Search Results (351)

Osteoarthritis (OA) is a chronic progressive joint disease characterized by cartilage degradation, subchondral bone remodeling, and synovial inflammation. This complex disorder arises from the interplay between mechanical stress and inflammatory processes, which is mediated by interconnected molecular signaling pathways. This review explores the dual roles of inflammatory and mechanical signaling in OA pathogenesis, focusing on crucial pathways such as NF-kB, JAK/STAT, and MAPK in inflammation, as well as Wnt/β-catenin, Integrin-FAK, and Hippo-YAP/TAZ in mechanotransduction. The interplay between these pathways highlights a vicious cycle wherein mechanical stress exacerbates inflammation, and inflammation weakens cartilage, increasing its vulnerability to mechanical damage. Additionally, we discuss emerging therapeutic strategies targeting these pathways, including inhibitors of cartilage-degrading enzymes, anti-inflammatory biologics, cell-based regenerative approaches, and non-pharmacological mechanical interventions. By dissecting the molecular mechanisms underlying OA, this review aims to provide insights into novel interventions that address both inflammatory and mechanical components of the disease, paving the way for precision medicine in OA management. Full article

Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article

Sirtuins (SIRTs), a family of NAD+-dependent enzymes, play crucial roles in epigenetic regulation, metabolism, DNA repair, and stress response, making them relevant to glioma biology. This review systematically summarizes the molecular mechanisms and context-specific functions of SIRT1–SIRT7 in central nervous system tumors, with particular focus on gliomas. SIRT1, SIRT3, SIRT5, and SIRT7 are often overexpressed and promote glioma cell proliferation, stemness, therapy resistance, and metabolic adaptation. Conversely, SIRT2, SIRT4, and SIRT6 generally exhibit tumor-suppressive functions by inducing apoptosis, inhibiting invasion, and counteracting oncogenic signaling. Preclinical studies have identified several sirtuin modulators—both inhibitors and activators—that alter tumor growth, sensitize cells to temozolomide, and regulate pathways such as JAK2/STAT3, NF-κB, and mitochondrial metabolism. Emerging evidence positions sirtuins as promising targets for glioma therapy. Future studies should evaluate sirtuin modulators in clinical trials and explore their potential for patient stratification and combined treatment strategies. Full article

Transcription factors (TFs) are proteins that control gene expression by binding to specific DNA sequences and are essential for cell development, differentiation, and homeostasis. Dysregulation of TFs is implicated in numerous diseases, including cancer, autoimmune disorders, and neurodegeneration. While TFs were traditionally considered “undruggable” due to their lack of well-defined binding pockets, recent advances have made it possible to modulate their activity using diverse pharmacological strategies. Major TF families include NF-κB, p53, STATs, HIF-1α, AP-1, Nrf2, and nuclear hormone receptors, which take part in the regulation of inflammation, tumor suppression, cytokine signaling, hypoxia and stress response, oxidative stress, and hormonal response, respectively. TFs can perform multiple functions, participating in the regulation of opposing processes depending on the context. NF-κB, for instance, plays dual roles in immunity and cancer, and is targeted by proteasome and IKKβ inhibitors. p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat. STATs, especially STAT3 and STAT5, are oncogenic and targeted via JAK inhibitors or novel PROTAC degraders, for instance SD-36. AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK. Nrf2, a key antioxidant regulator, can be activated by agents like DMF or inhibited in chemoresistant tumors. Pharmacological strategies include direct inhibitors, activators, PROTACs, molecular glues, and epigenetic modulators. Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential. Full article

Vitiligo, an autoimmune disorder causing depigmented skin patches, includes two types, segmental (SV) and non-segmental (NSV). Previously, NSV was off-label treated using Calcineurine inhibitors (Tacrolimus and Pimecrolimus). In 2022, the FDA approved Ruxolitinib cream, targeting the JAK/STAT pathway for NSV treatment based on promising results. This research conducts a retrospective descriptive safety assessment of Tacrolimus, Pimecrolimus, and Ruxolitinib safety in vitiligo treatment, utilizing the FDA Adverse Event Reporting System (FAERS) database spanning the period from 2013 to 2023 and including patients aged 2 years and above, encompassing both brand and generic names. A total of 844 adverse event reports involving 388 patients were extracted and categorized into dermatological and systemic groups for analysis. Tacrolimus resulted in 12 hospitalizations, two life-threatening events, and four disabilities. Pimecrolimus exhibited urticaria and pigmentation disorders, with tooth fracture as the primary systemic event. Pericarditis was the predominant systemic side effect of Ruxolitinib, followed by anemia, headache, and urosepsis. Local dermatological side effects reported were generally mild, not warranting treatment cessation. In conclusion, vitiligo significantly impacts patients’ psychological well-being, necessitating continuous post-marketing safety monitoring for topical medications. Full article

Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), remains a therapeutic challenge due to its aggressive nature, limited treatment options, and high recurrence rates. Current therapies, including chemotherapy and immune checkpoint inhibitors, face resistance driven by tumor heterogeneity, immunosuppressive signaling, and dysregulated redox pathways. This review explores silibinin’s potential to modulate the tumor immune microenvironment (TIME) and overcome therapeutic resistance in TNBC. Silibinin exerts multifaceted anticancer effects by suppressing PD-L1 expression through the inhibition of JAK/STAT3 signaling and MUC1-C interaction, attenuating NF-κB-driven inflammation, and downregulating CCL2-mediated recruitment of tumor-associated macrophages (TAMs). Additionally, silibinin disrupts redox adaptation by targeting the Nrf2-EGFR-MYC-TXNIP axis, enhancing oxidative stress and chemosensitivity. Preclinical studies highlight its ability to inhibit epithelial–mesenchymal transition (EMT), reduce cancer stem cell (CSC) populations, and synergize with existing therapies like PD-1 inhibitors. Despite its low bioavailability, advanced formulations such as liposomes and nanoparticles show promise in improving delivery and efficacy. By reshaping TIME through dual antioxidant and immunomodulatory mechanisms, silibinin emerges as a viable adjunct therapy to reverse immunosuppression and chemoresistance in TNBC. Full article

Psoriasiform dermatitis refers to a spectrum of inflammatory skin disorders that resemble psoriasis both clinically and histologically. These conditions can occur idiopathically or as paradoxical reactions to biologic or targeted therapies, particularly in patients with atopic or autoimmune backgrounds. Histologic features often include acanthosis, parakeratosis, and lymphocytic infiltrates, but without the full molecular signature of classical psoriasis. This review provides an overview of psoriasiform dermatitis with a focus on its clinical presentation, differential diagnosis, and the immune pathways involved. Drug-induced forms, especially those triggered by anti-TNF agents, IL-4/IL-13 blockers, and JAK inhibitors, are highlighted due to their growing clinical relevance. We also summarize the main topical and systemic treatments, including corticosteroids, calcineurin inhibitors, PDE4 inhibitors, and JAK-STAT- or IL-23-targeted therapies. A better understanding of psoriasiform dermatitis is crucial to improve diagnosis and to guide treatment, especially in complex or refractory cases. Full article

Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In this study, we assessed the antiproliferative effects of clinically approved JAK2 inhibitors in TNBC cell lines (MDA-MB-231 and HS578T) using the MTT assay. Among the four JAK2 inhibitors evaluated (fedratinib, cerdulatinib, peficitinib, and filgotinib), fedratinib significantly inhibited the proliferation of TNBC cells with IC₅₀ values below 2 μM. Fedratinib also demonstrated superior efficacy in inhibiting long-term colony formation compared to other JAK2 inhibitors. Western blot analyses showed that fedratinib uniquely inhibits the phosphoinositide 3-kinase (PI3K)/AKT pathway and moderately affects the MAP kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, in addition to targeting JAK2/STAT3 signaling. Moreover, fedratinib distinctly decreased MYC and cyclin D1 protein levels while inducing poly (ADP-ribose) polymerase (PARP) cleavage and apoptotic cell death more effectively than other JAK2 inhibitors. We next investigated the effects of simultaneously inhibiting JAK2/STAT3 together with the MEK/ERK or PI3K/AKT pathways, as well as the impact of triple pathway inhibition. Notably, combining ceduratinib with either cobimetinib (MEK inhibitor) and ipatasertib (AKT inhibitor) or trametinib (MEK inhibitor) and alpelisib (PI3K inhibitor) mimicked the effects of fedratinib on the cell proliferation, MYC and cyclin D1 suppression, and pro-apoptotic protein induction. These finding suggest that JAK2 inhibition enhances the anticancer effects of concurrent MEK/ERK and PI3K/AKT pathway inhibition, while JAK2 inhibition alone shows minimal efficacy in TNBC cells. Full article

