Tumor organoids preserve the cellular heterogeneity and structural complexity of native tumors, providing robust platforms for mechanistic studies, preclinical drug testing, and translational oncology research. However, their predictive performance is not an intrinsic property of organoids. It is shaped by platform design, including culture format, matrix composition, medium formulation, and the extent of multicellular reconstruction. This review examines how these design variables influence model fidelity, reproducibility, tumor microenvironment reconstruction, and drug-response interpretation. We compare major culture formats and matrix systems, discuss strategies for incorporating stromal and immune components, and evaluate current and emerging uses of AI-assisted analysis for organoid-derived phenotypic data. Overall, this review highlights how integrated tumor organoid design can strengthen pharmacological modeling and oncology translation.
Skeletal muscle, once regarded solely as a contractile tissue, is now recognized as a dynamic endocrine organ that secretes exercise-induced myokines—bioactive peptides with autocrine, paracrine, and endocrine functions. These myokines coordinate systemic energy homeostasis by regulating glucose and lipid metabolism, mitochondrial function, inflammation, and interorgan communication. Building on our previous review published in 2018, this review synthesizes major advances in exercise-induced myokines within an evidence-based framework considering mechanistic support and translational relevance. We highlight both well-established and emerging myokines, including interleukin-6 (IL-6), irisin, myostatin, growth differentiation factor 11 (GDF11), IL-15, brain-derived neurotrophic factor (BDNF), meteorin-like (METRNL), secreted protein acidic and rich in cysteine (SPARC), fibroblast growth factor 21 (FGF21), β-aminoisobutyric acid (BAIBA), leukemia inhibitory factor (LIF), apelin, and musclin, and discuss their roles across major target tissues including skeletal muscle, liver, adipose tissue, and bone. We also summarize natural and synthetic compounds reported to modulate myokine expression, secretion, or activity, and discuss the opportunities and current limitations of targeting myokine pathways. Although several myokine axes show therapeutic promise, the current literature indicates substantial heterogeneity in causal evidence, receptor or target certainty, and translational readiness. These insights support a more selective view of myokines as biologically heterogeneous mediators of muscle–organ crosstalk and provide a framework for mechanism-based therapeutic development in metabolic disease.
Extracellular heat shock protein 90 alpha (eHsp90α) has been implicated in promoting cancer cell invasion and metastasis. However, the role of eHsp90α in the tumor microenvironment remains poorly understood. In the present study, we provide the first evidence that eHsp90α aggravates the invasiveness of cancer-associated fibroblasts (CAFs) through low-density lipoprotein receptor-related protein 1 (LRP1) and consequent upregulation of epithelial–mesenchymal transition (EMT)-associated transcription factor expression. We observed that eHsp90α induces CAFs invasiveness. However, silencing of Twist, Snail and Slug expressions significantly attenuated eHsp90α-induced CAFs invasiveness. In addition, transfecting CAFs with LRP1 short interfering RNA (siRNA) markedly inhibited eHsp90α-induced CAFs invasion and EMT-associated transcription factor expression. Intriguingly, we observed that the epidermal growth factor receptor (EGFR)/AKT signaling is located downstream of LRP1 and governs eHsp90α-induced Twist and Snail but not Slug expression required for CAFs invasion. Moreover, we demonstrated that these EMT-associated transcription factors of CAFs are indispensable for breast cancer cell invasion. Collectively, the present data reveal that eHsp90α increases CAFs invasiveness through LRP1 and subsequent EMT-associated transcription factor expression to promote breast cancer invasion, presenting potential therapeutic targets to impede breast cancer progression.
Liver organoids are emerging as human-relevant three-dimensional in vitro systems for chemical safety assessment, however, their application value depends on their ability to generate decision-ready evidence within clearly defined context-of-use (CoU). Here, we review the biological fidelity, quality assessment, exposure characterization, and validation requirements of liver organoids across three CoUs: (1) hazard screening and identification, (2) mechanistic elucidation of hazard, and (3) quantitative risk assessment support. Within this CoU framework, we review recent advances in liver organoids and their applications to chemical safety assessment, highlighting models that already provide useful evidence and those where implementation remains partial or inconsistent. Based on this review, we discuss the major barriers to broader regulatory adoption, which include insufficient biological implementation, limited reproducibility, insufficient exposure characterization, and a lack of harmonized performance criteria and standardization frameworks. By evaluating liver organoids in relation to clearly defined decision questions rather than generalized technological promise, this review clarifies their current contributions, explains why their contributions remain CoU-dependent, and outlines key priorities for developing decision-ready liver organoid platforms for next-generation chemical safety assessment.
