Sarcopenia and glucocorticoid-induced myopathy are significant forms of muscle atrophy that pose considerable public health challenges. In this regard, preventing muscle atrophy is crucial for enhancing quality of life and increasing life expectancy. In this study, we investigated the effect of recombinant human KAI1 (rhKAI1) on myogenic differentiation and its protective effect against dexamethasone-induced muscle atrophy. rhKAI1 enhanced myogenic differentiation in both murine C2C12 myoblasts and primary human endometrial stromal cells, as evidenced by upregulation of myogenic regulatory factors and increased myotube formation. These effects were accompanied by increased phosphorylation of Akt and AMPK. In a dexamethasone (Dex)-induced atrophy model, rhKAI1 increased myotube diameter, restored MyHC expression, and reduced the expression of the E3 ligase atrogin-1, accompanied by increased phosphorylation of Akt and AMPK. In addition, rhKAI1 administration improved Dex-induced functional impairment in mice, as reflected by increased grip strength and improved rotarod performance. Molecular analyses further showed that rhKAI1 modulated Dex-induced fiber-type-related gene expression by restoring MYH7 (type I) and reducing MYH4 (type IIb) expression. Collectively, our findings demonstrate that rhKAI1 promotes myogenic differentiation and alleviates several functional and molecular features associated with glucocorticoid-induced muscle deterioration. These results support the potential of rhKAI1 as a candidate molecule for further investigation in steroid-induced muscle dysfunction.

Mesenchymal stem cells (MSCs) hold strong therapeutic potential due to their regenerative, anti-inflammatory, and immunomodulatory properties. A key factor in their effectiveness is the ability to home in to injured sites. However, clinical outcomes are limited by poor homing efficiency, insufficient migration, tracking challenges, and risks of unwanted differentiation. This review explores the molecular mechanisms of MSC homing, particularly the CXCR4/SDF-1 axis and matrix remodeling. We highlight recent advances in using nanoparticles-such as magnetic, silica, and polymer-based systems-to enhance chemokine receptor expression and homing. Future directions include MSC engineering, advanced tracking, and AI-guided delivery strategies to improve therapeutic efficacy.

Background: The progression of idiopathic pulmonary fibrosis (IPF) involves distal airway remodeling and bronchiolization; however, the mechanisms driving these changes, particularly the contributions of epithelial stem cells, are not fully understood. K13+ hillock cells, normally quiescent in proximal airways, were examined for their potential contribution to IPF pathogenesis. Methods: Spatial immunofluorescence was used to profile K13 expression along the airway axes in IPF and control lungs. Multiplex staining complemented by ex vivo culture assays was used to test expression stability. Single-cell RNA-sequencing (scRNA-seq) data were re-analyzed to identify cell subclusters and pathway enrichments. Meanwhile, cell-cell communication was inferred by using CellChat. Results: K13 was ectopically upregulated in IPF honeycomb cysts, triggering a proximal-like pseudostratified phenotype. This shift was marked by surges in K13+ regionally overlapping expression patterns (K5+, ~9%; CC10+, ~53%; ACE-TUB+, ~44%; MUC5AC+, ~23%) and a decline in SOX2 expression (~95% to ~64%), with ~70% of residual SOX2low cells exhibiting elevated K13. Accompanying the expansion of K13+ subclusters (basal: 1.8% to 41.5%; club: 10.7% to 31.5%), it was observed that the profibrotic markers (K17, S100A2, LGALS7, IGFBP6) and ontologies related to RNA processing, stress response, and senescence were also enriched. These subclusters also amplified pro-fibrotic signaling (e.g., TGF-β, SEMA3, and GALECTIN-9) associated with epithelial subtypes and HAS1high fibroblasts. Conclusions: Here, we demonstrate that K13+ cell activation is a pivotal event, driving the dysregulated proximalization of distal airways in IPF through fate reprogramming and epithelial-mesenchymal crosstalk. Thus, elucidating these K13-mediated fate dynamics provides a critical framework for understanding IPF pathogenesis.

