ABSTRACT Background Cellular plasticity and epithelial–mesenchymal transition (EMT) promote the initiation and progression of non-small cell lung cancer (NSCLC). Thioredoxin reductase 1 (TXNRD1), a key redox enzyme, has been linked to malignancy, but its mechanism in NSCLC remains unclear. We examined whether TXNRD1 regulates TGF-β1 autocrine signaling to drive EMT and stemness. Materials Stage-progression gene profiles were analyzed in the TCGA and GEO databases with an emphasis on redox gene families. TXNRD1 was manipulated by overexpression or knockdown in A549, H226, and H1299 cells, followed by migration/invasion, spheroid assays, ELISA for cytokines, and RT-qPCR/Western blot for EMT markers. RNA-seq with pathway enrichment analyses was used to identify downstream programs. An orthotopic lung cancer mouse model was established using TXNRD1-WT cells, TXNRD1-deficient cells, and TXNRD1-deficient cells treated with TRi-1. Tumor progression was monitored by bioluminescence imaging at 6 and 12 weeks after transplantation. Results TXNRD1 expression was ~2-fold higher in advanced-stage NSCLC and was validated in tumor tissues. CRISPR/Cas9 or siRNA knockdown reduced EMT-associated genes and decreased TGF-β1 production in A549 and H226 cells. TXNRD1 overexpression increased EMT and stemness markers and produced larger, more compact spheres with higher sphere numbers in H1299 cells. RNA-seq indicated the TXNRD1 pathway activates the TGF-β1 pathway to promote EMT, motility, and stemness via an autocrine loop; knockdown or TXNRD1 inhibition suppressed metastatic tumor growth in vivo. Conclusions Our study identifies TXNRD1 as a crucial regulator of cellular plasticity and metastasis in NSCLC via the TGF-β1 pathway, suggesting that targeting TXNRD1 may reduce metastatic potential and improve patient survival.
Yaw-Dong Lang, Shin-Yuan Gu, Jou-Ho Shih et al.· Cancer Biology & Therapy· 0 citations
BACKGROUND
Traumatic brain injury (TBI) disrupts anatomical structure and cellular signaling, yet the molecular mechanisms governing endogenous repair remain incompletely defined. Accumulating evidence implicate an increased risk of developing to neurodegenerative diseases for TBI patients, in part through chronic neuroinflammation, protein aggregation, and progressive synaptic dysfunction. However, a critical unmet need is that no approved medicine directly promotes neurite regrowth and functional recovery after TBI.
PURPOSE
To identify candidate compounds that can promote neurite regrowth of injured brain neurons and improve functional outcome of TBI mice. The mechanism of action of the lead compound will be determined.
STUDY DESIGN
Through an extensive screening of plant extracts, we have identified a nature compound, isorhoifolin, that promotes neurite regrowth of injured cortical and hippocampal neurons. Functional assays were conducted to assess behavioral efficacy and the direct protein targets of isorhoifolin were identified.
RESULTS
Using complementary in vitro, ex vivo, and in vivo models of TBI, we demonstrated that isorhoifolin attenuated both cytosolic and mitochondrial reactive oxygen species, highlighting its role in redox homeostasis. Comparative structure-activity analyses revealed that the closely related flavonoids exhibited divergent biological efficacy, indicating that specific chemical features determine functional outcomes. In vivo, isorhoifolin crossed the blood-brain barrier and significantly improved motor coordination following experimental TBI. Transcriptomic profiling and cellular thermal shift assay (CETSA) further revealed that isorhoifolin bound directly to sphingosine-1-phosphate receptor-3 (S1PR3) and exerted temporally structured effects on injury-responsive networks. In human transcriptomic data, we found activation of S1P receptor-related pathways in TBI patients and the expression of S1PR3 was increased approximately 40%. Importantly, the current work delineates a neuron-centric role for S1PR3 in regulating structural repair that is mechanistically distinct from the known functions of S1PRs in immune cells. Biochemical assays supported a model in which isorhoifolin facilitates neurite repair through inhibiting neuronal S1PR3-CK2-GSK3β signaling axis. In parallel, isorhoifolin interacted directly with N-ribosyldihydronicotinamide:quinone reductase 2 (NQO2) based on proteomic CESTA, and genetic knockdown as well as inhibition of NQO2 in astrocytes promote neurite regrowth of injured cortical neurons.
CONCLUSION
Together, these findings define mechanistically distinct yet coordinated neuronal and astrocytic pathways that are responsible for isorhoifolin-enhanced structural and functional recovery after TBI, and identify S1PR3 and NQO2 as direct and druggable targets.
Yi Wang, Wen-Lin Liao, Chen Wang et al.· Phytomedicine· 0 citations
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