Sepsis-associated encephalopathy (SAE), the most common neurological complication of sepsis with high mortality, lacks effective treatments. Although microglia play a significant role in SAE pathogenesis, the mechanisms of M2 microglial exosomes (M2-EXOs) and their microRNAs (miRNAs) remain unclear. The present study demonstrated that both M2 microglial conditioned media (M2-CM) and M2-EXO promote the phenotypic transformation of M1 microglia toward the M2 phenotype. In M2-EXO, among the differentially expressed miRNAs, miR-1949 exhibited the most significant difference. The dual-luciferase assay showed that miR-1949 could bind to the 3’UTR of Dickkopf-related protein 1 (DKK1). Further experiments confirmed that M2-EXO-miR-1949 mimic mediated microglial phenotypic transformation by inhibiting DKK1 and activating the Wnt/β-catenin pathway. Notably, a single injection of M2-EXO (10 μg/mouse, i.c.v.) or M2-EXO-miR-1949 mimic (0.1 nmol/mouse, i.c.v.) significantly reduced the mouse sepsis score (MSS), decreased cortical neural cell damage in SAE mice induced by lipopolysaccharide (LPS), inhibiting abnormal microglial activation and alleviating neuroinflammation. Meanwhile, M2-EXO-miR-1949 mimic markedly inhibited DKK1 and activated the Wnt/β-catenin pathway in vivo. What’s more, the effects of M2-EXO-miR-1949 mimic were reversed by the Wnt/β-catenin pathway inhibitor XAV939. In contrast, the effect of M2-EXO-miR-1949 inhibitor (0.1 nmol/mouse, i.c.v.) was opposite to that of M2-EXO-miR-1949 mimic. Furthermore, co-transfection of the M2-EXO-miR-1949 mimic and inhibitor mutually neutralized their opposing effects, resulting in no significant changes in the expression of inflammatory and pathway-related markers, thereby confirming the functional specificity of exosomal miR-1949. In summary, the present study indicates that M2-EXO, especially its contained miR-1949, ameliorates LPS-induced SAE in mice through inhibiting DKK1 to activate the Wnt/β-catenin pathway, thereby leading to microglial phenotypic transformation and neuroinflammation inhibition. This study reveals a novel mechanism by which M2-EXO and miRNA ameliorate SAE, providing a theoretical basis for further studies.
Chronic inflammation drives the pathogenesis of diverse disorders, yet current anti-inflammatory strategies often lack mechanistic selectivity. Glycyrrhizic acid (GL), a major triterpenoid saponin from Glycyrrhiza species, exhibits broad anti-inflammatory effects, but its mechanism has been viewed as non-specific. In this review, we propose an integrated framework positioning high-mobility group box 1 (HMGB1) as one major molecular hub for GL’s action. Mechanistically, our molecular docking analysis suggests that GL may interact with the Box B domain of HMGB1 andmay potentially interfere with its engagement with TLR4 and RAGE, thereby orchestrating a cascade inhibition of downstream NF-κB, MAPK, and NLRP3 inflammasome pathways. Beyond this core signaling axis, we systematically analyze how GL context-dependently modulates macrophage polarization, monocyte-derived macrophage differentiation, and Th17/Treg balance. We further synthesize its effects across liver, autoimmune, metabolic, oncologic, neurological, and renal diseases, revealing shared mechanisms and disease-specific adaptations. Finally, we critically evaluate translational bottlenecks—including isomer-specific bioavailability, the pseudoaldosteronism risk, and formulation challenges—and propose strategies to overcome them. By shifting from a descriptive summary to a mechanism-centered, integrative analysis, this review provides a conceptual framework for developing GL as a multitarget anti-inflammatory agent, while acknowledging its limitations including low oral bioavailability, microbiota-dependent metabolism, pseudoaldosteronism risk, and limited clinical evidence.
