Search Results (1,287)

Although oxidants are known to be deleterious for cellular homeostasis by oxidizing macromolecules like DNA or proteins, they are also involved in signaling processes essential for cellular proliferation and survival. Here, we investigated the role of superoxide anion (O₂⁻) and hydrogen peroxide (H₂O₂) homeostasis for the proliferation and survival of classical Hodgkin’s lymphoma (cHL) cell lines. Inhibition of NADPH oxidases (NOX) using apocynin (Apo) and diphenylene iodonium (DPI), or treatment with the antioxidant butylated hydroxyanisole (BHA), significantly reduced proliferation and induced apoptosis in HL cell lines. These effects correlated with transcriptomic alterations involving redox regulation, immune signaling, and cell cycle control. Interestingly, treatment with DPI or antioxidants attenuated constitutive Signal Transducer and Activator of Transcription (STAT) activity, as seen by decreased phospho-STAT6 levels and reduced STAT6 DNA binding. This suggests a sensitivity of the Janus kinase (JAK)/STAT pathway in cHL cell lines to O₂⁻ and H₂O₂ depletion. Functional assays confirmed this by demonstrating partial restoration of proliferation or apoptosis in L428 cells that expressed constitutively active STAT6 or were transfected with small interfering RNAs (siRNAs) that targeted STAT regulators. These findings highlight that oxidants, particularly H₂O₂, act as both general oxidative stressors and essential modulators of oncogenic signaling pathways. Specifically, maintenance of oxidant homeostasis is critical for sustaining JAK/STAT-mediated growth and survival programs in cHL cells. Targeting redox homeostasis might offer a promising therapeutic strategy to impair JAK/STAT-driven proliferation and survival in cHL. Full article

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitis. The prevalence of RA is estimated to be 0.5–1% worldwide. Methods: This work investigated the therapeutic effects and underlying mechanisms of blue mussel (Mytilus galloprovincialis) oil (BMO) on RA in rats, using green-lipped mussel oil (GMO) and Antarctic krill oil (KO) as controls. Results: The results suggested that BMO, GMO, and KO all alleviated paw swelling in rats and reduced serum levels of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and pro-inflammatory cytokines such as TNF-$\alpha$ and IL-17. Histopathological assessment further revealed that BMO, GMO, and KO prevented synovial fibroplasia, mitigated inflammatory cell infiltration, and improved cartilage damage in ankle joints. Overall, BMO exhibited slightly superior alleviating effects compared with GMO and KO. Plasma lipidomics analysis revealed that the lipid metabolites altered by BMO showed significant correlations with RA-related indicators, particularly pro-inflammatory cytokines. Functional enrichment analysis suggested the involvement of inflammation-related pathways, particularly the NF-$\kappa$B signaling pathway. Further validation demonstrated that BMO effectively suppressed the production of inflammatory cytokines (TNF-$\alpha$, IL-17) and the expression of NF-$\kappa$B p65, JAK2, and STAT3 proteins in synovial tissue. And IL-17 production in footpad tissues is closely associated with CD3-positive T cells. Similar effects were also observed for GMO and KO. Conclusions: Collectively, BMO might ameliorate RA by inhibiting NF-$\kappa$B and JAK2/STAT3 signaling pathways. Full article

Adiposity-Based Chronic Disease (ABCD) is known to increase the risk of aggressive prostate cancer (PCa), recurrent disease after treatment for localized PCa, and PCa mortality. A key mechanistic link contributing to this enhanced risk is chronic inflammation originating from excess white visceral adipose tissue (WAT; VAT) and periprostatic adipose tissue (ppWAT). Contributing to systemic inflammation is gut dysbiosis, which itself may be caused by ABCD as well as background local inflammation (prostatitis), which is common in aging men and may be exacerbated by the urinary microbiome. Investigating the molecular biology driving inflammation and its association with increased PCa risk, a recent paper applied a network and gene set enrichment to adipokine drivers in the ABCD-PCa network. It found prominent roles for MCP-1, IL-1β, and CXCL-1 in addition to confirming the importance of exposure to lipopolysaccharides and bacterial components, corroborating the role of gut dysbiosis. To further unravel the mechanistic links between ABCD and PCa risk, this critical review will discuss the current literature on prominent inflammatory signaling pathways activated in ABCD; the influence of gut dysbiosis, the urinary microbiome, and chronic prostatitis; and current hypotheses on how these domains may result in the development of aggressive PCa over a man’s life. Moreover, we performed a novel pathway enrichment analysis to further evaluate the associations between ABCD, PCa risk, gut dysbiosis, and the prostate microbiome, the results of which were partitioned into extracellular and intracellular signaling pathways. In the extracellular space, novel mechanistic links between gut dysbiosis and MCP-1, IL-1β, CXCL1, and leptin via bacterial pathogen signaling and the intestinal immune network (for IgA production), crucial for gut immune homeostasis, were found. Within the intracellular space, there were downstream signals activating chemokine and type 2 interferon pathways, focal adhesion PI3K/Akt/mTOR pathways, as well as the JAK/STAT, NF-κB, and PI3K/Akt pathways. Overall, these findings point to an emerging molecular pathway for PCa oncogenesis influenced by ABCD, gut dysbiosis, and inflammation, and further research, possibly with lifestyle program-based clinical trials, may discover novel biomarker panels and molecular targeted therapies for the prevention and treatment of PCa. Full article