Background: Glucocorticoids (GCs) are a key pathogenic factor in steroid-induced avascular necrosis of the femoral head (SANFH). GCs can directly damage bone microvascular endothelial cells (BMECs), leading to impaired intraosseous blood supply. Recent studies suggest the Hippo signaling pathway may be involved in the pathogenesis of SANFH; however, its role in vascular endothelial repair and angiogenesis remains unclear. This study aims to investigate the therapeutic effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on SANFH, with a particular focus on their protective or reparative mechanisms on BMECs. Methods: In vivo, a SANFH mouse model is established and divided into NC, MPS, and hUC-MSCs groups, followed by Micro-CT imagin, hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) (n = 8 per group). In vitro, BMECs are divided into NC, dexamethasone (Dex), hUC-MSCs, and Fer-1 groups to analyze cellular biological behaviors. Target protein expression is assessed using Western blotting and immunofluorescence microscopy. Ferroptosis-related markers are detected via biochemical assays. Mitochondrial ultrastructural changes are observed using transmission electron microscopy. Results: In vivo, the MPS group exhibited significant bone cavitation, sparse trabeculae, and disrupted trabecular architecture in the femoral head. The hUC-MSCs group showed marked improvement in bone microstructure, HE staining showed a significant decrease in the empty lacunae rate in the femoral head, and IHC results revealed markedly increased expression of cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF). In vitro, Dex stimulation suppressed BMECs proliferation. In Dex-treated cells, levels of intracellular reactive oxygen species (ROS), lipid peroxides, ferrous ion (Fe2+), malondialdehyde (MDA), acyl-CoA synthetase long chain family member 4 (ACSL4) and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) were all increased, while expression of glutathione (GSH) and glutathione Peroxidase 4 (GPX4) was reduced. Transmission electron microscopy revealed plasma membrane rupture and reduction or loss of mitochondrial cristae. Furthermore, Dex promoted Hippo-mediated phosphorylation of Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ), upregulated NOX4 expression, and suppressed CD31 and VEGF expression. Following hUC-MSCs treatment, BMECs demonstrated enhanced proliferation, migration, and tube-forming capacity. Cellular GSH and GPX4 levels increased, antioxidant capacity was restored, peroxide accumulation decreased, and cells were protected from ferroptosis-effects comparable to those in the Fer-1 group. Additionally, hUC-MSCs inhibited YAP/TAZ phosphorylation and promoted elevated expression of CD31 and VEGF. Conclusions: These findings suggest that hUC-MSCs may attenuate Dex-induced ferroptosis in BMECs, enhance BMEC migration and angiogenesis, and improve femoral head microstructure in SANFH through modulation of the Hippo-YAP/TAZ signaling pathway. This study provides novel insights into the therapeutic potential of hUC-MSCs for SANFH.