Using a 1H-NMR-guided isolation approach, twelve novel hasubanan alkaloids, bishernsubanins A-D (1-4) and hernsubanines G-N (5-12), along with eight known monomeric analogues (13-20), were isolated from Stephania japonica var. discolor. Notably, compounds 1-4 represent a new class of homologous dimeric hasubanan alkaloids. Their structures were elucidated by comprehensive spectroscopic data analysis, including NMR, ECD calculations, and single crystal X-ray diffraction. Their biosynthetic pathways are proposed to involve redox reactions, free radical coupling, isomerization, and condensation reactions. All isolates were evaluated for anti-neuroinflammatory activity in vitro. Alkaloids 1, 3, 4, 7, and 11-13 exhibited better inhibitory effects on nitric oxide production in lipopolysaccharide (LPS) induced BV-2 microglial cells than minocycline. Among them, the new compound bishernsubanin A (1) could inhibit Iba-1 expression, and suppress the release of inflammatory factors in LPS stimulated BV-2 microglial cells. Molecular docking, immunofluorescence, and drug affinity responsive target stability (DARTS) studies indicated that compound 1 modulates toll-like receptor 4 to exert its anti-neuroinflammatory effect, positioning it as a promising naturally derived candidate for neuroinflammatory inhibition.
Previous studies have shown that Quzhou Fructus Aurantii extract (QFAEE) ameliorates lipopolysaccharide (LPS)-induced acute lung injury (ALI) by modulating the Stimulator of interferon genes (STING) pathway. Nevertheless, the mechanisms underlying the anti-inflammatory effects of nobiletin (Nob), the primary bioactive component of QFAEE, have not been clearly elucidated. The present study aimed to investigate the protective effects of Nob on a mouse model of LPS-induced ALI and elucidate its underlying mechanism. The pulmonary inflammatory response in mice was quantified by performing fluorescence-based RT‒qPCR, bronchoalveolar lavage fluid (BALF) cell counting, and hematoxylin‒eosin (HE) staining. Transcriptomic profiling was performed to explore the mechanisms by which Nob ameliorates LPS-induced ALI. The anti-inflammatory mechanisms were further elucidated using western blotting, immunohistochemical staining, cellular thermal shift assays (CETSAs), and microscale thermophoresis. Functional validation was conducted using the STING agonist vadimezan (DMXAA), the STING inhibitor SN-001, and STING-knockout (STING-KO) mice. Nobiletin-loaded liposomes (Nob-Lipo) significantly attenuated LPS-induced pulmonary inflammation in mice. The results of the transcriptomic analysis suggested that this protective effect was associated with the modulation of the type I interferon pathway. In RAW264.7 and THP-1 cells, pretreatment with Nob effectively attenuated the interferon regulatory factor 3 (IRF3)-mediated type I interferon response and nuclear factor kappa-B (NF-κB)-dependent proinflammatory cytokine expression following DMXAA-induced STING pathway activation. Furthermore, the STING inhibitor SN‑001 markedly suppressed LPS‑induced inflammatory responses, as evidenced by significantly reduced levels of proinflammatory cytokines and interferon‑stimulated genes, and effectively blocked the nuclear translocation of NF‑κB and IRF3. Notably, after inhibitor treatment, Nob no longer exerted its previously observed anti‑inflammatory effects, further supporting the critical regulatory role of STING in LPS‑mediated inflammation and indicating that the anti‑inflammatory activity of Nob is primarily dependent on the STING pathway. Moreover, in STING‑KO mice with LPS‑induced ALI, the loss of the protective effect of Nob further confirmed that its anti‑inflammatory activity depends on STING, highlighting the essential role of STING signaling in mediating its protective effects. In conclusion, the protective effect of Nob on an LPS-induced ALI model is mediated primarily through the modulation of STING signaling.
