Paligenosis defines a tightly controlled program through which terminally differentiated cells re‑enter the cell cycle and contribute to tissue repair after injury. This review systematically introduces the concept, the three sequential stages of paligenosis—mTORC1 suppression with autophagy initiation, followed by mTORC1 reactivation and stemness gene induction, and finally proliferation with lineage restoration—as well as the underlying molecular networks involving autophagy, metabolic rewiring, and epigenetic remodeling. The article then compares paligenosis with other forms of cellular plasticity such as dedifferentiation, transdifferentiation, epithelial‑mesenchymal transition, and induced pluripotency, highlighting its unique stepwise, reversible and intralineage nature. A major focus is the dual role of paligenosis: while it ensures efficient regeneration in tissues like the stomach and pancreas, its persistent or dysregulated activation under chronic stress or oncogenic signals can drive metaplasia, tumor initiation, metastasis and therapy resistance. The review closes by discussing biomarker prospects for distinguishing adaptive repair from malignant drift, and the therapeutic potential of modulating paligenotic pathways for regenerative medicine and cancer treatment.

The paligenosis program consists of three well‑defined stages. Stage I (mTORC1 inhibition/autophagy initiation) occurs upon tissue injury, where reactive oxygen species accumulate and trigger suppression of mechanistic target of rapamycin complex 1. Key regulators such as DDIT4, ATF3 (which upregulates RAB7), and the cystine/glutamate antiporter xCT are activated. Autophagy clears differentiation‑associated organelles like rough endoplasmic reticulum and mitochondria, while quality control mechanisms—including DNA damage response and DDIT4‑mediated screening—ensure that only genomically stable cells proceed. Cells that fail this checkpoint may undergo apoptosis or proliferate aberrantly, increasing tumor risk. Stage II (plasticity acquisition/mTORC1 reactivation) is marked by the loss of mature markers (e.g., p57, MIST1) and expression of stemness‑associated factors such as SOX9, CD44v, LGR5 and c‑MYC. IFRD1, a key regulator in this phase, facilitates mTORC1 reactivation partly by inhibiting p53. Without IFRD1, cells undergo autophagy and dedifferentiation but cannot reactivate mTORC1, stalling regeneration. Stage III (metabolic reprogramming and cell cycle re‑entry) sees fully activated mTORC1 driving biosynthetic processes—protein synthesis, lipid metabolism, nucleotide production—via S6K and 4E‑BP1, supporting proliferation. The entire axis is tightly controlled by a central quality‑control gate, with DDIT4 acting in stage I and IFRD1 in stage II to license regenerative progression while limiting oncogenic transformation.

Beyond the core autophagy‑mTORC1 axis, the review speculates on other pathways that likely contribute to paligenosis. The Hippo pathway may sense energy stress and modulate autophagy independent of YAP/TAZ. Notch signaling could regulate stemness restoration and plasticity maintenance, though its aberrant activation in stage III might drive malignant transformation, as seen in Barrett’s esophagus. Wnt/β‑catenin signaling, critical for tissue regeneration, may cooperate with mTORC1 to promote cell cycle re‑entry, but persistent activation heightens tumorigenic risk. Metabolic reprogramming is integral: amino acid deprivation inhibits mTORC1 via Sestrin2‑GATOR2, prioritizing autophagy; later, autophagy‑derived substrates (amino acids, lipids, glucose, nucleotides) feed nutrient‑sensing pathways to reactivate mTORC1. Disruptions in this metabolic crosstalk, such as loss of branched‑chain amino acid catabolism, can chronically activate mTORC1 and promote cancer. Epigenetic regulation also plays a pivotal role: histone modifiers (acetyltransferases, demethylases) and non‑coding RNAs influence autophagy‑related gene expression and stemness gene activation. For instance, Ezh2 shapes T‑cell plasticity, and BRD2 stabilizes glioblastoma stemness. mTORC1‑driven metabolites (acetyl‑CoA, SAM) provide substrates for histone modifications, creating a metabolism‑epigenetics feedback loop that can either support repair or, when derailed, lead to lineage infidelity and malignant transformation.

Compared with other plasticity mechanisms, paligenosis occupies a distinct niche. Dedifferentiation involves partial loss of mature identity without a structured three‑stage progression and is often governed by Hippo‑YAP/TAZ signaling. Transdifferentiation converts one differentiated cell type directly into another, typically without a proliferative intermediate. Epithelial‑mesenchymal transition enhances motility and invasiveness but does not follow the autophagy‑stemness‑proliferation sequence. Induced pluripotency is an artificial, exogenous factor‑driven process. Paligenosis is unique in its sequential, reversible and intralineage nature—it restores the original epithelial fate after damage, not switches lineages. Functionally, paligenosis serves tissue repair, but its repeated activation under chronic inflammation or oncogenic mutations can drive pathological progression. In the stomach, persistent paligenosis leads to spasmolytic polypeptide‑expressing metaplasia, a precursor to intestinal metaplasia and gastric cancer. In the pancreas, acinar‑to‑ductal metaplasia induced by paligenosis‑like programs can progress to pancreatic intraepithelial neoplasia. During tumor progression, cancer cells may hijack paligenosis‑like programs: single‑cell sequencing of gastric cancer peritoneal metastases revealed cells expressing three‑stage paligenosis signatures, suggesting lineage reconfiguration for metastatic adaptation. In colorectal cancer, chemotherapy‑surviving cells exhibit mTORC1 suppression and enhanced autophagy (stage‑I features), then re‑enter a drug‑tolerant persister state and later reactivate proliferative programs, mirroring paligenosis stage III. Thus, paligenosis contributes not only to tumor initiation but also to metastasis and therapy resistance.

Biomarker prospects for distinguishing adaptive repair from malignant drift are discussed. Adaptive repair shows transient stage‑I markers (xCT, ATF3, transient LC3‑II elevation) followed by mTORC1 reactivation and lineage restoration. Malignant drift is indicated by persistent stress/autophagy signatures, failure to restore lineage markers (e.g., GIF, pepsinogens, CPA1, MUC2), uncoupled proliferation with elevated pS6/p4EBP1, c‑MYC, Ki‑67 alongside declining lineage identity, and sustained EMT/stemness features (low E‑cadherin, high vimentin, persistent SOX9/LGR5/CD44v). Circulating surrogates (exosomal xCT, cfDNA) and metabolic imaging (¹⁸F‑FDG PET) may offer longitudinal monitoring.

Therapeutically, paligenosis presents both opportunities and challenges. Modulating upstream regulators (Sestrin2, DDIT4, xCT, IFRD1) could precisely control the “gating mechanism” of paligenosis, enhancing repair or blocking pathological activation. Epigenetic modifiers (HDACs, H3K27me3 regulators) are additional leverage points. Inducing paligenosis might enable “in situ regeneration” when stem cell pools are depleted, particularly in chronic injury or aged tissues. Conversely, targeting paligenosis‑like programs in cancer could suppress metastasis and overcome drug resistance. Key challenges remain: crosstalk with the microenvironment (fibroblasts, immune cells) is poorly understood; downstream transcriptional networks of mTORC1 in stage III need clarification; and a unified cross‑tissue molecular framework is lacking. Future research integrating multi‑omics and organoid models will be essential to translate paligenosis biology into clinical applications for regenerative medicine and oncology.

DOI
10.1007/s11684-025-1197-4