Purpose: Castration-resistant prostate cancer (CRPC) responds poorly to conventional chemotherapy. We evaluated a cell-based enzyme-prodrug therapy using adipose-derived stem cells (ADSCs) engineered to express cytosine deaminase (CD) or carboxylesterase 2 (CE2), paired with their respective prodrugs 5-fluorocytosine (5-FC) or irinotecan (CPT-11), to compare their antitumor efficacy. Materials and Methods: Human telomerase reverse transcriptase (hTERT)-immortalized ADSCs were transduced with CD or CE2, and transgene expression and stem cell phenotype were confirmed. CD expression was verified at the transcript level and by functional 5-FC-to-5-fluorouracil (5-FU) conversion, whereas CE2 expression was verified by transcript analysis and immunoblotting. Tumor tropism toward PC3 prostate cancer cells was tested using migration assays and analysis of chemoattractant ligand/receptor expression. Prodrug-induced self-killing and bystander tumor cell killing were assessed through viability assays and co-culture with PC3 cells. For the CE2/CPT-11 system, SN-38 was not directly quantified; functional activity was inferred from prodrug-dependent cytotoxicity and in vivo efficacy. In vivo efficacy was evaluated in nude mice with PC3 tumors treated systemically with engineered ADSCs plus prodrug. Results: CD- and CE2-expressing ADSCs were successfully established and retained mesenchymal stem cell (MSC) characteristics. Both cell types exhibited significant migration toward PC3 cells. The CE2/CPT-11 system produced stronger prodrug-mediated cytotoxicity than CD/5-FC, with CE2-modified ADSCs showing higher sensitivity to CPT-11 and inducing greater apoptosis in co-cultured PC3 cells. In vivo, both treatments suppressed tumor growth, but CE2/CPT-11 achieved greater inhibition (tumor volume ~26% of control vs. ~32% for CD/5-FC at day 14). No overt clinical toxicity was observed based on body weight and daily clinical monitoring; however, hematology/serum chemistry were not assessed. Conclusions: Engineered ADSCs home to CRPC tumors and enable local prodrug activation, producing significant antitumor effects. Within the constraints of our in vitro assays and subcutaneous xenograft model, CE2/CPT-11 demonstrated stronger efficacy outcomes than CD/5-FC. Mechanistic attribution to intratumoral SN-38 exposure should be confirmed by direct metabolite measurements in future studies.

Background/Objectives: Bile duct ligation (BDL), characterized by marked inflammation and fibrosis, effectively mimics many clinical conditions and is a valuable tool for investigating biliary regeneration. Our objective was to clarify the therapeutic benefits of adipose-derived stem cell (ADSC) treatment and signaling pathways mediating regenerative processes in a rat model of BDL. Methods: The BDL model was performed on Sprague-Dawley rats, and ADSC was administered intrasplenically at a dose of 106 cells per animal. Liver function tests, gene and protein expression analyses, histological evaluation, and immunohistochemistry staining were performed to assess liver function, signaling pathways, inflammation, and fibrosis. Results: ADSC treatment returned liver function to sham levels. ADSC upregulated the Hes1 gene and protein expression in the early and late term. Inflammation, fibrosis, and total damage scores were decreased following ADSC treatment compared with the control. Immunohistochemistry staining revealed higher CD90, CD44, and CD29 stem cell marker expression in the ADSC treatment group. Conclusions: ADSC administration reduced fibrosis and biliary damage and restored liver function, potentially in a manner mediated by upregulated Hes1 expression, supporting its promise in biliary regeneration.

Background/Objectives: Pulmonary fibrosis is a chronic, progressive lung disease marked by scarring and inflammation, leading to impaired respiratory function. This study aimed to investigate the combined therapeutic effects of pirfenidone (PFD), metformin (MET), and bone marrow-derived mesenchymal stem cells (BM-MSCs) on bleomycin (BLM)-induced pulmonary fibrosis in rats. Methods: Forty-eight Western Albino rats were divided into six groups: normal control, BLM-positive control, and four treatment groups receiving PFD, MET, BM-MSCs, and their combination. Treatments were administered for four weeks starting on day 21 post-BLM instillation. Lung tissues were analyzed for oxidative stress markers, inflammatory cytokines, apoptotic markers, and fibrogenic gene expression. Histopathological changes were assessed using hematoxylin and eosin (H&E) and Masson's trichrome staining. Results: The combination therapy significantly reduced oxidative stress and inflammatory markers while enhancing antioxidant capacity. It decreased pro-apoptotic Bcl-2-associated X protein (BAX) and increased anti-apoptotic B-cell lymphoma 2 (Bcl-2) levels. Additionally, anti-inflammatory interleukin-10 (IL-10) was elevated, while tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta 1 (TGF-β1) levels were markedly lowered. Gene expression analysis showed a significant downregulation of matrix metalloproteinase-9 (MMP-9) and collagen type 1 alpha 1 (Col1α1). Histologically, the combination treatment group exhibited minimal fibrosis and inflammation, closely resembling normal lung tissue. Conclusions: The combination of PFD, MET, and BM-MSCs offered superior therapeutic efficacy in treating BLM-induced pulmonary fibrosis compared to individual treatments. This multimodal approach effectively targets oxidative stress, inflammation, apoptosis, and fibrosis, suggesting strong potential for future clinical application.

