are crucial for maintaining cellular redox balance and protecting against oxidative stress-related diseases. Understanding the mechanisms of these modifications provides insights into the molecular basis of oxidative stress and offers potential therapeutic strategies for diseases associated with oxidative damage. The study of Keap1 PTMs is essential for developing new treatments and interventions targeting oxidative stress-related conditions.