Graft-versus-host disease (GVHD) remains a significant barrier to the success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), contributing to long-term morbidity and non-relapse mortality in both pediatric and adult populations. Central to GVHD pathophysiology is the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, where JAK2 mediates key pro-inflammatory cytokines, including IL-6, IFN-γ, and GM-CSF. These cytokines promote donor T cell activation, effector differentiation, and target organ damage. The introduction of ruxolitinib, a selective JAK1/2 inhibitor, has transformed the treatment landscape for steroid-refractory acute and chronic GVHD, leading to improved response rates and durable symptom control. However, its limitations—such as cytopenias, infectious complications, and incomplete responses—have catalyzed the development of next-generation agents. In 2024, the FDA approved axatilimab, a CSF-1R inhibitor that targets monocyte-derived macrophages in fibrotic chronic GVHD, and remestemcel-L, an allogeneic mesenchymal stromal cell therapy, for pediatric steroid-refractory acute GVHD. Both agents offer mechanistically distinct and clinically meaningful additions to the therapeutic armamentarium. In parallel, emerging combination strategies involving JAK2 inhibitors and novel biologics show promise in enhancing immune tolerance while preserving graft-versus-leukemia (GvL) effects. Recent advances in biomarker development, such as the MAGIC Algorithm Probability (MAP), are enabling early risk stratification and response prediction. The integration of these tools with organ-specific and personalized approaches marks a shift toward more precise, durable, and tolerable GVHD therapy. This review highlights the current state and future direction of JAK2 inhibition and complementary therapies in the evolving GVHD treatment paradigm. Full article

Multiple lines of evidence suggest that endothelial dysfunction is a key player in the pathogenesis of COVID-19, with cytokine storm as one of the main primary causes. Among the mechanisms underlying endothelial damage, clinical findings identify alterations in arginine metabolism, as patients with severe COVID-19 exhibit lower levels of nitric oxide synthase (eNOS) and upregulated arginase. In this study, we investigated, in human endothelial cells (HUVECs), the effect of conditioned medium from macrophages activated with SARS-CoV-2 Spike protein (CM_S1) on arginine metabolism. The results indicate that CM_S1 causes a marked decrease in eNOS and an increase in arginase, along with a greater intracellular arginine content and the induction of the CAT2 transporter. These effects are ascribable to the inflammatory mediators released by macrophages in CM_S1, mainly TNFα and IL-1β. Since infliximab, an antibody targeting TNFα, and baricitinib, an inhibitor of the JAK/STAT pathway, correct the observed imbalance between eNOS and arginase, our findings suggest the potential efficacy of a combined therapy to counteract endothelial dysfunction in COVID-19. Full article

Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK gene, such as ETV6::SYK and ITK::SYK, have emerged as rare but potentially targetable genetic events in both myeloid and lymphoid neoplasms. SYK, a non-receptor tyrosine kinase critical for hematopoietic signalling, can become constitutively activated through gene fusions, driving oncogenesis via the PI3K/AKT, MAPK, and JAK-STAT pathways. ETV6::SYK has been primarily associated with myeloid neoplasms, often presenting with eosinophilia, bone marrow dysplasia, and skin involvement. In vitro and in vivo models confirm its leukemogenic potential and identify SYK as a therapeutic target. Although SYK inhibitors like fostamatinib have shown transient efficacy, resistance mechanisms, possibly involving alternative pathway activation, remain a challenge. The ITK::SYK fusion, on the other hand, has been identified in peripheral T-cell lymphomas, particularly of the follicular helper T-cell subtype, with similar pathway activation and potential for targeted intervention. Additional rare SYK fusions, such as PML::SYK and CTLC::SYK, have been reported in myeloid neoplasms and juvenile xanthogranuloma, respectively, expanding the spectrum of SYK-driven diseases. Accumulating evidence supports the inclusion of SYK fusions in future classification systems and highlights the need for broader molecular screening and clinical evaluation of SYK-targeted therapies. Full article

