Purpose: Redox homeostasis plays an important role in the osteogenic differentiation of human mesenchymal stem cells (hMSCs) for bone engineering. Oxidative stress (OS) is believed to induce osteoporosis by changing bone homeostasis. Selenium nanoparticles (SeNPs), an antioxidant with pleiotropic pharmacological activity, prevent bone loss. However, the molecular mechanism underlying the osteogenic activity during hMSC–SeNP interaction is unclear. Methods: This study assessed the effects of different concentrations (25, 50, 100, and 300 ng/mL) of SeNPs on the cell viability and differentiation ability of human embryonic stem cell-derived hMSCs. In addition, we analyzed OS markers and their effect on mitogen-activated protein kinase (MAPK) and Forkhead box O3 (FOXO3) during osteogenesis. Results: SeNPs increased the cell viability of hMSCs and induced their differentiation toward an osteogenic over an adipogenic lineage by enhancing osteogenic transcription and mineralization, while inhibiting Nile red staining and adipogenic gene expression. By preventing excessive reactive oxygen species accumulation, SeNPs increased antioxidant levels in hMSCs undergoing osteogenesis compared to untreated cells. In addition, SeNPs significantly upregulated the gene and protein expression of phosphorylated c-Jun N-terminal kinase (JNK) and FOXO3a, with no significant change in the expression levels of extracellular signal-related kinase (ERK) and p38 MAPK. Conclusion: The results approved that low concentrations of SeNPs might enhance the cell viability and osteogenic potential of hMSCs by moderating OS. Increased JNK and FOXO3a expression shows that SeNPs might enhance osteogenesis via activation of the JNK/FOXO3 pathway. In addition, SeNP co-supplementation might prevent bone loss by enhancing osteogenesis and, thus, can be an effective candidate for treating osteoporosis through cell-based therapy.

Protein phosphatase 2A (PP2A) is a critical tumor suppressor frequently inactivated in hematological malignancies, yet the mechanisms underlying this dysregulation remain poorly defined. Here, we investigated a novel interaction between the PP2A catalytic subunit (PP2Ac) and the adaptor protein CIN85. Analyzing transcriptomic datasets from AML, CML, CLL, and ALL patients, alongside functional validation in K562 and THP1 leukemia cell lines via RT-qPCR, immunoblotting, phosphatase activity assays, pharmacological modulation (FTY720 and Okadaic acid), siRNA-mediated knockdown, and proliferation assays, we found that CML and CLL exhibit reduced PP2A and elevated CIN85, with activated AKT, SRC, and GSK-3β levels. Pharmacological activation of PP2A reduced AKT and GSK-3β phosphorylation, while inhibition had opposing effects, confirming PP2A’s regulatory role. Crucially, CIN85 silencing markedly enhanced PP2A phosphatase activity without changing PP2Ac protein levels, leading to robust dephosphorylation of AKT, SRC, and GSK-3β and significantly suppressing leukemic cell proliferation. Collectively, these results identify CIN85 as a previously unrecognized endogenous negative regulator that directly suppresses PP2A function in leukemia. Importantly, disrupting the PP2Ac-CIN85 complex effectively restores PP2A tumor-suppressive activity, dampens oncogenic signaling, and inhibits growth, providing mechanistic clarity and positioning this protein-protein interface as one of the possible therapeutic targets for treating hematological cancers.