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Cells can switch their fates, either by reverting to a more primitive phenotype (dedifferentiating) or by directly converting to another specialized cell type (transdifferentiating). A mature cell can become a progenitor-like cell through such cell plasticity events and contribute to tissue repair after injury. It has been proposed that the cellular mechanisms that convert mature cells into proliferating progenitors may be evolutionarily conserved. Autophagy, the pivotal first step in one such proposed, evolutionarily conserved program (paligenosis), is employed by cells to downscale the mature cell architecture and degrade and recycle organelles, ultimately liberating molecular building blocks such as fatty acids, amino acids, and nucleotides that activate mTORC1 to fuel cell cycle entry. The induction of autophagy after injury is conserved across tissues and species and contributes to repair. Because plasticity is often linked to tumorigenesis, autophagy may be key to understanding cancer origins. Failure to undergo autophagy during the plasticity required for tissue repair also likely contributes to various diseases. This chapter summarizes the current state of autophagy in cell plasticity and related emerging developments.

Differentiated cells across multiple species and organs can re‐enter the cell cycle to aid in injury‐induced tissue regeneration by a cellular program called paligenosis. Here, we show that activating transcription factor 3 (ATF3) is induced early during paligenosis in multiple cellular contexts, transcriptionally activating the lysosomal trafficking gene Rab7b. ATF3 and RAB7B are upregulated in gastric and pancreatic digestive‐enzyme‐secreting cells at the onset of paligenosis Stage 1, when cells massively induce autophagic and lysosomal machinery to dismantle differentiated cell morphological features. Their expression later ebbs before cells enter mitosis during Stage 3. Atf3 (–/–) mice fail to induce RAB7‐positive autophagic and lysosomal vesicles, eventually causing increased death of cells en route to Stage 3. Finally, we observe that ATF3 is expressed in human gastric metaplasia and during paligenotic injury across multiple other organs and species. Thus, our findings indicate ATF3 is an evolutionarily conserved gene orchestrating the early paligenotic autodegradative events that must occur before cells are poised to proliferate and contribute to tissue repair.