Background/Objectives: Obesity-associated hyperleptinemia has been linked to breast cancer (BC) progression via mechanisms that remain incompletely understood. This study explores the role of leptin and its receptor (LEPR) in facilitating BC cell proliferation, migration, epithelial–mesenchymal transition (EMT), and STAT3 signaling pathway activation. Methods: We analyzed gene expression and survival data from TCGA BRCA dataset. MCF-7 and MDA-MB-231 BC cells were exposed to leptin at 10 ng/mL (lean-associated levels) and 100 ng/mL (elevated levels linked to obesity). MTT assays, colony formation tests, wound-healing and tumor spheroid dissemination experiments evaluated cell proliferation and migration. Immunofluorescence and Western blot analysis assessed changes in EMT markers and cytoskeletal alterations, while Western blotting and qPCR assessed STAT3 and NCOA1 expression and activation levels. Results: Elevated LEPR expression was linked with unfavorable prognosis in BC patients. Higher doses of leptin (100 ng/mL) significantly enhanced cellular proliferation rates and migratory capabilities, in both cell lines, and promoted EMT characteristics marked by downregulated E-cadherin and cytoskeleton structural changes. Whereas heightened JAK2/STAT3 signaling correlated with elevated leptin dosages, STAT3 inhibition using AG490 reversed leptin-induced migration while reinstating E-cadherin levels to baseline. Furthermore, leptin upregulated NCOA1, an essential STAT3 coactivator, facilitating increased expression of Cyclin D1 and VEGF target genes. Clinical positive relationships were seen between LEP/LEPR expressions and NCOA1 levels and between NCOA1 and various gene signatures related to STAT3/P-STAT3 within BC specimens. Conclusions: Obesity-associated hyperleptinemia enhances aggressiveness in BC through a mechanism involving LEPR-mediated activation pathways encompassing NCOA1/STAT3, which drive proliferation, migration, and EMT. This assigns a potential therapeutic utility for obesity-related advancements found within BC pathology. Full article

Background: The traditional formula Liqi Yangyin (LQYY) has shown clinical and preclinical efficacy for depression with constipation, yet its molecular mechanisms remain incompletely defined. This study aimed to elucidate its mechanisms using an integrative approach. Methods: Constituents of LQYY were profiled by UPLC-MS/MS and integrated with network pharmacology and molecular docking to identify brain-accessible components and putative targets. A chronic unpredictable mild stress (CUMS) model was used for experimental validation. Outcomes included behavioral tests (sucrose preference test, open field test, and forced swimming test), gastrointestinal indices, including fecal water content, time of first black stool, and intestinal propulsion rate, histopathology of the prefrontal cortex (PFC) and colon, TUNEL staining, NeuN immunofluorescence, Western blotting, and qRT-PCR. Results: LQYY attenuated CUMS-induced weight loss and depressive-like behaviors and improved intestinal transit metrics. It reduced neuronal apoptosis in the PFC and ameliorated colonic injury. Mechanistically, docking and enrichment analyses highlighted hub targets (STAT3, AKT1, ESR1, IL-6, TNF, TP53) and the JAK/STAT pathway. In vivo, LQYY decreased IL-6, TNF-α, ESR1, TP53, and STAT3, and increased AKT1 in the PFC and colon; it also reduced the TUNEL-positive rate and restored NeuN labeling, upregulated Bcl-2, and downregulated p-JAK2/JAK2 and p-STAT3/STAT3 ratios, and the expression of Bax and cleaved-caspase-3 in the PFC, consistent with the suppression of pro-inflammatory and apoptotic signaling. Conclusions: LQYY exerts antidepressant and pro-motility effects in CUMS mice by modulating JAK2/STAT3-centered networks and inhibiting neuronal apoptosis, thus supporting a multi-component, multi-target strategy for treating depression with constipation, and providing a defined molecular hypothesis for future investigation. Full article

