Paligenosis: dual potential of mature cell plasticity in regeneration and tumorigenesis

Abstract

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.

Keywords

paligenosis / cellular plasticity / mTORC1 signaling / autophagy / regeneration / tumorigenesis

1 Introduction

Cell fate plasticity has long been a central focus in biological research. As early as 1891, German biologist Hans Driesch demonstrated that blastomeres separated from sea urchin embryos could develop into complete individuals [1], challenging the prevailing belief in irreversible cell fate. In the 1950s, John Gurdon further advanced this concept by showing that the nuclei of differentiated cells retain full developmental potential through the successful cloning of Xenopus laevis embryos [2]. This work laid the foundation for studies on dedifferentiation and cellular plasticity. In the early 21st century, Shinya Yamanaka provided direct evidence of cell fate plasticity by reprogramming mature fibroblasts into induced pluripotent stem cells (iPSCs) using four transcription factors (Oct4, Sox2, Klf4, and c-Myc) [3]. Together, these milestones—from dedifferentiation to the theoretical framework of plasticity and the development of iPSC technology—demonstrate that mature cells are not irreversibly fixed in their differentiated states. Rather, under specific conditions, they can revert to a more developmentally potent state to adapt to environmental cues or facilitate regeneration [4].

However, under physiological conditions, dedifferentiation does not always involve a full return to pluripotency. Instead, it often reflects regulated partial plasticity. In tissues such as the gastrointestinal tract and pancreas, which may not always rely on a dedicated, permanent stem-cell reservoir for repair, certain mature cells can adopt a stem-like phenotype and re-enter the cell cycle following injury, thereby contributing to tissue repair [5]. This process, referred to as paligenosis in recent studies [6], is an endogenous regenerative response to tissue injury, marked by pronounced plasticity and dynamic regulation. The concept of paligenosis offers a novel framework for understanding how mature cells reacquire stem-like properties to facilitate regeneration following damage.

Ongoing research increasingly highlights the dual role of paligenosis in both tissue regeneration and tumorigenesis. While paligenosis enables mature cells to regain proliferative capacity and promote repair, its chronic or repeated activation—particularly under conditions of persistent inflammation—may lead to mutation accumulation and genomic instability, thereby driving cancer development [7]. Compared to the traditional “cancer stem cell” model, this perspective emphasizes the central role of differentiated cell plasticity in carcinogenesis, and further explains how cancer cells may undergo paligenosis after therapy, leading to recurrence and drug resistance [8,9]. Therefore, a comprehensive understanding of the molecular regulatory networks governing paligenosis could enhance our knowledge of normal tissue regeneration and inform novel strategies for cancer prevention and therapy.

This review aims to systematically summarize recent advances in paligenosis research, with an emphasis on its molecular mechanisms, metabolic regulation, and physiological and pathological significance, thereby offering new insights and directions for future basic and clinical investigations.

2 Three-stage process of paligenosis

To make scope and generalizability explicit, we annotate mechanistic statements throughout Section 2 using the inline format [Tissue | Species | Modality | Evidence]. Tissue specifies the lineage (e.g., Stomach/Chief, Pancreas/Acinar, Colon/Goblet); Species indicates the experimental model (Human, Mouse, Zebrafish, etc.); Modality summarizes the experimental approach (in vivo, in vitro, ex vivo/organoid; LT = lineage tracing; sc = single-cell RNA-seq); and Evidence denotes strength: E1 = causal (genetic perturbation with and/or lineage tracing), E2 = strong associative/mechanistic, E3 = preliminary. Figure legends repeat the shorthand at first use, and Table S1 lists all tagged claims with citations.

Stage I (S1, mechanistic target of rapamycin complex 1 (mTORC1) inhibition/autophagy initiation): in the early phase of tissue injury, mature cells undergo a highly orchestrated structural and metabolic remodeling process. This stage is marked by the suppression of mTORC1 signaling and activation of autophagy, which facilitates the removal of differentiation-associated organelles—such as the rough endoplasmic reticulum (ER) and mitochondria—thereby laying the groundwork for cellular plasticity and regeneration [10] (Fig. 1). This process engages extensive quality control mechanisms, including the DNA damage response (DDR) and oxidative stress pathways, ensuring that only genomically stable and metabolically adaptive cells progress to the next stage [Stomach/Chief | Mouse | invivo, LT | E1] [11]. For example, upregulation of DDIT4 promotes autophagy by inhibiting mTORC1 and prevents cells with chromosomal abnormalities from entering the regenerative trajectory. Although Ddit4^−/− mice are still capable of initiating paligenosis, they exhibit a significantly elevated risk of spontaneous tumorigenesis [11] (Fig. 1). Similarly, in gastric epithelium, ADAR1 contributes to quality control by modulating the double-stranded RNA response; its loss leads to aberrant interferon signaling and failed regeneration [Gastric Chief | Mouse | in vivo (± organoid, ± LT) | E1] [12]. These mechanisms safeguard the fidelity of tissue regeneration while limiting aberrant proliferation and tumorigenic risk. Moreover, injury-induced accumulation of reactive oxygen species (ROS) upregulates ATF3, which in turn regulates RAB7 to promote autophagosome maturation and fusion with lysosomes—key events in maintaining efficient autophagic flux [Stomach/Chief | Mouse | invivo, LT | E1] [13]. Concurrently, the expression of the xCT (SLC7A11) transporter is upregulated to facilitate glutathione synthesis, thereby mitigating oxidative stress [Stomach/Chief | Mouse | invivo (± LT) | E1] [14]. Thus, ROS accumulation is considered a critical initiating signal of paligenosis [Stomach/Chief | Mouse | invivo, LT | E1] [15]. Overall, this initial phase encompasses not only organelle clearance and energy mobilization but also the implementation of stringent screening mechanisms that retain cells with regenerative potential through metabolic and stress-adaptive processes.