The widespread dissemination and serious clinical consequences of hypervirulent Klebsiella pneumoniae (hvKP), an encapsuled gram-negative pathogenic bacterium characterized by its specific virulence factor hypermucoviscosity (HMV), is becoming a concerning global public threat. In contrast to the common health care-associated infection of classical K. pneumoniae (cKp), hvKP is more virulent and capable of causing community-acquired invasive infections in healthy individuals, which mainly relies on the increased production of capsular polysaccharides (CPS) termed hypercapsule, and capsule-associated HMV. The indispensable role of capsule in mediating immune evasion, including resisting phagocytic engulfment and the killing of serum and host-derived antibacterial peptides, and other pathogenesis, renders it an attractive target for drug development against K. pneumoniae. Here, we identified the natural phenylpropanoid compound cinnamic acid (CA) as an effective inhibitor of K. pneumoniae capsule. The significant inhibition effect of CA on capsule biosynthesis was verified by both biochemical analysis and microscopic observation, and such drug action functioned in multiple K. pneumoniae strains. Mechanistically, CA hindered capsule biosynthesis by increasing bacterial carbon metabolism and consequently energy metabolism. Accordingly, hypercapsule-conferred hypermucoviscosity phenotype of hvKP was prominently impeded by CA. As a result, the cellular adherence and phagocytosis ratio, as well as serum killing and antibacterial peptide activity, were all improved by the inhibitor. In vivo, CA treatment significantly protected Galleria mellonella and mice from lethal hvKP infection. In conclusion, this study demonstrates that CA is a potent K. pneumoniae capsule inhibitor, which provides an alternative therapeutic strategy and active compound for K. pneumoniae infections.
Mitochondrial DNA copy number (mtDNA-CN) is a critical marker of mitochondrial health and plays a key role in cellular bioenergetics. Alterations in mtDNA-CN have been associated with aging, metabolic disorders and neurodegenerative diseases. Recent studies have revealed that various plant-derived extracts, as well as the secondary metabolites they produce, known as phytochemicals, can modulate mtDNA-CN through mechanisms including the regulation of mitochondrial biogenesis, oxidative stress, and mtDNA repair. This review examines plant-derived extracts and phytochemical compounds from a wide range of plant species- including Ginkgo biloba, Crocus sativus, Curcumin and many others- able to modulate mtDNA dynamics, scavenging oxygen free radicals and improving antioxidant defense systems.
Lactylation, as a novel post-translational modification, plays a key role in gene transcription and protein expression, serving as an important link between cellular metabolism and functional regulation. Ferroptosis is a regulatory form of cell death characterized by iron-dependent lipid peroxidation, and its abnormal regulation is closely associated with the onset and progression of various diseases, including tumors, degenerative diseases, and ischemia–reperfusion injury. Recent studies have shown that lactylation can regulate ferroptosis-related pathways and key targets through multiple mechanisms, regulate ferroptosis and thereby influence disease progression. This review first comprehensively summarizes the mechanisms of lactylation and ferroptosis, then systematically reviews the regulatory mechanisms and roles of lactylation in ferroptosis, and finally, we summarize the role of lactylation-regulated ferroptosis in various diseases and its potential as a therapeutic target. The aim is to deepen our understanding of the regulatory mechanisms and roles of lactylation in ferroptosis and to lay the foundation for the development of precision treatment strategies for related diseases.
