Chronic sleep loss accelerates colorectal cancer risk by disabling a nocturnal autophagy‑dependent quality‑control system for mismatch repair (MMR) proteins in colonic epithelium. During sleep, circadian‑driven expression of the lysosomal regulator TFEB peaks, coupling mTORC1 inhibition to the initiation of selective autophagy that targets oxidized or misfolded MMR complexes (e.g., MSH2, MLH1) for degradation. This process mirrors the brain’s glymphatic triage: only functional repair proteins are allowed to persist, while damaged subunits are cleared, preventing the accumulation of a mutator phenotype. Melatonin, whose secretion is maximal at night, amplifies TFEB activity and stabilizes the autophagosome‑lysosome fusion machinery, thereby coupling the circadian clock to proteostatic surveillance. When sleep is fragmented, TFEB activation blunts, autophagic flux falls, and damaged MMR proteins persist, impairing DNA mismatch correction and fostering field cancerization. This hypothesis is testable in aged murine colonic organoids subjected to controlled sleep‑fragmentation protocols. Predictions include: (1) reduced LC3‑II/I ratios and elevated p62 levels in organoids from sleep‑disrupted mice; (2) increased half‑life of MSH2 and MLH1 proteins measured by cycloheximide chase; (3) elevated microsatellite instability and point‑mutation burden after chronic disruption; (4) rescue of MMR fidelity by pharmacological TFEB activation (e.g., trehalose) or melatonin supplementation. Falsification would occur if sleep disruption fails to alter MMR protein turnover or mutation rates despite verified autophagy inhibition. Linking circadian proteostasis to genomic stability provides a mechanistic bridge between epidemiological associations of shift work with colorectal cancer and the observed rise of dMMR tumors in the elderly.