Background: Inflammatory bowel disease (IBD) involves chronic intestinal inflammation, epithelial barrier disruption, and dysbiosis, with environmental factors playing a significant role in its pathogenesis. Previous work revealed that cold exposure alleviates colitis in mice; this study extends that finding by demonstrating that cold exposure enhances intestinal regeneration even in healthy mice, upregulating proliferation markers (Mki67, PCNA, Cyclin D1). Methods: Applying this pro-regenerative effect to a colitis model, we investigated the underlying mechanisms through multi-omics analysis, transmission electron microscopy (TEM), immunofluorescence, and pathological staining as well as 16S rRNA sequencing. Results: We found that cold exposure activates intestinal epithelial proliferation pathways. Further analysis indicated that cold exposure induces colonic stem cell regeneration, upregulating stem cell markers Lgr5 and Ascl2. Notably, colonic transcriptomic profiling revealed the emergence of a Paneth-like cell phenotype, characterized by altered expression of specific lineage genes. Furthermore, cold exposure simultaneously promoted the accumulation of secretory granules and upregulated the expression of antimicrobial peptide genes (such as Lysozyme and Defa) in ileal Paneth cells. This enhanced ileal antimicrobial defense effectively reshaped the gut microbiota in inflamed intestines. Conclusions: This research elucidates a mechanism whereby cold adaptation promotes mucosal repair by integrating localized colonic epithelial regeneration with enhanced ileal Paneth cell-mediated antimicrobial defense. This offers compelling new perspectives on how environmental factors, such as cold exposure, could influence the pathophysiology of IBD and contribute to intestinal regeneration, which may provide foundational theoretical support for the future diagnosis and treatment of IBD.

Background/Objectives: Sebaceous carcinomas (SebCAs) of the ocular adnexa, primarily arising from the Meibomian glands, are locally aggressive eyelid tumors with metastatic potential. Upregulation of the oncogene MYC has been demonstrated in SebCA, suggesting a role in tumor initiation and progression. In other epithelial tumors, the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway has been implicated in stem cell renewal via MYC activation and stabilization. This study aimed to evaluate the effects of pharmacologic and genetic modulation of the IIS pathway on MYC expression in human Meibomian gland epithelial cells (HMGECs) and meibocytes of adult C57B6 mice. Methods: HMGECs were incubated with either IIS activators or inhibitors or were subject to transfection with either an IGF1R plasmid or siRNA before assessments of viability, proliferation, immunostaining, and MYC quantification were performed. Murine eyelids were treated topically with small-molecule IIS modulators prior to tissue harvest for histology, immunolabeling, and qPCR. Results: HMGECs treated with IIS activators demonstrated downregulated IGF1R and upregulated MYC expression, increased viability and proliferation, and reduced autophagy, while treatment with inhibitors yielded the inverse effects. Incubation with the selective insulin receptor agonist, demethylasterriquinone B1, yielded the most phenotypic variability. IGF1R-overexpressing HMGECs exhibited relative upregulation of both Akt and MYC. Murine eyelids treated with an IIS agonist demonstrated a more mesenchymal phenotype and significantly induced MYC expression. Conclusions: Collectively, these results suggest that the IIS pathway may represent a novel approach for regulating high MYC expression in SebCA.

