Jul 2026· International Immunopharmacology· Vol 187, pp.
117185
· 0 citations· 100 references
Medicine
TL;DR
This review systematically integrates existing preclinical and early clinical evidence within the framework of "cytokine signaling networks", focusing on elucidating the molecular mechanisms and biological effects of selinexor in suppressing proinflammatory factor production, mitigating oxidative stress, and regulating inflammatory tissue-remodeling networks.
Abstract
Selinexor (KPT-330), the first oral selective nuclear export inhibitor, simultaneously modulates key signaling pathways, including NF-κB, JAK/STAT, FOXO, Nrf2, and NLRP3, by blocking XPO1-mediated nuclear export, thereby offering a novel multi-target strategy for treating chronic inflammatory diseases. This review systematically integrates existing preclinical and early clinical evidence within the framework of "cytokine signaling networks", focusing on elucidating the molecular mechanisms and biological effects of selinexor in suppressing proinflammatory factor production, mitigating oxidative stress, and regulating inflammatory tissue-remodeling networks. Recent findings further indicate that SINE compounds can remodel proteostasis, including ankyrin repeat and SOCS box-containing protein 8 (ASB8)/Cullin-RING ligase 5 (CRL5)-associated XPO1 degradation and regulation of the ACE2-TMPRSS2-XPO1 coronavirus-entry network. However, current evidence primarily stems from in vitro and animal studies, and randomized controlled trials in human chronic inflammatory diseases are lacking. Moreover, hematopoietic and gastrointestinal toxicities observed in oncology settings suggest a narrow therapeutic window. This review emphasizes a stepwise translational logic from protein turnover and receptor regulation to next-generation XPO1 inhibitors. At present, selinexor is more suitable as a mechanistic tool for exploring the XPO1-inflammation axis, whereas inflammatory-disease translation will require eltanexor or related agents with more favorable tissue distribution and tolerability, together with precisely stratified clinical studies.
The mechanisms of cGAS-STING activation in aging-including mitochondrial DNA leakage, nuclear envelope disruption, and retrotransposon activation-and its role in driving cellular senescence and the senescence-associated secretory phenotype (SASP) are reviewed.
Yutong Wei, Sutong Cai, Yanan Ji et al.· Biochemical Pharmacology· 2 citations
Porcine reproductive and respiratory syndrome virus (PRRSV) remains a significant pathogen in swine, causing major economic losses globally, with few antiviral treatment options available. Ebselen, a synthetic organoselenium compound known for its antioxidant, was explored for its potential to inhibit PRRSV replication. Our findings suggest that Ebselen significantly reduced viral RNA and protein levels across multiple PRRSV strains in a dose-dependent manner. Time-of-addition assays revealed that Ebselen primarily interferes with viral biosynthesis phase, though it does not inhibit the viral 3C-like protease (nsp4) directly. Transcriptomic profiling and biochemical assays indicated that Ebselen activates the NRF2 antioxidant response pathway by upregulating TRIM16 and SQSTM1, which disrupt KEAP1-NRF2 interactions, thereby stabilizing NRF2. This leads to increased expression of NRF2-regulated antioxidant enzymes and mitigation of PRRSV-induced oxidative stress. Moreover, Ebselen exhibited anti-inflammatory effects by reducing proinflammatory cytokine production. In vivo challenge experiments further showed that Ebselen treatment significantly decreased pulmonary viral loads and alleviated lung histopathological damage. These findings support potential of Ebselen as a host-targeted antiviral strategy, highlighting its dual role in managing oxidative stress and inflammation, offering a promising approach to combat PRRSV.
Xinrong Wang, Yan Guo, Linjie Hou et al.· Veterinary Microbiology· 0 citations
This study investigates the synergistic therapeutic potential of Rivastigmine (RVG) and Epigallocatechin (EGC) in Alzheimer’s disease (AD), a multifactorial neurodegenerative disorder characterized by neuroinflammation, oxidative stress, and dysregulated signaling pathways. Conventional therapies primarily provide symptomatic relief and target limited pathways, highlighting the need for multi-target strategies with improved efficacy and safety. An integrated in silico approach combining pharmacokinetic evaluation, network pharmacology, molecular docking, and molecular dynamics simulations is used to determine the synergistic potential of RVG and EGC. Pharmacokinetic analysis indicates favorable drug-likeness and acceptable ADME/Tox profiles for both compounds. Network pharmacology identified 146 overlapping targets associated with AD, highlighting key hub genes including NFKB1, MAPK1, STAT1, PRKACA, GRB2, LYN, and PTPN11, which are involved in neuroinflammation, synaptic signaling, and neuronal survival. Functional enrichment analysis indicated significant involvement of MAPK/ERK signaling and immune-regulatory pathways. Importantly, the PD-1/PD-L1 signaling pathway is identified as a novel mechanism connecting neuroimmune modulation with intracellular kinase-driven neurodegeneration. Molecular docking studies showed strong binding affinities of RVG and EGC toward key AD-related targets, particularly MAPK1, supported by stable hydrogen bonding and interaction profiles. Molecular dynamics simulations confirmed stable protein-ligand interactions, with EGC contributing structural stability and RVG exhibiting adaptive flexibility within the binding pocket. These results suggest that the RVG-EGC combination exhibits synergistic potential by simultaneously modulating neuroinflammatory, oxidative stress, and kinase-mediated signaling pathways. The integration of PD-1/PD-L1 and MAPK/ERK signaling provides a novel mechanistic pathway for multi-target therapeutic intervention in AD.