Stage II (S2, plasticity acquisition/mTORC1 reactivation): following autophagic clearance and energy accumulation, paligenotic cells transition into the second phase, characterized by the dismantling of the differentiated state and the activation of regenerative programs. During this stage, mTORC1 signaling is reactivated and closely linked to the induction of stemness-associated gene expression [Stomach/Chief | Mouse | in vivo, LT | E1] [16] (Fig. 1). For instance, gastric chief cells undergoing regeneration lose differentiation markers such as p57 and MIST1 [Stomach/Chief | Mouse | in vivo (± LT), organoid | E1] [17] and begin expressing stem-like factors including CD44v, SOX9, LGR5, and c-MYC [Pancreas/Acinar | Mouse & Human | in vivo, sc, organoid | E2] [18]. These molecular changes facilitate intralineage reprogramming—a restricted form of plasticity—tailored to meet the demands of tissue repair. Studies have shown that fully differentiated cells, such as gastric chief cells, pancreatic acinar cells, and intestinal goblet cells, can revert to a regenerative intermediate state in response to injury [Intestine/Epithelium | Mouse (± Human organoid) | in vivo, organoid | E2] [6,19]. A key regulator of this phase is IFRD1, which is upregulated across various paligenosis models and plays an essential role in reactivating mTORC1 signaling [16]. Functional experiments demonstrate that in Ifrd1^−/− mice, autophagy and dedifferentiation occur, but mTORC1 activation fails, stalling the paligenotic process. Interestingly, this phenotype is rescued in Ifrd1^−/−, Trp53^−/− double-knockout mice, suggesting that IFRD1 promotes mTORC1 reactivation, at least in part, through inhibition of p53 [16] (Fig. 1). Given p53’s established role in quality control, IFRD1 may function as a molecular checkpoint that ensures only cells that have successfully completed the initial clearance phase re-enter the regenerative trajectory.

Stage III (S3, metabolic reprogramming and cell cycle re-entry): once selection and reprogramming are complete, paligenotic cells with regenerative potential enter the third stage: cell cycle re-entry and functional proliferation. At this point, mTORC1 is fully activated, driving biosynthetic programs essential for proliferation—including protein synthesis, lipid metabolism, and nucleotide production, via canonical targets such as S6K and 4E-BP1 [20] (Fig. 1). However, the molecular mechanisms by which paligenotic cells maintain plasticity during this proliferative phase remain relatively underexplored. Available evidence suggests that mTORC1 not only acts as a mitogenic signal but also plays a central role in sustaining plasticity. One potential mechanism is through its regulation of metabolism, which continuously supplies energy and biosynthetic substrates to support macromolecule synthesis. Another possibility is that mTORC1 serves as an environmental sensor, integrating cues such as nutrient availability, redox status, and inflammatory signals, and relaying them to chromatin remodeling and transcriptional programs. This enables cells to remain in a regeneration-competent state—both plastic and primed for fate specification [21].

The three stages of paligenosis are sequential and tightly interconnected (Fig. 1). The initial phase functions as an orderly “cellular reset” program: through autophagy and quality control pathways involving molecules such as ATF3, xCT, and DDIT4, cells dismantle their differentiated state and transition to a plastic, regeneration-competent phenotype. Although direct evidence of paligenosis has been mainly documented in gastric and pancreatic models, accumulating research across diverse organs supports the existence of paligenosis-like regenerative programs. These processes share the core features of the paligenotic sequence—autophagy initiation, stage-specific mTORC1 suppression and reactivation, and transient induction of stemness. For instance, autophagy-dependent regenerative responses resembling the initial stage of paligenosis have been observed in the intestine, where epithelial cells acquire regenerative competence upon autophagy induction [19]. Similarly, liver regeneration involves transient inhibition followed by reactivation of mTORC1 signaling, mirroring the metabolic dynamics of paligenosis [Liver/Hepatocyte | Mouse | in vivo | E2] [22]. Furthermore, studies in bone [23] and neural tissues [Peripheral nerve/Schwann | Mouse | in vivo | E2] [24] have demonstrated that mature cells rely on autophagy-mediated remodeling to regain regenerative potential. Collectively, these findings suggest that the paligenosis-like program constitutes a conserved regenerative mechanism extending beyond the gastrointestinal system. Moreover, autophagy represents a conserved and fundamental mechanism, beyond a generic damage response for triggering fate remodeling and proliferation in mature cells across tissue types [25].

