Editorial: Epigenetics and stem cell therapy in cancer and diseases

Stem cell therapy and epigenetics of stem cells represent two deeply interconnected areas of biomedical research, especially in the context of cancer and diseases. Stem cell therapy involves pluripotent or multipotent stem cells to repair or replace damaged tissues. The most common sources include embryonic stem cells (ESCs), adult stem cells such as hematopoietic stem cells (HSCs), and induced pluripotent stem cells (iPSCs). In cancer research field, hematological cancers are commonly treated with bone marrow transplants using HSCs, mesenchymal stem cells (MSCs) are being engineered to deliver anti-cancer agents within the tumor bulk, iPSCs offer patient-specific cancer models or regenerative treatments post-therapy. In addition, stem cell therapy has shown advantages also in neurodegenerative diseases such as Parkinson's and amyotrophic lateral sclerosis (ALS), or in cardiovascular diseases, autoimmune disorders and diabetes. In the field of regenerative medicine, the role of epigenetic regulation in maintaining stem cell pluripotency and directing lineage specification is a topic of active investigation. These processes are critical in human embryonic stem cells (hESCs), where dynamic chromatin remodeling governs both self-renewal and differentiation potential. Epigenetic dysregulation in stem cells is linked to developmental disorders, aging, and chronic inflammatory diseases.In tumors, cancer stem cells (CSCs) which represent a particularly aggressive subpopulation characterized by self-renewal, resistance to therapy and metastatic capacity, are often regulated by aberrant epigenetic mechanisms. Uncovering epigenetic changes specific to CSCs is essential for identifying novel therapeutic strategies aimed at eradicating these resilient cells. (Műzes and Sipos, 2019). Preliminary data support their therapeutic potential in myocardial infarction, cerebral hemorrhage, retinal degeneration, and lung injury. To translate hAECs into a robust commercial product, concerted efforts must address scalable expansion, rigorous phenotypic characterization, and industrial-grade manufacturing processes. Such advances will bridge the gap between bench and bedside, fulfilling the promise of safe, effective, and ethically sound cell therapy, opening new scenarios in the field of stem cell therapy.Mengistu D.Y. et al. https://doi.org/10.3389/fmmed.2025.1530719 highlight how DNA methylation, histone modifications, and microRNAs (miRNAs) regulate the expression of the TARDBP gene, encoding TDP-43, an RNA-binding protein that is a pathological hallmark of ALS, and how the epigenetic deregulations contribute to disease progression. Both gain and loss-of-function of TDP-43 are implicated in ALS, yet the precise balance required for neuronal integrity remains unclear. DNA methylation has been shown to regulate TARDBP expression and isoforms. In vitro, knockdown of DNA methyltransferases (DNMTs) correlates with increased TDP-43 levels. In aging murine brains, increased repressive H3K27me3 and decreased H2A.Z acetylation at the TARDBP promoter reflect a more condensed chromatin structure and reduced gene expression. A conserved mechanism has been identified in Drosophila, where age-dependent H3K9me3 deposition at the TBPH promoter (TDP-43 ortholog) by the histone methyltransferase Su(var)3-9 suppresses gene expression and impairs locomotion. Genetic ablation of Su(var)3-9 reverses this phenotype, and similar effects are seen in human cells, suggesting a conserved regulatory axis. Finally, miRNAs contribution to this regulatory network was analyzed. Several miRNAs affect TARDBP expression, and ASL-related proteins are involved in miRNA biogenesis, suggesting a feedback mechanism.These findings delineate an evolutionarily conserved epigenetic framework governing TDP-43 expression. Characterizing and manipulating this network may offer novel therapeutic strategies to restore TDP-43 homeostasis and modify disease progression in ALS.Recently, many epigenetic modifications have been involved in initiating and maintaining CSCs in various pediatric and adult cancer types (Veschi et al., 2019) (Veschi and Thiele, 2017) (Veschi et al., 2020) (Veschi et al., 2025).