Background: Right-sided colon cancer (RCC) is clinically aggressive and prone to liver metastasis, yet the cellular basis underlying its metastatic potential remains unclear. This study aimed to delineate the single-cell landscape of primary RCC tumors with and without liver metastasis. Methods: Public single-cell RNA sequencing datasets of primary right-sided colon tumors from eight patients (five with liver metastasis and three without metastasis) were integrated and analyzed. Malignant cells were identified by copy number variation inference. Tumor subclusters, differential gene expression, pathway enrichment, metabolic activity, and pseudotime trajectories were systematically compared between RCC with liver metastasis (RCC_LM) and without metastasis (RCC_noM). Results: RCC_LM tumors exhibited higher genomic instability and a significantly higher proportion of cells in G1 phase, suggesting that altered cell cycle progression is a key feature of tumors with metastatic potential. Five tumor subclusters were identified, with stem-like tumor cells significantly enriched in RCC_LM, whereas enterocyte-like cells predominated in RCC_noM. The primary tumor samples from tumors that metastasized displayed transcriptional programs indicative of epithelial-mesenchymal transition, extracellular matrix remodeling, inflammatory signaling, and metabolic reprogramming involving glycolysis and oxidative phosphorylation. Trajectory analyses indicated that RCC_LM tumors were enriched in early pseudotime states, suggesting increased cellular plasticity. Conclusions: These findings indicate that liver metastatic potential in RCC is marked by stem-like tumor states, metabolic plasticity, and microenvironmental remodeling, providing insight into the cellular mechanisms underlying RCC progression.

Background: Bone remodeling depends on the dynamic balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Follistatin-like 1 (FSTL1) has been reported as an osteoclast-secreted protein that inhibits osteoclast differentiation, but its direct effects on osteoblast differentiation remain unclear. This study aimed to determine whether FSTL1 regulates osteoblast differentiation and mesenchymal stem cell migration and characterizes its role in osteoclast-osteoblast cellular cross-talk under in vitro conditions. Methods: Bone marrow-derived macrophages (BMMs) and stromal cells (BMSCs) from mice were used to induce osteoclast and osteoblast differentiation, respectively. Chemotaxis was assessed by Transwell migration, and osteoblast differentiation was evaluated in BMSC and MC3T3-E1 cells using staining, qRT-PCR, Western blotting, and proliferation assays. Results: FSTL1 significantly suppressed osteoclast differentiation and resorptive activity, confirmed by TRAP staining and pit assay, respectively. Expression of osteoclast markers such as NFATc1, TRAP, and DC-STAMP was reduced under FSTL1 treatment. In BMSCs, FSTL1 did not affect proliferation but significantly enhanced chemotaxis. Moreover, FSTL1 promoted osteogenic differentiation and mineralization, as demonstrated by increased ALP activity and Alizarin Red S staining. In MC3T3-E1 pre-osteoblasts, FSTL1 increased cell proliferation and mineralization by MTS and Alizarin Red staining. Key osteogenic markers, including Runx2 and osteocalcin, were also upregulated. Conclusions: Osteoclast-derived FSTL1 significantly suppresses osteoclastogenesis and promotes mesenchymal cell chemotaxis and osteogenic differentiation, indicating a role in regulating osteoclast-osteoblast cellular interactions in vitro. Targeting FSTL1 signaling may represent a promising therapeutic strategy for osteoporosis and other disorders of impaired bone remodeling.