mTORC1 signaling also serves as a central axis of the paligenotic program. Its dynamic regulation—initial suppression followed by subsequent reactivation—shapes both the metabolic state and the plastic potential of regenerating cells [16,20]. Although its specific role in paligenosis has only recently been delineated, the importance of mTORC1 in tissue regeneration is well established. Stage-specific mTORC1 activation has been observed during regeneration in muscle, intestine, liver, and the nervous system, and across multiple species including invertebrates, amphibians, reptiles, and mammals (for evidence tagging and grading, see Table S1) [26–30]. This highlights its conserved function in orchestrating regenerative responses across tissues and evolutionary lineages. The temporally controlled inhibition and reactivation of mTORC1 are essential for plasticity regulation: suppression facilitates the dismantling of the terminally differentiated state, while reactivation supports biosynthesis and proliferation [Reprogramming/MEF | Mouse | in vitro | E2] [31]. Furthermore, by sensing amino acid availability, energy status, and redox balance [28–31], mTORC1 may act as a temporal integrator that precisely regulates the progression of each paligenotic stage.

3 Molecular regulatory network

Recent research on paligenosis has revealed several core regulatory nodes. In Stage I, the ATF3–RAB7 axis and DDIT4-mediated inhibition of mTORC1 initiate autophagy, facilitating energy reprogramming and organelle clearance. In Stage II, mTORC1 reactivation, in coordination with the transcription factor IFRD1, appears to be a critical mechanism for establishing cellular plasticity. In Stage III, mTORC1 regulates both metabolism and cell cycle progression, thereby sustaining the plastic state and promoting proliferation. Together, these findings suggest a fundamental regulatory framework centered on an autophagy–transcriptional remodeling–mTORC1 signaling axis. However, as a recently proposed model of cellular plasticity, paligenosis remains in its early stages, and its molecular mechanisms are far from fully elucidated. Additional regulatory pathways likely contribute to this process and await systematic investigation. Drawing on insights from regenerative biology and cellular plasticity, this section speculates on other pathways potentially involved in paligenosis (Fig. 2).

3.1 Canonical signaling pathways

Although direct evidence is currently lacking, canonical signaling pathways such as Wnt/β-catenin, Notch, and Hippo are known to play critical roles in autophagy, tissue regeneration, and cellular plasticity, suggesting they may also contribute significantly to paligenosis.

The Hippo pathway is closely linked to cellular responses to energy stress [32]. Core kinases in this pathway, including MAP4K2 and LATS2, can sense energy stress and modulate mTORC1 activity, thereby coordinating autophagy [33,34]. Additionally, Hippo signaling can regulate autophagy independently of YAP/TAZ-mediated transcription [35]. In the context of paligenosis, the Hippo pathway may serve as a key “energy stress–autophagic response” module in the first stage. It not only regulates mTORC1 activity to determine autophagy activation or suppression but may also directly modulate autophagy-related gene expression, potentially functioning as an initiating mechanism in paligenosis (Fig. 2).

The Notch pathway, a highly conserved mechanism governing cell fate decisions, plays critical roles in tissue development, stem cell maintenance, and regeneration. Its functions are highly context-dependent, varying by cell type, tissue environment, and developmental stage. For example, in the intestinal stem cell system, Notch activity dictates differentiation toward absorptive or goblet lineages [36]. During natural transdifferentiation, Notch signaling may either promote or inhibit fate reprogramming, depending on the timing and magnitude of activation [37]. In dental pulp and bone, Notch activation significantly affects regenerative capacity [38,39], highlighting its role in reprogramming and fate maintenance. Notch can also integrate environmental cues through crosstalk with pathways such as FoxO and NF-κB to sustain undifferentiated states [40,41]. Thus, in the second stage of paligenosis—characterized by activation of stemness-associated genes and reestablishment of plasticity—Notch signaling may serve as a key regulator of stemness restoration and plasticity maintenance (Fig. 2).

Critically, in the third stage of paligenosis, if cell cycle re-entry is not tightly regulated, aberrant Notch activation may increase the risk of malignant transformation. In studies on Barrett’s esophagus, Notch has been shown to promote the transition from dedifferentiated phenotypes to adenocarcinoma [42]. By maintaining stemness, inhibiting differentiation, and interacting with pathways such as mTORC1 and NF-κB, Notch can drive abnormal proliferation and immune evasion, acting as an oncogenic driver in various tumors [43]. These findings underscore the carcinogenic potential of dysregulated paligenosis.