Hidradenitis suppurativa (HS) and atopic dermatitis (AD) are both inflammatory dermatoses that can significantly impact patient quality of life, however, limited research exists regarding their association. The purpose of this comprehensive review is to compare the inflammatory pathogenesis of HS and AD, explore the associations between these diseases, and discuss standalone and concomitant disease treatment options. Although HS and AD are understood to be primarily driven by the Th1 and Th2 inflammation pathways, respectively, these conditions both utilize the Janus Kinase/Signal transducer and activator of transcription (JAK/STAT) pathway to promote inflammation. Newer research also suggests that IL-36 and IL-1 receptor-associated kinase 4 (IRAK4) may be two additional inflammatory signals shared between the HS and AD disease pathways. These shared mechanisms are reflected in patient presentations as HS and AD are often concomitantly present and demonstrate a bidirectional association in the current literature. Treatment options for concomitant disease are limited, but leverage the shared immune pathogenesis of both diseases. Dupilumab has been reported to improve both HS and AD symptoms in select patients. JAK inhibitors are currently FDA-approved for the treatment of AD, and early trials have suggested benefits from JAK inhibitors such as upadacitinib, povorcitinib, and topical ruxolitinib for HS. Possible future avenues for research on treating both HS and AD include IRAK-4 inhibitors such as zabedosertib and BAY1830839, and diet and gut microbiome modifications. Full article

Reciprocal signaling between acute myeloid leukemia (AML) cells and the surrounding bone-marrow microenvironment (BMME) promotes AML progression through several mechanisms. One of the most important mechanisms is the induction of Galectin-3 (Gal-3) expression by AML cells and bone marrow mesenchymal stromal cells (BM-MSCs). Emerging evidence indicates that Gal-3 upregulation in the BMME promotes AML cell adhesion and survival, leading to the development of chemotherapy resistance, relapse, and poor prognosis. Identifying the biological function and critical signaling pathways of Gal-3 may contribute to overcoming acquired drug resistance and preventing post-treatment relapse. Gal-3 is involved in several molecular signaling pathways, including PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, JAK/STAT, JNK, Wnt/β-catenin, PLC/PKC and NF-κB, which are interconnected to promote AML cell survival and resistance to chemotherapy. This review focuses on the biological effects, molecular mechanisms of action and regulation of Gal-3 in the pathogenesis and progression of AML. The therapeutic potential of potent synthetic small-molecule Gal-3 inhibitors in high-risk patients with AML is also discussed based on preclinical and clinical evidence from several human diseases. Currently, the effect of these Gal-3 inhibitors in AML has not been investigated either in vitro or in vivo. The findings provide a rationale for targeting Gal-3 that may be a very promising therapeutic approach, especially for patients with relapsed/refractory AML, and may enhance the efficacy of conventional chemotherapeutic drugs and/or immune checkpoint inhibitors. Full article

Lichen planus (LP) is a chronic inflammatory disorder affecting approximately 1% of the population. It presents with a wide range of clinical manifestations, mainly involving the skin, mucosal surfaces, and skin appendages, and is often characterized by a relapsing course and variable response to treatment. Although several therapeutic strategies are available, many are off-label and show limited efficacy in resistant forms. Increasing evidence points to the central role of the JAK/STAT signaling pathway in the immunopathogenesis of LP, with cytokines such as interferon-gamma and interleukin-21 playing key roles in sustaining chronic inflammation. Based on this rationale, Janus kinase (JAK) inhibitors have recently been proposed as potential therapeutic agents in LP. This review explores the biological basis for their use and systematically summarizes the existing clinical evidence on the use of JAK inhibitors in cutaneous, mucosal, appendageal, and nail variants of LP. The preliminary data suggests favorable outcomes in many patients with difficult-to-treat disease, with an acceptable safety profile. Further prospective trials are needed to establish their definitive role in the management of LP. Full article

Crohn’s disease is a chronic inflammatory granulomatous disease of the gastrointestinal tract. The global incidence and prevalence of Crohn’s disease have significantly increased, largely due to genetic susceptibility, environmental changes, and advancements in diagnostic technology. In recent years, the pharmacologic treatment of Crohn’s disease has been rapidly changing, and although biologics have improved the prognosis of patients to a certain extent, they still have certain limitations. Oral small molecule drugs like JAK inhibitors have become a research hotspot because of their advantages of targeting and regulating the JAK/STAT pathway, convenient administration, and rapid onset of action. JAK inhibitors exhibit divergent therapeutic profiles. Clinical trials have shown that tofacitinib demonstrates limited efficacy in Crohn’s disease management. Filgotinib initially showed clinical remission in phase 2 trials; while its subsequent phase 3 studies failed to demonstrate consistent endoscopic improvement. In contrast, upadacitinib achieved notable clinical remission rates during both induction and maintenance phases of phase 2 trials. However, long-term safety concerns, including thromboembolic events, cardiovascular events, opportunistic infections, and potential malignancy risks, warrant cautious clinical application. This article systematically reviews the pathophysiology of Crohn’s disease, and the evidence for the efficacy and safety of JAK inhibitors to guide clinical practice and research. Full article