Cellular senescence and cancer reflect divergent responses of cellular stress, yet how this fate decision is regulated has remained unclear. This study identifies the ubiquitin ligase UBR4 as a key regulator that determines whether lung epithelial cells, in response to mitochondrial damage, undergo oncogenic transformation or enter senescence. UBR4 promotes the clearance of dysfuncctional mitochondria through mitophagy-a selective form of autophagy that removes damaged mitochondria-thereby supporting mitochondrial health and enabling tumor progression. In contrast, the loss of UBR4 impairs this cleanup process, resulting in mitochondrial dysfunction, oxidative stress, and energy depletion, ultimately triggering cellular senescence. Moreover, UBR4-deficient cells also secrete pro-senescent factors that induce secondary senescence in neighboring cells. In animal models, UBR4 loss significantly suppresses tumor growth, and patient data show that UBR4 levels increase with cancer stage and correlate with poor prognosis. These findings show that UBR4 plays an important role in managing the health and function of mitochondria and in deciding how cells respond to stress. UBR4 acts like a molecular switch that senses problems in mitochondria and helps determine whether cells continue to grow or enter a permanent stop in growth called senescence. The study suggests that UBR4 could be a useful target for developing new treatments and a potential marker for hard-to-treat lung cancers. It also emphasizes the wider importance of mitochondrial changes in linking cancer development and aging at the cellular level.

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