Michael acceptors are a class of compounds with potential anti-cancer properties. They act by binding to nucleophilic sites in biological molecules, disrupting cancer cell function and inducing cell death. Their ability to be modified and targeted makes them promising for cancer therapy. The anti-cancer effects of Michael acceptors are due to their chemical structure and reactivity, allowing them to selectively target disease-associated proteins with minimal toxicity. These compounds, often derived from plants, exert effects via signaling pathways such as Keap1-NRF2-ARE and NF-κB, showing antioxidant and anti-inflammatory activities, making them promising for treating diseases associated with oxidative stress, inflammation, and cancer. Nitro fatty acids (NFAs), another type of Michael acceptor, have shown therapeutic efficacy in animal models of inflammation and cancer, leading to Phase II clinical trials for pulmonary arterial hypertension. Michael acceptors can form covalent bonds with nucleophilic residues in proteins, modulating protein pathways to exert physiological effects. They play a central role in regulating signaling pathways such as Keap1-NRF2-ARE and NF-κB, making them promising candidates for treating various diseases. The kinetics of inhibition via Michael reactions differ between reversible and irreversible covalent inhibitors. Reversible inhibitors can be released from non-target proteins, reducing off-target toxicity, while irreversible inhibitors form stable adducts. Covalent binding to proteins is crucial in biochemistry, affecting protein structure and function, and has applications in drug discovery, enzyme inhibition, and protein engineering. Transcription factors such as NF-κB, PPAR-γ, and STAT3, as well as nuclear export receptor XPO1 and oncoprotein c-Myc, are potential targets of Michael acceptors. These compounds regulate gene expression, influencing cancer development and progression. In cancer chemotherapy, Michael acceptors target specific enzymes and proteins crucial for cancer cell growth and survival. They can undergo Michael addition reactions with cysteine residues, leading to post-translational modifications that disrupt essential cellular functions. Tyrosine kinase inhibitors (TKIs), cyclin-dependent kinase (CDK) inhibitors, Aurora kinase (AURK) inhibitors, and BTK inhibitors are examples of Michael acceptors used in cancer treatment. These drugs target specific signaling pathways, offering precise and tailored approaches to cancer therapy. Natural Michael acceptors, such as alkaloids (e.g., piperine and sinomenine) and terpenes (e.g., zerumbone and eupalinolide J), have shown anti-cancer properties. These compounds target various molecular pathways involved in cancer development and progression, offering potential for novel cancer therapeutics. Their diverse chemical structures and mechanisms of action highlight the importance of natural products in cancer research and treatment.Michael acceptors are a class of compounds with potential anti-cancer properties. They act by binding to nucleophilic sites in biological molecules, disrupting cancer cell function and inducing cell death. Their ability to be modified and targeted makes them promising for cancer therapy. The anti-cancer effects of Michael acceptors are due to their chemical structure and reactivity, allowing them to selectively target disease-associated proteins with minimal toxicity. These compounds, often derived from plants, exert effects via signaling pathways such as Keap1-NRF2-ARE and NF-κB, showing antioxidant and anti-inflammatory activities, making them promising for treating diseases associated with oxidative stress, inflammation, and cancer. Nitro fatty acids (NFAs), another type of Michael acceptor, have shown therapeutic efficacy in animal models of inflammation and cancer, leading to Phase II clinical trials for pulmonary arterial hypertension. Michael acceptors can form covalent bonds with nucleophilic residues in proteins, modulating protein pathways to exert physiological effects. They play a central role in regulating signaling pathways such as Keap1-NRF2-ARE and NF-κB, making them promising candidates for treating various diseases. The kinetics of inhibition via Michael reactions differ between reversible and irreversible covalent inhibitors. Reversible inhibitors can be released from non-target proteins, reducing off-target toxicity, while irreversible inhibitors form stable adducts. Covalent binding to proteins is crucial in biochemistry, affecting protein structure and function, and has applications in drug discovery, enzyme inhibition, and protein engineering. Transcription factors such as NF-κB, PPAR-γ, and STAT3, as well as nuclear export receptor XPO1 and oncoprotein c-Myc, are potential targets of Michael acceptors. These compounds regulate gene expression, influencing cancer development and progression. In cancer chemotherapy, Michael acceptors target specific enzymes and proteins crucial for cancer cell growth and survival. They can undergo Michael addition reactions with cysteine residues, leading to post-translational modifications that disrupt essential cellular functions. Tyrosine kinase inhibitors (TKIs), cyclin-dependent kinase (CDK) inhibitors, Aurora kinase (AURK) inhibitors, and BTK inhibitors are examples of Michael acceptors used in cancer treatment. These drugs target specific signaling pathways, offering precise and tailored approaches to cancer therapy. Natural Michael acceptors, such as alkaloids (e.g., piperine and sinomenine) and terpenes (e.g., zerumbone and eupalinolide J), have shown anti-cancer properties. These compounds target various molecular pathways involved in cancer development and progression, offering potential for novel cancer therapeutics. Their diverse chemical structures and mechanisms of action highlight the importance of natural products in cancer research and treatment.