Macrophages play a crucial role in regulating immune responses, inflammation, and tissue repair. Depending on environmental cues, they polarize into pro-inflammatory M1 or anti-inflammatory, pro-regenerative M2 phenotypes. Extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have emerged as key mediators of intercellular communication and immune modulation. This study investigates the effects of matrix-bound vesicles (MBVs) and small extracellular vesicles (sEVs) derived from human umbilical cord MSCs (UC-MSCs) on human monocyte-derived macrophages (MDMs) in vitro. Both MBVs and sEVs reduced pro-inflammatory activation of M1 macrophages, downregulating the expression of CXCL10 and CD86 while increasing the M2 marker CD206. MBVs exerted a stronger suppressive effect on M1 MDM phenotype markers as well as on STAT1, STAT2, and IRF9 mRNA levels in M1 macrophages, indicating the inhibition of the JAK/STAT1 signaling pathway involved in the pro-inflammatory activation of macrophages. Functionally, both vesicle types enhanced phagocytosis of FITC-labeled E. coli by M1 and M0_GM macrophages, promoting a shift toward an M2-like phenotype. Moreover, MBVs and sEVs attenuated reactive oxygen species (ROS) production, with sEVs showing a more pronounced effect both on ROS generation and on the expression of NOX2 complex subunits (p47^phox, p67^phox) in M1 macrophages. These findings demonstrate that MBVs and sEVs from UC-MSCs possess distinct yet complementary immunomodulatory and antioxidant properties on MDMs, suggesting their potential as promising cell-free therapeutic agents for inflammatory and degenerative diseases. Full article

Immune dysregulation and chronic inflammation are central contributors to many diseases. Curcuma longa L. and Echinacea purpurea (L.) Moench are widely used medicinal plants with extensive preclinical evidence supporting immunomodulatory effects. Their key metabolites, curcuminoids, turmerones, alkamides, polysaccharides, and caffeic acid derivatives, engage with critical pathways, including NF-κB, MAPK, JAK/STAT, and Nrf2. This interaction modulates cytokine production, oxidative stress responses, and both innate and adaptive immune activities. Although numerous mechanistic and early clinical studies support these actions, human evidence remains inconsistent, partly due to poor and variable oral bioavailability and substantial heterogeneity in extract composition, despite the existence of some standardized preparations. Recent technological strategies, including micelles, phytosomes, phospholipid complexes, nanoemulsions, polymeric nanoparticles, and liposomal systems, have improved solubility, stability, and systemic exposure of key metabolites, particularly curcuminoids. However, clinical results are still limited and often derived from small or heterogeneous trials. This review summarizes the ethnopharmacological background, mechanistic data, clinical findings, and formulation advances for both species and highlights the translational barriers that restrict their therapeutic application. Rigorous clinical studies using standardized and technologically optimized preparations are required to determine the true immunomodulatory potential of C. longa and E. purpurea. Full article

(1) Background: All-trans retinoic acid (ATRA) has transformed the treatment of acute promyelocytic leukemia (APL) by inducing terminal myeloid differentiation. However, its efficacy in non-APL acute myeloid leukemia (AML) is limited. Exploring combination strategies that enhance ATRA-induced differentiation may broaden its therapeutic potential. (2) Methods: A literature search of PubMed using the keywords “ATRA,” “myeloid,” and “differentiation inducer or enhancer” identified more than 500 published papers as of November 2025. Pre-clinical and clinical studies were reviewed, with a focus on mechanisms, combination partners, and translational relevance. (3) Results: Clinical evidence confirms that ATRA combined with arsenic trioxide or epigenetic modulators achieves high remission rates in APL and selected AML subtypes. Pre-clinical studies show synergistic differentiation effects when ATRA is combined with CDK and kinase inhibitors, nucleotide synthesis inhibitors, DNA-damaging agents, Bcl-2/MDM2 inhibitors, proteasome inhibitors, cytokines, glycosylation modifiers, natural products, and antibiotic-derived compounds. Mechanistically, these combinations modulate key signaling pathways (MAPK, Akt, JAK/STAT), stabilize RARα, remodel chromatin, and perturb nucleotide metabolism. Although translation to non-APL AML remains limited, these findings provide a rational basis for future clinical trials. (4) ATRA-based combination therapies represent a promising strategy to extend differentiation therapy beyond APL. This review, authored solely by the investigator, highlights molecular targets and potential enhancers warranting further clinical evaluation in AML. Full article