The Wnt/β-catenin pathway is central to tissue regeneration and cell fate regulation and plays key roles in maintaining plasticity, initiating proliferation, and guiding differentiation. During regeneration of organs such as the heart [44], skeletal muscle [45], and liver [46], Wnt/β-catenin signaling drives activation and expansion of stem/progenitor cells. This pathway facilitates the transition from quiescence to proliferation by downregulating p53 activity or modulating epigenetic regulators such as LSD1 [47,48], enabling both stemness maintenance and cell cycle re-entry. This dual role is particularly relevant during the third stage of paligenosis, where Wnt/β-catenin may act in concert with mTORC1 to reactivate cellular plasticity (Fig. 2).

However, persistent Wnt/β-catenin activation also heightens tumorigenic risk by promoting uncontrolled proliferation and resistance to apoptosis [49]. This dual role in repair and oncogenesis underscores the importance of precisely regulating Wnt/β-catenin activity during paligenosis to avoid malignant progression.

3.2 Metabolic reprogramming

The transition from a stably differentiated state to a plastic state is inherently dependent on comprehensive metabolic restructuring. Throughout paligenosis—including stemness activation and cell cycle re-entry—metabolic reprogramming not only supplies energy but also functions as a signaling mechanism that drives fate reprogramming. mTORC1, a key metabolic regulator linking environmental nutrient status to cell fate, plays a central role in this process [16].

By integrating signals from amino acids, glucose, and lipids, mTORC1 governs the transition from quiescence to plastic or proliferative states. In models of tissue regeneration and organ development—such as cardiomyocyte regeneration [50] and intestinal stem cell maintenance [51]—mTORC1 activation is tightly associated with dynamic metabolic pathway shifts, especially in glycolysis, oxidative phosphorylation, and polyamine biosynthesis—all of which influence stem cell fate (Fig. 2).

Amino acid deprivation inhibits mTORC1 activation at the lysosome through Sestrin2-mediated suppression of the GATOR2 complex, thereby prioritizing autophagy during energy stress [52]. This mechanism supports mTORC1 inhibition and autophagy initiation in the first stage of paligenosis, positioning Sestrin2 as a potential metabolic sensor for plasticity induction. In the second stage, autophagy-derived substrates—such as amino acids, lipids, glucose, cholesterol, and purine nucleotides—are sensed by nutrient-sensing pathways to facilitate mTORC1 reactivation [53–57]. During the third stage, reactivated mTORC1 integrates these signals to upregulate biosynthetic processes, including rRNA transcription, ribosome biogenesis, and lipid and nucleotide synthesis [58], providing structural and energetic support for proliferation.

Importantly, metabolic dysregulation during paligenosis may lead to pathological outcomes. In β-cell maturation, a switch between mTORC1 and AMPK determines metabolic plasticity and disease susceptibility [59]. Disruptions in branched-chain amino acid metabolism chronically activate mTORC1, promoting tumorigenesis [60]. Moreover, crosstalk between mTORC1 and mTORC2/AKT signaling amplifies metabolic signaling effects, as shown in c-MYC-driven hepatocarcinoma models where TSC dysregulation activates both pathways to drive oncogenesis [61]. These findings highlight how impaired nutrient sensing during paligenosis can lead to aberrant proliferation and malignancy.

3.3 Epigenetic regulation

Epigenetic regulation bridges environmental cues and gene expression by modulating chromatin structure through DNA methylation, histone modifications, and non-coding RNAs, thereby enabling dynamic control of cell fate [62]. During paligenosis, the reactivation of stemness genes and reconfiguration of cell identity likely depend on epigenetic remodeling. In some contexts, these mechanisms may also mediate pathological reprogramming.

At different stages of paligenosis, epigenetic mechanisms support both the initiation and maintenance of plasticity (Fig. 2). In the first stage, under energy stress, autophagy alters the metabolic landscape, while epigenetic factors modulate autophagy activation. Nutrient deprivation induces histone-modifying enzymes, such as acetyltransferases and demethylases, which regulate autophagy-related gene expression and initiate stress responses [63,64]. Non-coding RNAs have also been shown to influence autophagy, thereby impacting early fate decisions [65].

In the second and third stages, epigenetic mechanisms sustain plasticity by regulating stemness gene expression and cell cycle progression (Fig. 2). In various tissues, epigenetic reprogramming has been shown to alter lineage identity, such as Ezh2 in T cell plasticity [66] and BRD2 in glioblastoma stemness maintenance [67]. Moreover, mTORC1 reactivation not only marks a metabolic turning point but also facilitates cell cycle re-entry by regulating transcription factors and chromatin accessibility. Acetylation affects key cell cycle regulators (e.g., CHK2, CDK1) during mitotic progression [68,69], while mTORC1-driven accumulation of metabolites like acetyl-CoA, lactate, and SAM provides substrates for histone modifications, creating a feedback loop between metabolism and epigenetics.

DNA methylation, histone modifications, and non-coding RNAs collectively fine-tune transcriptional programs to support the shift from stable differentiation to plasticity [70,71]. While this regulation is essential for effective tissue repair, it also poses an oncogenic risk by compromising lineage fidelity, as observed in the gastrointestinal tract, prostate, and nervous system [72–74]. Understanding the dynamic roles of epigenetic regulation in paligenosis will be key to harnessing regenerative capacity while avoiding pathological plasticity and malignant transformation.

