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INTERNATIONAL CONGRESS OF

CancerGenetics

• Tumor-Suppressor Checkpoints in Partial Reprogramming: Balancing Epigenetic Rejuvenation, Lineage Fidelity, and Oncogenic Risk

• Maryam Heydari,¹ Shirin Farivar,^2,*
  1. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, 1983969411, Evin, Tehran, Iran
  2. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, 1983969411, Evin, Tehran, Iran
  
  
  
• Introduction: Partial reprogramming offers a potential route to reverse selected age-associated molecular changes and improve tissue function without completing somatic-cell conversion to pluripotency. Its therapeutic promise, however, is inseparable from the risk that increased cellular plasticity may erode lineage identity, compromise tissue competence, or enable oncogenic escape. Tumor-suppressor pathways are positioned at this boundary because they couple reprogramming competence to cell-cycle restraint, stress responses, damage surveillance, survival, and cellular selection. This review examines how the p53–p21 and INK4A/ARF–RB/p53 networks shape the balance among epigenetic rejuvenation, reversible regenerative plasticity, lineage fidelity, genomic quality, and cancer-related risk during partial reprogramming.
• Methods: This integrative, mechanistically oriented review prioritizes studies of partial, transient, cyclic, targeted, or incomplete reprogramming and interprets them alongside foundational full somatic-cell reprogramming studies and cancer-genetic evidence. Evidence was stratified by experimental proximity to partial rejuvenation and evaluated across reprogramming modality, factor composition, exposure duration, tissue and cell state, checkpoint context, senescence and stress responses, molecular aging, lineage state, differentiated function, genomic integrity, clonal behavior, and pathological outcomes. Particular attention was given to whether benefit reflected within-cell restoration, altered cellular composition, or selective survival. Direct findings were distinguished from cross-system mechanistic inference, and heterogeneous experimental designs were synthesized qualitatively rather than treated as quantitatively equivalent.
• Results: Evidence does not support a simple model in which stronger tumor-suppressor activity uniformly blocks rejuvenation or checkpoint suppression uniformly improves it. In transcription-factor-driven full reprogramming, p53–p21 reduces conversion efficiency while providing quality control by arresting or excluding DNA-damaged cells; loss or mutation of p53 can increase reprogramming competence while permitting genomic abnormalities or malignant potential. By contrast, recent chemical reprogramming evidence indicates that p53 can facilitate productive conversion, restrain excessive epithelial–mesenchymal transition through a BTG2-related program, and support genomic integrity, while chemical modulation of p21 permits proliferation despite retained p53. Direct partial-reprogramming studies reveal context-specific roles: p21 participates in myofiber-mediated niche remodeling through reduced Wnt4 signaling, enhancing satellite-cell activation and muscle regeneration, and contributes to senescence and apoptosis after transient OSKM exposure in lung cancer models. The INK4A/ARF network is similarly non-uniform. p16-high or INK4A/ARF-associated states can restrict cell-autonomous plasticity, yet senescent cells can promote neighboring-cell reprogramming through paracrine signals such as IL-6. Age-associated INK4A/ARF activation reduces reprogramming competence, but the relative contributions of ARF and INK4A differ across species and cell contexts. Cancer studies further show that TP53/RB1 deficiency can support consequential lineage plasticity, motivating genotype-aware safety testing in normal rejuvenating tissues. Across systems, molecular rejuvenation can precede overt dedifferentiation, but useful remodeling may also coexist with temporary suppression of somatic identity or deliberate entry into regenerative progenitor- or fetal-like states. Conversely, incomplete or prolonged reprogramming can produce dysplasia, tumors, severe organ dysfunction, oxidative stress, DNA-damage signaling, apoptosis, and loss of tissue function. Importantly, in sustained hepatic OSKM exposure, N-acetylcysteine (NAC) reduced oxidative stress and improved survival without abolishing core reprogramming-associated plasticity, separating a modifiable stress-mediated toxicity component from plasticity itself. These observations indicate that exposure depth and duration, cellular target, tissue state, genotype, and reprogramming modality jointly determine outcome. They also show that a younger molecular profile, reduced senescence markers, or absence of pluripotency markers cannot alone establish functional restoration or oncological safety. A central unresolved question is whether checkpoint pathways directly constrain reversible reprogramming depth, principally alter which cells survive and expand, or perform both functions. We therefore propose a checkpoint-aware assessment framework integrating molecular aging, lineage identity and provenance, tissue-specific function, checkpoint competence, genomic integrity, DNA-damage and senescence responses, escape potential, clonal behavior, exposure persistence, and long-term tumor and organ-toxicity surveillance.
• Conclusion: Partial reprogramming should be optimized for controllable, limited remodeling rather than maximal reprogramming efficiency. Current evidence supports tumor-suppressor checkpoints as context-dependent regulators of competence, stress handling, quality control, tissue communication, and selection, but does not establish a universal checkpoint setting that guarantees safe rejuvenation. The most defensible translational objective is the least extensive intervention capable of producing durable molecular and functional benefit while preserving or appropriately restoring lineage competence, genomic integrity, and tumor-suppressive surveillance. Future studies should independently manipulate reprogramming exposure and checkpoint status in aged, genetically heterogeneous, and cancer-prone tissues and link longitudinal single-cell state measurements to lineage, genomic, clonal, functional, and long-term pathological outcomes.
• Keywords: Partial reprogramming tumor suppressor epigenetic rejuvenation lineage plasticity oncogenic risk