Gastric cancer (GC) is a malignant neoplasm displaying highly cancer-related mortality globally. Although our previous studies have confirmed that vitamin D possessed a direct anti-cancer effect on GC cells, the regulatory role of vitamin D on gastric tumor microenvironment (TME) remains unexplored. This study aims to expound the modulation of vitamin D on TME especially on GC-associated fibroblasts (CAFs) and to further elucidate the essential role of the CAFs-derived exosomal ingredients in tumor-stroma crosstalk. Patient-derived primary CAFs enhanced the aggressive characteristics of GC cells. When co-cultured with GC cells, CAFs pretreated with 1,25(OH)2D3 (1,25D3), the active form of vitamin D exhibited a significant inhibitory effect on cancer cell invasion and migration. Additionally, exosomes isolated from 1,25D3-pretreated CAFs were found to mediate this inhibitory effect, significantly reducing the migratory and invasive capacity of GC cells. Exosomal RNA sequencing revealed a significant upregulation of miR-378c in CAF-derived exosomes following 1,25D3 treatment. Fluorescence tracing assays confirmed that this treatment augmented the transfer of CAF-derived exosomal miRNA-378c into GC cells. Mechanistically, this elevated miR-378c directly targeted ketodihydrosphinganine reductase (KDSR) in GC cells, further leading to the attenuation of tumor growth in a 615 mice model. Immunophenotypic analysis further revealed that treatment with ago-miR-378c significantly increased intratumoral Granzyme B and CD3 levels and downregulated Foxp3 expression, indicating an activated state of antitumor immunity and a relief from immune suppression within the TME. Correspondingly, the expression of TNF-α and IL-6 was found to be up-regulated, while the immunosuppressive factor IL-10 was reduced in the ago-miR-378c group in comparison to the control group. Moreover, systemic administration of vitamin D suppressed CAF-mediated promotion of in vivo tumor growth, concomitant with elevated intratumoral miR-378c and diminished KDSR expression in a nude mice model. Taken together, our results demonstrate that vitamin D reprograms CAFs to impede GC progression and to promote an anti-tumor immune microenvironment, which might be mediated by exosomal miR-378c/KDSR axis, highlighting a potential therapeutic strategy of using vitamin D to counteract CAF-driven oncogenesis in GC.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising candidates for Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, their effects in non-diabetic populations, independent of metabolic confounding, remain unclear. We evaluated the effects of GLP-1RAs on cognition, clinical outcomes, biomarkers, and safety in non-diabetic individuals with PD, AD, and mild cognitive impairment. We assessed the clinical meaningfulness of these effects using minimal clinically important difference thresholds. Relevant studies were retrieved from PubMed, Embase, and Web of Science from inception to November 2025. A random-effects meta-analysis was applied to calculate standardized mean differences (SMDs), mean differences (MDs), and risk ratios with 95
Ischemic acute kidney injury (AKI) remains a major clinical challenge, characterized by high morbidity, mortality, and a substantial risk of progression to chronic kidney disease. Accumulating evidence indicates that ischemic AKI is not merely a transient hemodynamic disorder but a complex, biologically orchestrated process driven by microvascular dysfunction, innate immune activation, inflammatory signaling, and maladaptive tissue repair. Despite advances in supportive care, effective disease-modifying therapies are still lacking. Recent studies have highlighted that key signaling pathways, including Toll-like receptor/nuclear factor-κB (TLR/NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), purinergic P2X7 receptor–inflammasome signaling, heat-shock protein–mediated stress responses, and phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) cascades, govern the initiation, amplification, and resolution of ischemic renal injury. These pathways converge on downstream cellular effectors such as cell adhesion molecules (CAMs), which orchestrate leukocyte recruitment, endothelial-epithelial interactions, and spatial propagation of inflammation within the renal microvasculature. Natural compounds have emerged as promising therapeutic candidates for ischemic AKI due to their pleiotropic pharmacological properties and ability to modulate multiple pathogenic signaling networks simultaneously. A growing body of experimental evidence demonstrates that polyphenols, glycosides, saponins, and related phytochemicals attenuate ischemic renal injury by suppressing inflammatory signaling, reducing CAM expression, preserving microcirculatory integrity, and promoting adaptive repair. Furthermore, advances in nanocarrier-based delivery systems have substantially enhanced the translational potential of these compounds by improving bioavailability, renal targeting, and pathway-specific modulation. In this review, we provide a comprehensive, signaling-centered analysis of ischemic AKI pathogenesis and systematically map natural compounds to their molecular targets and downstream inflammatory effectors. By integrating mechanistic insights with emerging nanotherapeutic strategies, this work offers a structured framework for the rational development of multi-target, mechanism-based interventions for ischemic AKI. It highlights key challenges and future directions for clinical translation.
