Hypothesis 1: Radiation-induced pericyte senescence is driven by a late-stage autophagy defect at the lysosome acidification and TFEB-recovery step, not by loss of autophagosome formation. Damaged lysosomes would trap LC3-positive cargo, amplify ROS, and sustain SASP signaling. Test: lysosomal pH, cathepsin maturation, TFEB nuclear translocation, and tandem LC3 reporters after irradiation.
Hypothesis 2: The dominant lesion is defective mitophagy through the PINK1-PRKN axis, causing persistence of damaged mitochondria that lock pericytes into a senescent, inflammatory state. Test: mitochondrial membrane potential, Parkin recruitment, mito-QC reporters, and rescue with mitophagy activators.
Hypothesis 3: DNA damage chronically activates mTORC1 and suppresses ULK1-dependent autophagy initiation, with SASP cytokines reinforcing the block. In this version the defect is early and signaling-centered rather than lysosome-centered. Test: ULK1 phosphorylation, mTORC1 readouts, rapalog rescue, and time-resolved flux mapping.