4 Comparison between paligenosis and other plasticity mechanisms

Paligenosis is a recently defined mechanism of mature cell plasticity characterized by its phased progression, reversibility, and role in tissue repair. It has been extensively validated across various stress-induced contexts. However, cellular fate reprogramming encompasses additional mechanisms, including dedifferentiation, transdifferentiation, epithelial-mesenchymal transition (EMT), and induced pluripotency—all of which contribute to development, homeostasis, regeneration, and tumor progression (Table 1, Fig. 3).

Among these processes, dedifferentiation exhibits the greatest conceptual overlap with paligenosis, as both are stress-induced and involve loss of mature identity and partial acquisition of stem-like features. Nevertheless, paligenosis differs by its structured, stepwise progression—comprising autophagy-mediated remodeling, transient stemness induction, and mTORC1-driven proliferative re-entry—whereas dedifferentiation usually represents a partial and transient adaptive response governed mainly by Hippo–YAP/TAZ signaling. Functionally, paligenosis serves as a regenerative and reversible program for tissue repair, while dedifferentiation primarily facilitates cellular adaptation and may act as an early or preparatory phase preceding other reprogramming events. These distinctions are summarized in Table 1.

From a mechanistic standpoint, paligenosis is typically triggered by endogenous tissue stress and exhibits a conserved, stepwise progression [75]. Dedifferentiation shares phenotypic similarities with early-stage paligenosis, such as loss of mature cell identity and acquisition of partial stem-like features. However, it often remains a transient adaptive state that does not proceed to proliferation or redifferentiation [76]. In contrast, transdifferentiation entails a direct conversion between two differentiated cell types—usually without broad epigenetic reprogramming or intermediate stem-like states—as observed in the transformation of esophageal squamous epithelium into intestinal-type columnar cells under chronic inflammation [77]. Paligenosis, by comparison, represents a lineage-conserved transformation involving sequential cellular remodeling rather than inter-lineage conversion. EMT reprograms cellular architecture and enhances motility and invasiveness, often associated with stemness features, but its trajectory diverges from the autophagy–stemness–proliferation sequence characteristic of paligenosis [78]. iPSC reprogramming relies on exogenous transcription factors (e.g., Oct4, Sox2, Klf4, and c-Myc) to revert somatic cells to a pluripotent state, representing a synthetic and experimentally induced pathway [3].

At the molecular level, the Hippo signaling pathway is a key regulator of dedifferentiation [79]. Its inactivation leads to dephosphorylation and nuclear translocation of YAP/TAZ, which, in cooperation with TEAD transcription factors, promotes the expression of genes involved in stemness, proliferation, and dedifferentiation [80]. In organs such as the liver and heart, persistent YAP activation facilitates the re-entry of terminally differentiated cells into the cell cycle, enabling partial acquisition of progenitor-like traits and regenerative capacity [81,82]. YAP/TAZ also synergizes with Notch, Wnt/β-catenin, and PI3K-Akt signaling pathways to maintain dedifferentiation and modulate its reversibility and redifferentiation potential [83,84]. Notably, both paligenosis and transdifferentiation require the dismantling of original phenotypic constraints during initiation. Dedifferentiation may serve not only as an independent reprogramming process but also as a precursor phase in other forms of fate conversion [85], suggesting shared core signaling networks and evolutionary conservation among diverse plasticity mechanisms.

Transdifferentiation is governed by the coordinated action of multiple signaling pathways, with TGF-β signaling playing a central role. By inhibiting Smad2/3 phosphorylation, TGF-β facilitates the erasure of original transcriptional programs and enables lineage conversion [81]. Wnt/β-catenin signaling enhances reprogramming competence by upregulating plasticity-associated genes [86]. MAPK/ERK and PI3K-Akt pathways support survival and functional reconstruction by modulating cellular metabolism and the cell cycle [87,88]. Mechanistically, transdifferentiation closely parallels EMT, which is also initiated predominantly by TGF-β signaling through activation of transcription factors such as Snail, Twist, and ZEB, leading to loss of epithelial polarity and acquisition of mesenchymal characteristics [89,90]. The Wnt pathway further co-regulates EMT by promoting phenotypic remodeling and plasticity activation [91]. Although EMT does not typically involve inter-lineage conversion, its hallmark state transition and overlapping signaling architecture position it in close mechanistic proximity to transdifferentiation. Despite their distinct outcomes, paligenosis may also be regulated by Wnt and MAPK signaling during plasticity induction, metabolic reprogramming, and cell cycle re-entry, indicating potential mechanistic convergence with transdifferentiation and EMT in cell fate remodeling and phenotypic transition.

Functionally, paligenosis is primarily geared toward tissue repair. Its activation is temporally regulated, allowing mature cells to undergo cell cycle re-entry and subsequently redifferentiate into functional cells after damage resolution. In contrast, transdifferentiation and iPSC reprogramming are more commonly used in experimental settings to model artificial cell fate conversions, with limited physiological relevance in vivo. Dedifferentiation and EMT, on the other hand, frequently persist in the tumor microenvironment and are closely associated with pathological progression.