Vascular remodeling (VR) is a structural and functional adaptation of the vessel wall to hemodynamic, metabolic, and inflammatory stress. When persistent and dysregulated, it contributes to the progression of atherosclerosis, hypertension, pulmonary arterial hypertension, and brain microvascular disease. Endothelial senescence is increasingly recognized as a key component of this maladaptive transition, characterized by impaired endothelial homeostasis, reduced nitric oxide bioavailability, and a senescence-associated secretory phenotype (SASP) that can reshape vascular cell–cell communication and extracellular matrix remodeling. Recent evidence further suggests that mitochondrial dysfunction is closely linked to endothelial senescence through multiple mechanisms, including mtROS accumulation, mitochondrial DNA (mtDNA) damage and leakage, disturbed mitochondrial dynamics, and impaired mitophagy flux. In this review, we integrate these findings into a vascular-bed- and disease-stage-stratified conceptual framework, termed the mitochondrial dysfunction–endothelial senescence–vascular remodeling (MD–ES–VR) axis. Within this framework, mechanisms and interventions are interpreted according to evidence strength, causal level, vascular context, and remodeling stage. Current evidence most consistently supports roles for mitochondrial dysfunction in amplifying endothelial injury, inflammatory senescence-like signaling, and remodeling progression, whereas definitive proof for reversal of established structural lesions remains limited. We therefore propose that future studies should combine endothelial-specific and time-resolved designs with quantitative mitochondrial and senescence readouts and robust structural endpoints to better define causality, therapeutic windows, and translational potential.
Leptin, an adipose tissue-derived hormone, regulates multiple aspects of hepatic physiology beyond its well-established metabolic functions. Accumulating evidence indicates that leptin influences hepatocyte viability, yet its role in endotoxin-induced liver injury remains incompletely understood. In this study, we investigated the sensitizing effect of leptin on lipopolysaccharide (LPS)-induced hepatocyte toxicity. We found that leptin at a physiologically relevant concentration (20 ng/ml) markedly sensitized hepatocytes to LPS-stimulated apoptosis, whereas leptin or LPS alone exerted no significant effect. This sensitizing effect was not observed in hepatocytes derived from hepatocyte-specific interleukin-1 receptor type 1 (IL1R1)-deficient mice, indicating a critical role for IL-1R1 signaling in these effects. Essentially similar results were obtained for apoptotic cell death, as demonstrated by Annexin-V/7-AAD staining and altered expression of key biochemical markers of apoptosis. Moreover, leptin/LPS-induced apoptosis was significantly attenuated by neutralization of IL-1β, but not by an IL-1α antibody. The in vitro observations were further validated in vivo, where combined administration of leptin and LPS induced pronounced liver injury, as evidenced by elevated serum AST/ALT levels and enhanced apoptotic signaling, all of which were substantially prevented in hepatocyte-specific IL1R1 knockout mice. Additionally, co-treatment with leptin and LPS elicited robust inflammatory cytokine production under both in vitro and in vivo conditions; this effect was absent in IL1R1-deficient models. Notably, combined leptin and LPS stimulation promoted Th17 differentiation from naïve T cells, leading to B cell activation and enhanced antibody production in an IL1R1-dependent manner. Collectively, these results suggest that leptin sensitizes hepatocytes to endotoxin-induced apoptosis via IL-1β signaling-dependent mechanism, thereby amplifying hepatic inflammation and adaptive immune activation.
Glycosides are widely distributed plant secondary metabolites and constitute an important source of chemical diversity in Meliaceae and Rutaceae families. Therefore, this review aimed to compile glycosides reported from Meliaceae and Rutaceae families over four decades of investigation (1983–2024), covering flavonoid, aromatic, terpenoid, and other structurally distinct groups. Across these classes, reported biological activities included antioxidant, anti-inflammatory, antimicrobial, and cytotoxic effects, and other activities. The result showed that after comparing available data, biological activity was largely associated with aglycone framework, while glycosylation mainly contributed to structural diversification and influenced physicochemical properties such as solubility and stability. By collecting phytochemical classifications and reported bioactivity data, this review focused on clarifying general trends in glycoside distribution in Meliaceae and Rutaceae, thereby bridging the knowledge gaps in structure–activity relationships and pharmacological evaluation.
