The Keap1-Nrf2 signaling pathway plays a crucial role in cellular defense against oxidative stress. Keap1, a key transcriptional regulator, controls the activity of Nrf2 through various post-translational modifications (PTMs) such as alkylation, glycosylation, glutathionylation, S-sulfhydration, and others. These PTMs affect the binding affinity between Keap1 and Nrf2, leading to the accumulation and nuclear translocation of Nrf2, which activates downstream antioxidant genes. Understanding Keap1's PTMs is essential for comprehending Nrf2 signaling regulation and identifying novel drug targets and biomarkers for diseases like cancer, neurodegenerative disorders, and diabetes. The review covers the structure and function of Keap1, the molecular mechanisms of PTMs, and their implications in oxidative stress and related diseases. Key findings include the identification of specific modification sites and the role of PTMs in regulating Nrf2 activity. The study highlights the potential of Keap1 as a therapeutic target and the development of compounds that interfere with Keap1's inhibitory effect on Nrf2 to combat oxidative stress-related diseases.The Keap1-Nrf2 signaling pathway plays a crucial role in cellular defense against oxidative stress. Keap1, a key transcriptional regulator, controls the activity of Nrf2 through various post-translational modifications (PTMs) such as alkylation, glycosylation, glutathionylation, S-sulfhydration, and others. These PTMs affect the binding affinity between Keap1 and Nrf2, leading to the accumulation and nuclear translocation of Nrf2, which activates downstream antioxidant genes. Understanding Keap1's PTMs is essential for comprehending Nrf2 signaling regulation and identifying novel drug targets and biomarkers for diseases like cancer, neurodegenerative disorders, and diabetes. The review covers the structure and function of Keap1, the molecular mechanisms of PTMs, and their implications in oxidative stress and related diseases. Key findings include the identification of specific modification sites and the role of PTMs in regulating Nrf2 activity. The study highlights the potential of Keap1 as a therapeutic target and the development of compounds that interfere with Keap1's inhibitory effect on Nrf2 to combat oxidative stress-related diseases.