5 Physiological and pathological roles

5.1 Functions in tissue repair

During tissue repair, different tissues adopt diverse strategies for remodeling cell fate, depending on their structural complexity and stem cell reserves [75]. In some tissues, such as the small intestine, skin, and hematopoietic system, repair relies primarily on the rapid proliferation and differentiation of existing stem cells to maintain homeostasis [92–94]. In contrast, tissues like the liver and pancreas depend more on the activation and proliferation of facultative cells, which exhibit limited functionality under steady-state conditions but demonstrate robust proliferative potential following injury [95,96]. Distinct from these tissues, the gastric mucosa is directly exposed to an acidic environment and various exogenous damaging factors, making it highly susceptible to physical and chemical injuries. To meet the demands of repair, the gastric mucosa relies not only on the regenerative capacity of isthmal stem cells but also on the ability of mature chief cells to regain stem-like properties through paligenosis and participate in tissue restoration [97] (Fig. 4). Compared with conventional stem cell-driven repair mechanisms, paligenosis offers a flexible and efficient alternative pathway for tissue regeneration, especially when injury is severe or stem cell resources are limited.

Paligenosis is fundamentally a comprehensive cellular response to tissue injury, built upon tissue-level damage sensing and coordination with the immune system. Studies have shown that injury to parietal cells serves as a key trigger for initiating the paligenosis program. Subsequently, tuft cells release the alarmin IL-33, which activates type 2 innate lymphoid cells (ILC2s) and macrophages, leading to the secretion of IL-13 that promotes the onset of paligenosis [98]. As a type 2 cytokine, IL-13 may act as an exogenous inducer of paligenosis by enhancing autophagy [99] or by upregulating various cell cycle regulators to facilitate proliferation, thus advancing the process [100]. Therefore, paligenosis is not merely the result of cellular reprogramming, but rather a critical component within a signal-regulatory feedback loop—comprising damage sensing, immune mediation, and epithelial remodeling—at the tissue level that plays an essential role in repair.

Moreover, chief cells are located at the base of the epithelium, in close proximity to injury sites, allowing paligenosis to initiate without requiring cellular migration, thus conferring a spatial advantage. Studies indicate that within 48 h of injury, chief cells can complete organelle degradation and begin expressing stemness-associated genes, transforming into a proliferative intermediate cell population [75]. This positions paligenosis as a dominant early repair strategy, which is particularly vital when isthmal stem cells are depleted or damaged. In the later stages of repair, paligenotic cells can redifferentiate into chief cells or other lineages within a suitable microenvironment, thereby restoring both structure and function to reestablish mucosal integrity [101].

Although paligenosis enables chief cells to reconstruct lineage architecture and support mucosal repair during injury, its inherent plasticity also introduces potential risks (Fig. 4). The fate of paligenotic cells is highly dependent on the stability of the microenvironment and the precision of signal regulation. When inflammation persists or key signaling pathways such as mTORC1 become dysregulated, the reprogramming process may deviate from normal repair and instead progress toward spasmolytic polypeptide-expressing metaplasia (SPEM), which can potentially advance to intestinal metaplasia or even precancerous lesions [5]. Hence, paligenosis serves not only in regenerative repair but also as a critical watershed between homeostatic recovery and pathological transformation, where the quality and directionality of the process directly determine the outcome of tissue repair.

5.2 Potential roles in tumorigenesis and progression

In early theories of tumor origin, Cohnheim and other researchers proposed the Embryonal Rest Theory of Cancer, positing that cancer arises from undifferentiated cells remaining in the body from embryonic development, which can be aberrantly activated under specific conditions to initiate tumorigenesis [102]. This view inspired subsequent researchers to reconsider tumor initiation from the perspective of cellular potential. Since the 20th century, advances in stem cell biology have shifted focus toward the role of adult stem cells in cancer development [103]. Stem cells are widely considered more prone to oncogenic transformation due to their long-term self-renewal capacity and persistent proliferative activity, which facilitate the accumulation of mutations and clonal expansion [104].

However, increasing evidence suggests that differentiated cells also possess tumor-initiating potential, sparking renewed debate over the identity of cells of origin in cancer [7]. On the one hand, many tissues lack dedicated stem cells and instead rely on self-replicating differentiated cells with limited proliferative capacity to maintain homeostasis [95,96]. These differentiated cells can exhibit plasticity and oncogenic potential under certain conditions. For instance, in pancreatic models, introducing a KRAS mutation specifically into acinar cells—a differentiated population—can induce pancreatic intraepithelial neoplasia (PanIN) and even progress to adenocarcinoma [105]. Therefore, both tissue architecture and the tumorigenic potential of differentiated cells challenge the traditional stem cell-origin model of tumorigenesis. On the other hand, differentiated cells often rely on low-fidelity repair mechanisms such as non-homologous end joining (NHEJ) to resolve DNA double-strand breaks, making them more susceptible to structural mutations like chromosomal rearrangements, insertions, or deletions [106]. Moreover, the typically long lifespan and slow turnover of differentiated cells increase the likelihood of gradual mutation accumulation [7]. In contrast, stem cells employ more stringent DNA repair systems [107] and tend to respond to damage by differentiation rather than dedifferentiation, thereby reducing the risk of mutational burden.