Regorafenib, a multi-kinase inhibitor, has demonstrated clinical efficacy in various malignancies, including hepatocellular carcinoma (HCC), colorectal cancer (CRC), and gastrointestinal stromal tumors (GISTs). However, the emergence of resistance significantly limits its long-term therapeutic benefits. Rather than representing isolated molecular events, regorafenib resistance can be conceptualized as a dynamic process of “adaptive network collapse and rewiring”. Owing to its broad inhibition of angiogenic, stromal, and tumor-intrinsic kinases, regorafenib induces an initial collapse of signaling networks, which subsequently drives compensatory rewiring through receptor tyrosine kinase (RTK) bypass activation, cytokine-mediated feedback, and transcriptional reprogramming. Within this framework, resistance mechanisms can be hierarchically organized into drug-proximal adaptive signaling (VEGFR-associated pathways and RTK bypass), network-level regulatory processes (epigenetic modulation, drug transporters, and cancer stemness), and downstream phenotypic adaptations, including metabolic reprogramming, epithelial–mesenchymal transition (EMT), autophagy, and tumor microenvironment remodeling. These processes function in a coordinated manner to restore network robustness under sustained pharmacological pressure. Importantly, this integrative perspective provides a rationale for therapeutic intervention. While downstream adaptations may contribute to resistance maintenance, targeting key nodes of network rewiring—such as EGFR, STAT3, and microenvironmental signaling pathways—may offer more effective and durable strategies. Accordingly, combination approaches integrating regorafenib with targeted agents, immune checkpoint inhibitors (ICIs), metabolic modulators, or emerging therapeutic platforms are discussed. Overall, this review provides a systems-level understanding of regorafenib resistance and highlights the importance of mechanism-guided combination therapies and biomarker-driven strategies to improve clinical outcomes.
Paclitaxel (PTX) is a standard-of-care antineoplastic agent that stabilizes microtubules. However, its clinical utility is limited by dose limiting toxicities (e.g., myelosuppression and neuropathy), influencing decades of formulation development. Therefore, this review aims to analyze formulation strategies developed to address the three primary limitations. First, solvent-free formulations (e.g., albumin-bound PTX) mitigated the solvent-related toxicity and nonlinear pharmacokinetics of Cremophor EL-based PTX, improving the safety profile by eliminating hypersensitivity reactions. Second, intravenous formulations using liposomes or polymeric micelles for mitigating dose limiting toxicities via prolonged circulation and enhanced tumor retention demonstrated inconsistent clinical translation. Recently, active targeting platforms aimed to keep PTX largely inactive systemically while promoting mechanism-triggered delivery or tumoral uptake are under preclinical evaluation to expand the therapeutic index. Third, poor oral bioavailability, attributed to P-glycoprotein (P-gp)-mediated efflux and first-pass metabolism, was addressed via two strategies: gut-specific P-gp inhibition and lipid-based bypass formulations; however, interpatient absorption variability remains limited. In this review, decades of formulation research, tracing the evolution of PTX from a challenging molecule to a versatile therapeutic platform, were synthesized, highlighting the effect of addressing key biopharmaceutical and toxicity limitations in expanding its therapeutic index. Additionally, we examined the factors contributing to the frequent failure of passive targeting strategies to separate tumor exposure from systemic toxicity in human solid tumors. In conclusion, understanding PTX formulation strategies may facilitate future therapies to adopt flexible administration routes, incorporate biomarker-guided decision-making, and achieve controlled systemic exposure to reduce intrinsic dose-limiting toxicities.
Entrectinib, a Food and Drug Administration-approved medication for cancers such as non-small cell lung cancer, inhibits tropomyosin receptor kinases and penetrates the blood-brain barrier. Despite its approval, the effects of Entrectinib on neuroinflammatory responses and cognitive function within the central nervous system remain unclear. This study demonstrates that Entrectinib modulates lipopolysaccharide (LPS)-induced pro- and anti-inflammatory factors by suppressing JNK, p38, and AKT signaling, as well as NF-kappa B and STAT3 activity, in primary microglia. Entrectinib reduced CD16/32 levels, increased CD206 expression, enhanced phagocytic activity, and upregulated receptors and cytoskeletal genes in vitro. Additionally, Entrectinib decreased proinflammatory cytokines and inhibited JNK/p38/AKT and NF-kappa B/STAT3 signaling in the hippocampus of LPS-treated mice. Notably, Entrectinib ameliorated LPS-induced memory impairments in vivo. Collectively, these findings indicate that Entrectinib attenuates neuroinflammation and improves memory performance, supporting its potential therapeutic relevance for neuroinflammation-associated cognitive disorders.