Background/Objectives: The attention of world science has been focused on human umbilical cord blood cell (hUCB) products for the treatment of various human diseases. The prospects for using hUCB stem from the availability of the material, non-invasive collection procedure, low immunogenicity, multipotency and non-tumorigenicity. But information about the acute toxicity, reproductive and developmental toxicity of hUCB mononuclear cells (MNCs) remains insufficient. Thus, the aim of this study is to assess the reproductive and developmental toxicity of human umbilical cord blood mononuclear cells on Wistar rats. Methods: In the fertility and early embryonic development study, human umbilical cord blood mononuclear cells (hUCB-MNCs) were administered at dose levels of 4.28 × 108 cells/kg and 8.57 × 108 cells/kg to male and female rats during the pre-mating, mating and gestation period. In the embryo-fetal development study, the pregnant female rats also received hUC-MNCs at doses of 4.28 × 108 cells/kg and 8.57 × 108 cells/kg. Results: In gestational data, including fertility rate, pregnancy rate, corpora lutea and implantation sites counts, dead and absorption fetuses' number, body weight and craniocaudal size of fetuses, anomalies in fetal development showed no statistically significant changes in 4.28 × 108 cells/kg (low dose) and 8.57 × 108 cells/kg (high dose) dose groups of hUCB-MNCs to negative control group. External, visceral and skeletal examination of the fetuses in all experimental groups also showed no changes. Embryo-fetal development study in low and high groups of hUCB-MNCs application also showed no changes in the negative control group. Conclusions: This reproductive and developmental toxicity study demonstrates that hUCB-MNCs administered intravenously at doses up to 8.57 × 108 cells/kg do not cause adverse effects on fertility, embryo-fetal development, or postnatal offspring viability in Wistar rats. The absence of reproductive toxicity is mechanistically attributable to three intrinsic properties of hUCB-MNCs: their low immunogenicity, which prevents maternal immune activation; the protective function of the intact placental barrier; and their transient, paracrine-dominant mode of action, which limits exposure duration.

Tendon and ligament injuries are frequent in sport horses and are prone to recurrence due to incomplete healing. Platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) are increasingly used, but data controlled on the early effects of autologous MSCs remain limited. A prospective randomized, double-blind, placebo-controlled trial was conducted in horses with naturally occurring tendinopathies. After standardized PRP pretreatment, non-responders were randomized to receive intralesional autologous muscle-derived MSCs (mdMSCs, n = 17) or placebo (n = 6). Clinical and ultrasonographic parameters were evaluated at the recruitment period (T0) before the administration of the local treatment (T1), 4 (T2) and 8 weeks later (T3). Eighteen horses from both groups received at T2 a second intralesional injection of mdMSCs at the investigator's discretion; this phase was not randomized. Horses treated with mdMSCs showed significant improvements from T1 to T2 across both clinical and ultrasonographic parameters, whereas no significant changes were observed in the placebo group. Between-group comparison at T2 confirmed the significant superiority of mdMSCs. Further improvements were observed between T2 and T3 in the 18 horses that received a second injection. No systemic adverse events were recorded, and local reactions were mild and transient. This randomized controlled trial demonstrates early clinical and ultrasonographic efficacy of autologous mdMSCs in equine tendinopathy, with additional benefit from a second injection. The autologous approach combines efficacy and safety while avoiding the immunological and logistical constraints of allogeneic strategies.

Cultured meat, a sustainable alternative to conventional meat, addresses ethical and environmental challenges in livestock production. Its production relies on bovine muscle stem cells from adult muscle or fetal tissue, whose proliferation and differentiation vary with age and developmental stage. However, the molecular mechanisms underlying these variations remain unclear. RNA sequencing was performed to characterize the transcriptomic landscape of bovine muscle stem cells across developmental stages, including myogenic maturation. Differentially expressed genes and key signaling pathways regulating myogenesis were identified, and the functional impact of modulating the AKT-autophagy pathway on differentiation was assessed. Transcriptomic analysis revealed distinct age-dependent gene expression patterns. It was possible to classify cells into three categories: young undifferentiated, young differentiated, and old differentiated. Young undifferentiated-like cells exhibited upregulation of genes associated with active states during the transitions from quiescence to activation and, ultimately, to commitment, indicating that they had robust differentiation potential. In contrast, aged myogenic samples displayed gene expression profiles that acted as barriers to efficient myogenic differentiation. Notably, modulation of the AKT-autophagy pathway both facilitated the production of very mature myogenic cells and prevented spontaneous differentiation, thereby preserving differentiation capacity in vitro. These findings provide insights into age-dependent muscle stem cell differentiation and suggest strategies to optimize cultured meat production. The appropriate modulation of key signaling pathways may help us to overcome major challenges in achieving scalable and efficient cultured meat manufacturing.