The tumorigenic potential of differentiated cells is closely linked to mechanisms that can remodel their differentiated state, with paligenosis being a pivotal process. As a highly conserved dedifferentiation program, paligenosis enables stably differentiated cells to regain proliferative potential and reacquire plasticity under stress or injury conditions [75]. In normal tissue repair, this mechanism supports regeneration. However, under conditions of chronic inflammation, aberrant signaling, or genetic mutation, persistent activation or dysregulation of paligenosis may provide a route for differentiated cells to become tumorigenic [7] (Fig. 4). Studies have shown that in epithelial tissues like the stomach and pancreas, mature cells at the base of glands can undergo organelle degradation, metabolic reprogramming, and stemness activation via paligenosis, entering a proliferative state and forming intermediate cell populations with plasticity [6]. If these cells fail to properly redifferentiate and remain in a state of partial reprogramming, they may form pathological regenerative lesions such as SPEM or acinar-to-ductal metaplasia (ADM), both of which are recognized as precursors to adenocarcinoma [18,108]. While cellular plasticity through paligenosis supports regeneration, its repeated activation may also facilitate the accumulation of mutations, creating fertile ground for malignant transformation.

Paligenosis is not limited to the early stages of tumorigenesis but may also be reactivated during tumor progression, particularly in response to metastatic pressure or therapeutic interventions (Fig. 4). Single-cell sequencing has revealed a subpopulation of plastic tumor cells within peritoneal metastases of gastric cancer, exhibiting gene expression patterns consistent with the three stages of paligenosis, suggesting that cancer cells may exploit paligenosis-like programs for lineage reconfiguration and adaptive expansion [8]. In colorectal cancer, tumor cells that survive chemotherapy often exhibit mTORC1 suppression and enhanced autophagy—molecular and functional hallmarks reminiscent of early-stage paligenosis. These cells subsequently regain plasticity and initiate phenotypic reprogramming, entering a drug-tolerant persister (DTP) state. Upon removal of external stress, they can reactivate proliferative programs and resume rapid division, mirroring the mTORC1 reactivation and cell cycle re-entry observed in later stages of paligenosis [9] (Fig. S1). These findings suggest that paligenosis may participate not only in tumor initiation but also in mechanisms by which cancer cells achieve metastasis and therapeutic resistance. Therefore, elucidating the mechanisms of paligenosis holds promise not only for uncovering the origins of cancer and enabling early detection but also for identifying novel intervention points to disrupt tumor progression and overcome drug resistance.

5.3 Biomarker prospects and early indicators of malignant drift

To complement the progression framework outlined in Section 5.2, this section proposes pragmatic biomarker readouts to distinguish adaptive repair from early malignant evolution in chronically injured tissues of the stomach, pancreas, and colon. We emphasize trajectory-based interpretation aligned with the S1–S3 staging and quality-control (QC) framework, rather than reliance on isolated static measurements.

Malignant drift is indicated by persistent stress or autophagy signatures (e.g., xCT/SLC7A11, ATF3, sustained LC3-II expression with low p62 levels), failure to restore lineage markers (GIF/pepsinogens; CPA1/PRSS1; MUC2), and proliferation uncoupled from differentiation, characterized by mTORC1 hyperactivation (elevated pS6/p4EBP1), c-MYC upregulation, and Ki-67 positivity as lineage identity declines. Continued EMT and stemness features (low E-cadherin, high vimentin, persistent SOX9/LGR5/CD44v expression) further support a malignant trajectory. Circulating surrogates—such as exosomal or plasma xCT, stress-response transcripts, circulating free DNA (cfDNA) burden or variants—and metabolic imaging modalities (e.g., 18F-FDG PET, hyperpolarized-13C MRI) may offer complementary longitudinal monitoring. In contrast, adaptive repair is characterized by transient S1 markers, followed by mTORC1 reactivation and lineage restoration.

Looking ahead, clinical translation of these biomarker panels will require prospective, longitudinal studies integrating tissue, liquid biopsy, and imaging readouts; analytically robust and standardized assays for phospho-mTORC1, autophagy surrogates, xCT/ATF3, and lineage markers with rigorous pre-analytical control; and explicit temporal thresholds or composite indices that distinguishing transient repair from persistent drift while accounting for inflammatory confounders. Spatially resolved validation using multiplex IHC/IF or spatial transcriptomics will be essential to define epithelial-stromal interactions, alongside organoid- or PDX-based, time-locked perturbation studies with subsequent multicenter replication. Collectively, these strategies delineate a tractable path from hypothesis-generating panels to clinically actionable biomarkers capable of detecting malignant drift early enough to inform therapeutic intervention.

