Fasting disrupts the InsP₆-HDAC3 axis to drive ER stress-mediated clearance of DNA-damaged cells and enforce tissue quality control.

Fasting drives metabolic adaptation but also elicits acute cellular stress. How this stress shapes tissue integrity is unknown. Here, we show that in the intestine, fasting depletes growth factor signaling, which triggers cellular stress. This response functions as a tissue quality-control checkpoint that selectively eliminates pre-existing DNA-damaged cells while sparing healthy counterparts. A short-term fast diminishes TGF-β signaling and elicits endoplasmic reticulum (ER) stress, driving DNA-damaged intestinal cells beyond an apoptotic threshold, thereby reducing the inflammatory burden. Mechanistically, loss of TGF-β signaling triggers FBXO22-Cullin1-mediated degradation of the inositol kinase IPMK, leading to depletion of inositol hexaphosphate (InsP₆). InsP₆ loss attenuates HDAC3 activity and initiates coordinated epigenetic and post-translational reprogramming, thereby increasing CDK5RAP3 abundance. Elevated CDK5RAP3 inhibits ribosomal RPL26 UFMylation, thereby amplifying ER stress and selectively licensing apoptosis in DNA-damaged cells. Collectively, fasting disrupts a TGF-β-InsP 6 -HDAC3 axis to drive ER stress-dependent clearance of DNA-damaged cells, enforcing tissue quality control.