In the original publication [...].

Osteosarcoma (OS) is a highly aggressive bone cancer with limited therapeutic options. Carnosic acid (CA), a phenolic diterpene with well-established antioxidant properties, has shown anticancer activity, yet its mechanisms in OS remain unclear. In this study, we found that CA suppressed proliferation and induced apoptosis in human osteosarcoma cells in a dose-dependent manner. Mechanistically, CA activated the STING/IRF3 signaling pathway and enhanced nitric oxide (NO) production, factors closely linked to redox modulation and mitochondrial apoptotic signaling. Pharmacological inhibition or siRNA-mediated knockdown of STING, as well as blockade of NO synthesis, significantly reduced CA-induced apoptosis in vitro. In a xenograft mouse model, CA treatment suppressed tumor growth, and this effect was partially reversed by STING inhibition. These findings suggest that CA exerts antitumor effects in OS through modulation of innate immune and redox-related signaling pathways, supporting its potential as a therapeutic compound that links antioxidant and immunomodulatory actions.

Pathological accumulation of reactive oxygen species (ROS) is implicated in several diseases, including cancer, cardiovascular diseases, and aging. However, ROS play essential roles in cellular functions, including proliferation, differentiation, and immune responses, at physiological levels. In megakaryocytes, the cells responsible for producing platelets, ROS exert context-dependent effects, either promoting or impairing maturation depending on developmental stage and subcellular localization. In this review, we summarize current evidence demonstrating that balanced ROS signaling is required throughout megakaryocyte development. Further, we discuss how the source and timing of ROS generation determine their distinct stage-specific functions, and the role of ROS dysregulation in defective platelet production in conditions such as aging, inflammation, and hematopoietic stress. We further highlight the importance of redox regulation for efficient in vitro platelet manufacturing. Although stem cell-derived platelets hold great promise for addressing global platelet shortages, current systems produce significantly fewer platelets than are found naturally. We propose that limited understanding and poor control of ROS dynamics contribute to limited platelet yield and quality. By viewing ROS as tunable biological signals rather than solely as harmful byproducts, we emphasize redox modulation as a practical and actionable approach to enhance platelet biogenesis and support the development of next-generation platelet therapies.

Melanoma is an aggressive cancer characterized by a rapid metastatic process. Thus, understanding the mechanisms underlying its progression is urgently needed to improve patient outcomes. In this regard, there is consistent evidence of a tumor-sustaining crosstalk between melanoma and subcutaneous adipose tissue; however, the role of extracellular vesicles (EVs) in this communication still needs to be clarified. We demonstrated that the EVs derived from adipocytes did not alter melanoma cell proliferation but significantly promoted tumor cell migration and invasion by determining an enrichment in mesenchymal markers, such as N-cadherin and vimentin. In particular, these changes were accompanied by the transition towards a stem-like phenotype, characterized by enhanced spherogenic ability and ABCG2 upregulation; interestingly, this led to a reduced in vitro response to the BRAF inhibitor vemurafenib. Mechanistically, an increase in PGC-1α expression was found, resulting in higher mitochondrial mass and activity, ATP synthesis, and ROS overproduction; of note, treatment of melanoma cells with SR-18292 and XCT790, two inactivators of mitochondrial biogenesis, and N-acetylcysteine, a ROS scavenger, successfully counteracted the above EV-related effects, suggesting that mitochondrial function could be targeted to suppress the vesicular interactions between adipose tissue and melanoma. Taken together, these results highlight the crucial role played by EVs in melanoma stroma, pointing out the ability of adipocyte-derived vesicles to sustain cancer aggressiveness via PGC-1α-dependent mitochondrial reprogramming.