6 Therapeutic potential and future challenges

As a regeneration pathway driven by mature cells, paligenosis occupies a pivotal position at the intersection of tissue repair and disease progression, owing to its tightly programmed yet inherently plastic and unstable nature. This duality presents both exciting opportunities for regenerative medicine and significant challenges for precise therapeutic manipulation. Emerging studies suggest that various signaling nodes within the paligenosis process may serve as actionable targets, and modulating their trajectory could influence both the quality of tissue repair and the risk of tumor development.

In the initial stage of paligenosis, autophagy facilitates organelle degradation and liberates metabolic substrates to sustain energy homeostasis, while concurrently suppressing mTORC1 activity [16]. Conversely, mTORC1 reactivation in the subsequent stage is essential for initiating the plasticity program. Therefore, modulating upstream or downstream regulators—such as Sestrin2, DDIT4, xCT, and IFRD1—may enable precise control over the “gating mechanism” of paligenosis [15,16,109]. Similarly, regulating epigenetic modifiers (e.g., HDACs, H3K27me3, and non-coding RNAs) could modulate cellular responsiveness to paligenotic stimuli [110–112], offering molecular leverage points to correct aberrant activation or delayed redifferentiation. Building on the staged framework and QC gates (Fig. 1), we present a hypothesis-generating, preclinical roadmap (Table S2). This table aligns putative targets (e.g., Sestrin2, DDIT4, xCT, IFRD1, representative epigenetic regulators) with the stage most affected (S1–S3), the expected directional effect on repair versus tumor risk, tractable research tools (inhibitors/activators or genetic approaches), and key caveats. Because mechanisms and disease models remain incomplete and species-restricted, this table is intended to inform experimental prioritization and translational study design.

Paligenosis also holds unique clinical promise in tissue regeneration. Traditional tissue engineering approaches often rely on exogenous cell transplantation [113], whereas paligenosis provides a paradigm of “in situ regeneration”—functional repair achieved by reactivating the plasticity of endogenous mature cells, without the need for external cell sources. Particularly in contexts where stem cell pools are depleted or inflammation suppresses stemness activation, induction of paligenosis may offer an alternative mechanism to rapidly initiate cellular reconstruction at injury sites. Its demonstrated role in gastric and pancreatic tissue regeneration [75] underscores its translational potential. In the future, identifying small molecules that selectively activate the paligenotic program or using biomaterials and localized delivery systems to release regulatory factors may enable clinically controlled endogenous repair strategies. These approaches are particularly relevant in cases of chronic injury, age-related regenerative decline, or acute extensive damage.

The intersection of paligenosis with cancer therapy is also gaining increasing attention. Paligenosis-like programs may contribute not only to the early stages of tumorigenesis [7] but also to metastasis and therapy resistance [8,9]. As such, paligenosis is emerging as a promising target in cancer diagnostics and therapeutics. On one hand, late-stage or incompletely redifferentiated paligenotic cells often exist in a transitional state between dedifferentiation and plasticity activation, exhibiting stem-like traits and proliferative potential [11]. If identifiable surface markers or transcriptional signatures can be established, these cells could serve as early diagnostic indicators of repair status or tumor progression risk, while guiding targeted interventions. On the other hand, paligenosis-like programs may facilitate tumor cell lineage reprogramming and adaptation to the tumor microenvironment. Targeting relevant signaling axes may yield novel strategies to suppress metastasis and overcome drug resistance, thereby expanding the repertoire of therapeutic options in oncology.

However, realizing these therapeutic applications requires overcoming several key challenges. First, although paligenosis is an autonomous cellular behavior, it is profoundly influenced by the surrounding microenvironment. Other cell types—such as fibroblasts, immune cells, and endothelial cells—may contribute to its initiation and maintenance through paracrine interactions, a topic that remains insufficiently explored. Second, the transcriptional networks activated downstream of mTORC1 in the third stage of paligenosis are not well characterized, particularly in terms of chromatin remodeling, RNA processing, and integration with regenerative signaling. Moreover, current research on paligenosis remains largely confined to epithelial tissues such as the stomach and pancreas, lacking a unified, cross-tissue molecular framework, which limits its broader applicability. Future research should aim to construct a comprehensive molecular model of paligenosis that integrates metabolic, signaling, and epigenetic regulation across multiple tissues. Such efforts would enhance our understanding of this process in both physiological and pathological settings and support its translation into clinical practice.

7 Conclusions

In conclusion, paligenosis—as a plasticity program initiated by mature cells—is reshaping conventional paradigms of tissue regeneration and tumorigenesis. It reveals that terminally differentiated cells can, under specific conditions, regain regenerative potential, highlighting the remarkable adaptability of cellular fate regulation. As omics technologies and organoid models continue to advance, the temporal dynamics, spatial heterogeneity, and molecular circuitry of paligenosis will become increasingly well-defined, accelerating its transition from basic research to targeted intervention. A deeper understanding and strategic modulation of this process may open new avenues for tissue regeneration, early cancer prevention, and overcoming therapeutic resistance, offering forward-looking strategies for both regenerative medicine and oncology.

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