The loss of the cylindromatosis tumour suppressor (CYLD) inhibits apoptosis by activating NF-κB. CYLD is a deubiquitinating enzyme that regulates NF-κB activity by deubiquitinating TRAF2, a key adaptor protein in NF-κB signaling. Inhibition of CYLD leads to increased NF-κB activation, which enhances resistance to apoptosis, contributing to oncogenesis. This effect can be reversed by aspirin derivatives that inhibit NF-κB activity. CYLD interacts with NEMO, a component of the IKK complex, and regulates its activity through deubiquitination of TRAF2. CYLD knockdown increases IKK activity, leading to reduced IκBα levels and enhanced NF-κB activation. These findings suggest that CYLD functions as a negative regulator of NF-κB signaling, and its loss contributes to the development of familial cylindromatosis. The study also highlights the potential therapeutic application of NF-κB inhibitors in treating patients with familial cylindromatosis.The loss of the cylindromatosis tumour suppressor (CYLD) inhibits apoptosis by activating NF-κB. CYLD is a deubiquitinating enzyme that regulates NF-κB activity by deubiquitinating TRAF2, a key adaptor protein in NF-κB signaling. Inhibition of CYLD leads to increased NF-κB activation, which enhances resistance to apoptosis, contributing to oncogenesis. This effect can be reversed by aspirin derivatives that inhibit NF-κB activity. CYLD interacts with NEMO, a component of the IKK complex, and regulates its activity through deubiquitination of TRAF2. CYLD knockdown increases IKK activity, leading to reduced IκBα levels and enhanced NF-κB activation. These findings suggest that CYLD functions as a negative regulator of NF-κB signaling, and its loss contributes to the development of familial cylindromatosis. The study also highlights the potential therapeutic application of NF-κB inhibitors in treating patients with familial cylindromatosis.