Zou, Y.; Pasula, D. J.; Tang, R.; Komba, M.; Dai, D. L.; Soukhatcheva, G.; Verchere, C. B.; Luciani, D. S.

Hypoxia is a potent stressor and a major cause of {beta}-cell failure and loss after islet transplantation. Autophagy is a critical homeostatic mechanism that preserves organelle integrity and metabolic balance in cells under stress, but whether it supports {beta}-cell adaptation to sustained oxygen deprivation is unclear. Here, we used {beta}-cell-specific Atg5 knockout together with hypoxia and transplantation models, to demonstrate that autophagy is a major determinant of {beta}-cell survival during oxygen limitation and supports islet graft function. However, prolonged hypoxia suppressed autophagic flux, reduced lysosomal activity, and led to autophagosome accumulation, indicating failure of the lysosomal clearance pathway. This was accompanied by a marked reduction in transcription factor EB (TFEB) and its lysosomal target genes. Genetic and pharmacological activation of TFEB restored lysosomal gene expression and cathepsin B activity and improved {beta}-cell viability under hypoxia, implicating TFEB decline as a contributor to autophagy-lysosome dysfunction. Together, these findings outline a sequence in which autophagy initially safeguards {beta}-cells but becomes ineffective under sustained hypoxia as TFEB levels fall, identifying TFEB as a potential target to strengthen {beta}-cell resilience and survival in islet transplantation.