The study investigates the role of the cylindromatosis tumour suppressor gene (CYLD) in regulating NF-κB activity. Through a high-throughput RNA interference screen, the authors identified CYLD as a novel negative regulator of NF-κB. They found that CYLD binds to the NEMO component of the IκB kinase (IKK) complex and modulates its activity by de-ubiquitinating TRAF2. Inhibition of CYLD leads to increased resistance to apoptosis, suggesting a mechanism by which loss of CYLD contributes to oncogenesis. The anti-apoptotic effect of CYLD loss can be reversed by aspirin derivatives that inhibit NF-κB activity, indicating a potential therapeutic strategy for patients with familial cylindromatosis. The findings establish a direct link between the NF-κB signalling cascade and a tumour suppressor gene, providing insights into the regulation of cell growth and apoptosis.The study investigates the role of the cylindromatosis tumour suppressor gene (CYLD) in regulating NF-κB activity. Through a high-throughput RNA interference screen, the authors identified CYLD as a novel negative regulator of NF-κB. They found that CYLD binds to the NEMO component of the IκB kinase (IKK) complex and modulates its activity by de-ubiquitinating TRAF2. Inhibition of CYLD leads to increased resistance to apoptosis, suggesting a mechanism by which loss of CYLD contributes to oncogenesis. The anti-apoptotic effect of CYLD loss can be reversed by aspirin derivatives that inhibit NF-κB activity, indicating a potential therapeutic strategy for patients with familial cylindromatosis. The findings establish a direct link between the NF-κB signalling cascade and a tumour suppressor gene, providing insights into the regulation of cell growth and apoptosis.