Bhaswati Das, M. S. Umashankar· Scientia Pharmaceutica· 1 citation
Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound resistance to therapy, driven in part by its capacity to adapt to oxidative, metabolic, and proteotoxic stress. In this study, we investigated how the redox-active selenium compound Se-methylselenocysteine (MSC), following metabolic activation by kynurenine aminotransferase 1 (KYAT1), reprograms stress-response pathways in PDAC cells. RNA sequencing across three PDAC cell lines revealed pronounced, phenotype-dependent transcriptional adaptations upon MSC exposure. CAPAN-2 cells predominantly activated an NRF2-centered antioxidant response accompanied by ferroptosis-associated gene signatures, whereas PANC-1 cells exhibited robust co-activation of NRF2 and ATF4, along with induction of unfolded protein response signaling and extensive redox and metabolic remodeling. MSC treatment suppressed TXNIP, a negative regulator of the thioredoxin system, while inducing canonical NRF2 target genes including TXNRD1, NQO1, G6PD, SLC7A11, and GLRX. In MSC-responsive models, pathways linked to iron metabolism and ferroptosis-associated processes were significantly altered, accompanied by changes in iron-handling proteins and lipid peroxidation defenses. Functional assays further demonstrated increased lipid peroxidation and partial rescue of cytotoxicity by ferrostatin-1 and the iron chelator deferoxamine, supporting the involvement of iron-dependent oxidative stress mechanisms. In contrast, HPAF-II cells, characterized by low KYAT1 expression, showed minimal transcriptional engagement and intrinsic resistance to MSC. Collectively, these findings identify KYAT1-dependent metabolic activation and convergence of NRF2-ATF4 stress pathways as key determinants of MSC responsiveness, revealing phenotype-dependent remodeling of redox and ferroptosis-associated networks in PDAC. This work provides a mechanistic framework for exploiting redox vulnerabilities and supports the continued development of selenium-based therapeutic strategies in pancreatic cancer.
Mehran Ghaderi, Joakim Dillner, Mikael Björnstedt et al.· Free Radical Biology & Medic...· 0 citations
BACKGROUND
Chronic inflammatory disorders represent a major global health burden characterized by persistent immune activation, oxidative stress, and progressive tissue dysfunction. Dysregulated redox signaling has positioned the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (Nrf2) axis as an emerging therapeutic target.
METHODS
This review critically examines the mechanistic architecture and context-dependent regulation of KEAP1-Nrf2 signaling across chronic inflammatory disorders, integrating disease-specific evidence, signaling crosstalk, quantitative preclinical findings, therapeutic modulators, nanoenabled delivery systems, clinical evidence, patent trends, and artificial intelligence-assisted drug discovery strategies.
RESULTS
KEAP1-Nrf2 signaling extends beyond antioxidant defense to regulate immunometabolic homeostasis, mitochondrial function, inflammatory signaling, and cellular stress adaptation. Crosstalk with NF-κB, MAPK, PI3K/Akt, and inflammasome-associated pathways contributes to disease-specific inflammatory responses. Preclinical evidence supports natural and synthetic Nrf2 modulators, while nanotechnology-based approaches may improve delivery and tissue specificity. However, dose optimization, bioavailability, off-target effects, long-term safety, and patient heterogeneity remain important translational challenges.
CONCLUSION
KEAP1-Nrf2 represents a context-dependent therapeutic axis with substantial potential across chronic inflammatory diseases. Integrating quantitative evidence, precision delivery, biomarker-guided approaches, and computational strategies may facilitate clinical translation while addressing risks associated with sustained pathway activation.
Abdul Shadab· Immunological Investigations· 0 citations
Type 2 diabetes (T2D) is a metabolic syndrome frequently associated with obesity and endoplasmic reticulum stress-mediated inflammation, which can trigger the unfolded protein response (UPR), impair insulin signaling, and promote apoptosis. To identify potential natural therapeutic candidates, this study investigated the mechanisms of action of 14 compounds from Uncaria tomentosa (UT), a medicinal plant from the Amazon rainforest, using in silico modeling. The study focused on the UPR, TRAF2/JNK pro-inflammatory signaling pathway, and insulin signaling pathways, which play key roles in T2D. Some of the UT compounds were docked against several human proteins involved in these pathways, and molecular dynamics simulations confirmed stable interactions between the target proteins (PERK, TRAF2, JNK, TNF-α, IRS-1, PI3K, AKT, GSK3β, and PPARγ) and four of the UT compounds, 5-Carboxystrictosidine, Cinchonain, Epicatechin and Mitraphylline. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties analyses were conducted to predict the four compounds, revealing suitable pharmacokinetic properties. These findings suggest that specific UT compounds may be used in experimental tests to whether investigate their therapeutic potential in managing T2D by modulating signaling pathways related to the conditions UPR, inflammation, and insulin resistance.
Bruna Freitas Marchi, Shraddha Parate, V. Jha et al.· International Journal of Mol...· 0 citations
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