The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases. Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases. A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation.

Non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK)-fusion oncogene respond remarkably well to ALK-tyrosine kinase inhibitor (ALK-TKI) therapies. However, the emergence of resistance remains a major challenge in long-term ALK-TKI treatment. The aim of this study was to elucidate the factors contributing to the formation of drug-tolerant persister cells (DTPs) in ALK-positive lung cancer and to explore therapeutic strategies for targeting these cells. To this end, we performed genome-wide CRISPR-Cas9 knockout screening using patient-derived ALK-positive NSCLC cells. This screening identified the apoptosis-associated factor BMF as a key regulator of DTP formation. BMF expression increased within 24 h of ALK-TKI treatment or dual ERK and PI3K pathway inhibition. BMF-knockout cells exhibited impaired apoptosis and an increased DTP population following ALK-TKI treatment. This suggests that BMF plays a pivotal role in ALK-TKI-induced apoptosis induction. Pharmacological inhibition or siRNA-mediated knockdown of MCL-1 with ALK-TKI treatment effectively induced apoptosis and eliminated BMF knocked-out cells. Furthermore, siRNA-mediated knockdown of the transcription factor FOXO1 increased BMF expression, suggesting that FOXO1-mediated signaling contributes to the suppression of BMF. Thus, FOXO1 inhibition could enhance the efficacy of ALK-targeted therapies. Notably, the role of BMF observed in ALK-positive lung cancer models was recapitulated in ROS1-positive cell lines. Overall, BMF plays a critical role in apoptosis induction and is upregulated during targeted therapy for ALK/ROS1-positive lung cancer. BMF loss promotes DTP formation and contributes to therapeutic resistance. Targeting MCL-1 or FOXO1 may be a promising strategy for eliminating DTP cells and enhancing the efficacy of ALK/ROS1-TKIs.