Page 287 - EJMO-9-2

Eurasian Journal of
Medicine and Oncology QGJSF multi-target mechanisms in osteoporosis

and mineralization. Concurrently, it inhibits RANKL- negative regulators, such as PTEN/SHIP. 57-60 Aging-related
induced osteoclast pre-cursor maturation, playing a dual pathways include p16/RB and p53/p21, which induce cell
regulatory role in maintaining the balance between bone cycle arrest through DNA damage response and suppress
formation and resorption. 26-28 TP53, as a transcription osteogenesis (p53 inhibits Runx2/Osterix through
factor, suppresses osteoblast differentiation by blocking miR-145 targeting Cbfb 61,62 ), while NF-κB amplifies
OSX-DLX5 complex formation and inhibiting osteogenic bone damage through SASP-mediated inflammatory
gene expression (IBSP, COL1A1) while inducing pro- cascades. Non-coding RNAs (e.g., lncRNA ZFAS1/miR-
apoptotic genes (NOXA, PUMA). High-dose glucocorticoids 29a) epigenetically regulate Wnt/β-catenin and FoxO
activate the TP53 signaling pathway, downregulating OPG pathways to influence bone homeostasis. 63,64 The osteoclast
and upregulating RANKL to disrupt bone homeostasis; differentiation network centers on the M-CSF/RANKL-
excessive TP53 activation further induces osteoclast cycle RANK axis, activating NF-κB/MAPK/NFATc1 signaling.
arrest and ferroptosis. 29-36 ESR1 promotes BMSC osteogenic STAT3 synergizes with c-fos to enhance NFATc1 activity,
differentiation through the Wnt/β-catenin, PI3K/AKT, and whereas OPG, miRNAs (e.g., miR-34a-5p), and lncRNAs
MAPK/ERK pathways. Its knockdown significantly reduces (e.g., AK077216) modulate osteoclast-osteoblast balance
the expression of osteogenic markers (ALP, Runx2, OCN, in OP progression. 65-71 These pathways highlight molecular
OPN) and mineralized nodule formation. In gender-specific switches in OP pathogenesis, such as the HIF-1α-VEGF axis
regulation, ESR1 primarily affects cortical bone in male in bone-vascular coupling and FoxO/Wnt crosstalk driving
mice and trabecular bone in female mice. In osteoclasts, aging-related bone loss, and underscore therapeutic targets
ESR1 induces apoptosis through the FasL/Fas pathway to (e.g., PI3K/AKT plasticity, ncRNA-mediated epigenetic
inhibit bone resorption and is regulated by SIRT6 in bone regulation) for precision interventions.
quality modulation. 37-42 JUN, a component of the AP-1
complex, activates late-stage osteoblast differentiation The integration of molecular docking results with
genes through the JNK signaling pathway and participates network pharmacology and GEO validation analyses
in cell proliferation, stress responses, and apoptosis to provides a multi-layered mechanistic explanation for the
maintain osteocyte homeostasis. In summary, STAT3, therapeutic effects of QGJSF in OP. Molecular docking
43
AKT1, TP53, ESR1, and JUN play pivotal roles in studies revealed that key active components in QGJSF,
regulating bone metabolism, providing valuable insights including quercetin, dioscin, genistein, calycosin, and
into the pathophysiology of OP and highlighting potential berberine, exhibit strong binding affinities to critical
therapeutic targets. targets such as AKT1 and TP53, previously identified as
core therapeutic hubs and validated in the GEO dataset
Enrichment analysis shows that the therapeutic (GSE35958). For instance, quercetin and calycosin showed
mechanisms of QGJSF for OP involve the coordinated stable interactions with AKT1, a central regulator of the
regulation of multiple signaling pathways. Under hypoxic PI3K/AKT pathway, potentially enhancing its activation
conditions, HIF-1α promotes osteoclast differentiation to promote osteoblast survival and differentiation while
and glycolysis-mediated energy metabolism through suppressing osteoclastogenesis. Similarly, dioscin and
ANGPTL4, while downstream VEGF enhances osteoclast baicalein demonstrated high binding potential with TP53,
activity through autocrine/paracrine pathways and suggesting direct modulation of TP53-mediated apoptosis
mediates type H angiogenesis, directly linking bone and cell cycle arrest, counteracting bone loss. Notably,
mass regulation (HIF-1α deficiency causes bone loss, these docking results align with the GEO findings where
whereas overexpression promotes vascular-osteogenic AKT1 and TP53 exhibited significant dysregulation
coupling). 44-47 The FoxO pathway maintains redox (AUC = 1.000) in OP, reinforcing their roles as primary
homeostasis by activating antioxidant enzymes (e.g., targets of QGJSF.
SOD, Cat) and interacts with the Wnt/β-catenin
pathway: During aging, FoxO competes for β-catenin The identification of seven overlapping targets
binding, inhibiting Wnt signaling, while JNK-mediated (including AKT1 and TP53) across the GEO dataset and
FoxO phosphorylation further disrupts β-catenin/TCF QGJSF’s core targets further bridges the gap between
transcriptional activity, impairing osteoblast function. 48-55 computational predictions and experimental validation.
The PI3K/AKT pathway exhibits dual roles in bone While STAT3, ESR1, and JUN also showed binding
metabolism: Activation promotes osteoblast differentiation capabilities with QGJSF components, their lower diagnostic
(e.g., IL-37 enhances MSC osteogenesis and mineralization AUC values in GEO data compared to AKT1/TP53 suggest
through this pathway ), while M-CSF/RANKL-driven they may act as secondary or synergistic targets. This
56
PI3K/AKT signaling fuels osteoclastogenesis, which can hierarchical target prioritization, with AKT1 and TP53
be suppressed by phytoestrogens (e.g., resveratrol) and as the most diagnostically and mechanistically relevant,

Volume 9 Issue 2 (2025) 279 doi: 10.36922/EJMO025150103