Epigenetic dysregulation is a central driver of cancer progression, therapeutic resistance, and phenotypic plasticity. Among epigenetic mechanisms, microRNAs (miRNAs) and DNA methyltransferases (DNMTs) engage in reciprocal regulatory interactions that extend beyond transient gene control. Emerging evidence indicates that DNMT-miRNA feedback loops function as epigenetic memory units, stabilizing malignant cell states and enabling durable phenotypic inheritance even after removal of initiating stimuli under conditions shaped by persistent redox and stress signaling cues. In this review, we synthesize mechanistic, computational, and translational studies demonstrating how double-negative DNMT-miRNA feedback architectures generate bistable regulatory circuits that lock cancer cells into epithelial-mesenchymal transition, stem-like, and therapy-resistant states through redox-sensitive regulatory thresholds rather than static epigenetic alterations. This framework provides a unifying explanation for why transient environmental or therapeutic cues can induce long-lasting epigenetic reprogramming and why conventional single-target epigenetic inhibitors often fail to achieve durable clinical responses. Building on this concept, we propose that herbal medicines and plant-derived phytochemicals act as epigenetic reset signals capable of destabilizing pathological epigenetic attractor states encoded by DNMT-miRNA memory circuits by modulating intracellular redox balance and redox-responsive signaling pathways. Owing to their multi-component and systems-level regulatory properties, herbal interventions modulate miRNA expression, DNMT activity, and upstream stress-responsive pathways in a coordinated manner, facilitating transitions from memory-dominated states toward renewed epigenetic plasticity. We further discuss the translational implications of combining miRNA-based therapies with herbal medicine as a strategy for epigenetic reprogramming rather than transient suppression within a redox-guided therapeutic framework. Finally, we address key challenges and clinical feasibility considerations, including delivery, heterogeneity, and safety, and outline future directions for biomarker-guided and systems-informed epigenetic therapies that incorporate redox state as a functional determinant of epigenetic responsiveness. By reframing DNMT-miRNA interactions through the lens of epigenetic memory, this review highlights miRNA-herbal combination strategies as a forward-looking approach for overcoming therapeutic resistance and achieving durable reprogramming in cancer through selective manipulation of redox-sensitive epigenetic signaling circuits.

Excessive oxidative stress can cause irreversible cytotoxic damage to both healthy and cancer cells through the induction of reactive oxygen species (ROS) mediated lipid peroxidation. Ferroptosis has recently been shown to promote lipid peroxidation due to the over-accumulation of iron. Although cancer cells possess elevated antioxidant capacity to neutralize chemotherapy-induced oxidative stress, the co-delivery of polyphenol compounds such as curcumin (CUR) can overwhelm these defenses by elevating intracellular ROS levels to a toxic threshold, thereby increasing anticancer efficacy. In this study, we evaluated the potential of CUR to chemosensitize doxorubicin (DOX) towards the DOX-resistant lung cell line (H69AR). Our results demonstrated that the combination of DOX and CUR resulted in a concentration-dependent behavior, where low-dose concentrations exhibited antagonistic effects, while high-dose IC50-equivalent concentrations shifted towards synergism. The combination induced significantly greater mitochondrial dysfunction, ATP depletion, cytochrome C release, and caspase-3 activation. This also resulted in excessive ROS generation, intracellular iron overload, and lipid peroxidation, accompanied by a reduction in antioxidant enzymatic activities. Pretreatment with N-acetyl-L-cysteine (ROS inhibitor) and ferrostatin-1 (ferroptosis inhibitor) further supported the involvement of oxidative stress and ferroptosis in modulating apoptosis and DNA fragmentation. Molecular docking analyses supported the binding of CUR and DOX to key ferroptosis regulators. This study shows the potential of CUR to sensitize DOX-resistant cancer cells through ferroptosis-linked-oxidative stress targeting.