<p>Paligenosis is an emerging model of mature cell plasticity that enables terminally differentiated cells to re-enter the cell cycle and contribute to tissue regeneration following injury. This tightly regulated process involves an initial phase of autophagy-mediated organelle clearance coupled with mechanistic target of rapamycin complex 1 (mTORC1) suppression, followed by mTORC1 reactivation and stemness gene induction that establishes regenerative competence, ultimately culminating in proliferation and lineage restoration. While paligenosis provides an adaptive mechanism to rapidly replenish lost cells in tissues such as the stomach and pancreas, persistent activation under chronic stress or oncogenic signals may drive metaplasia and tumor initiation. Recent evidence further implicates paligenosis-like programs in cancer progression, metastasis, and therapy resistance, underscoring its dual roles in regeneration and disease. Ongoing investigation into the molecular circuitry of paligenosis—including metabolic rewiring, canonical signaling, and epigenetic remodeling—may yield new insights into both tissue repair and oncogenic transformation, offering novel opportunities for therapeutic targeting.</p>