Early-onset colorectal cancer (EOCRC) continues to rise, with the steepest increases observed among Hispanic/Latino (H/L) populations, underscoring the urgency of identifying ancestry- and treatment-specific biomarkers. The JAK-STAT signaling axis plays a central role in colorectal tumor biology, yet its relevance under FOLFOX-based chemotherapy in EOCRC remains poorly defined. In this study, we evaluated 2515 colorectal cancer (CRC) cases (266 H/L; 2249 non-Hispanic White [NHW]), stratifying analyses by ancestry, age of onset, and FOLFOX exposure. Statistical comparisons were performed using Fisher’s exact and chi-square tests, and survival patterns were assessed via Kaplan–Meier analysis. To extend conventional analytics, we deployed AI-HOPE and AI-HOPE-JAK-STAT, conversational artificial intelligence platforms capable of harmonizing genomic, clinical, demographic, and treatment variables through natural language queries, to accelerate multi-parameter biomarker exploration. JAK-STAT pathway alterations showed marked variation by ancestry and treatment context. Among H/L EOCRC cases, alterations were significantly enriched in patients who did not receive FOLFOX compared with those who did (21.2% vs. 4.1%; p = 0.003). A similar pattern emerged in late-onset CRC (LOCRC) NHW patients, where alterations were more frequent without FOLFOX exposure (13.3% vs. 7.5%; p = 0.0002). Notably, JAK-STAT alterations were significantly more common in untreated H/L EOCRC compared with untreated NHW EOCRC (21.2% vs. 9.9%; p = 0.002). Survival analyses revealed that JAK-STAT pathway alterations conferred improved overall survival across several NHW strata, including EOCRC treated with FOLFOX (p = 0.0008), EOCRC not treated with FOLFOX (p = 0.07), and LOCRC not treated with FOLFOX (p = 0.01). These findings suggest that JAK-STAT alterations may function as ancestry- and treatment-dependent prognostic markers in EOCRC, particularly among disproportionately affected H/L patients. However, prognostic interpretation in H/L subgroups is limited by small mutation-positive sample sizes, reflecting historical underrepresentation and highlighting the need for larger ancestry-balanced studies. The integration of AI-enabled platforms streamlined analyses and reveals the potential of artificial intelligence to accelerate discovery and advance precision medicine for populations historically underrepresented in cancer genomics research. Full article

Background: Hypertrophic cardiomyopathy (HCM) is increasingly recognized as a disorder shaped not only by sarcomeric mutations but also by complex immunogenetic and metabolic interactions. Emerging transcriptomic and single-cell analyses implicate immune dysregulation, RNA methylation, and necroptosis as critical modulators of myocardial remodeling. Objectives: This scoping review synthesizes bioinformatic, transcriptomic, and experimental data to delineate the immunogenetic architecture of HCM and identify candidate molecular targets for immune–metabolic modulation. Methods: Following Joanna Briggs Institute and PRISMA-ScR guidelines, we systematically searched PubMed, Embase, Web of Science, and GEO through September 2025 for studies evaluating immune infiltration, RNA regulation, and necroptosis in human HCM. Data were narratively synthesized across histologic, clinical, and multi-omics domains. Results: Among 8191 screened records, 25 studies met the inclusion criteria. Key immune–epigenetic regulators included the lncRNA–mRNA pair MIR210HG–BPIFC, m6A readers IGFBP3 and YTHDC1, and necroptosis gene JAK2. The HCM myocardium exhibited the depletion of reparative M2 macrophages and Tregs; enrichment of cytotoxic CD8⁺ T cells; and activation of the TNFα–NFκB, IL-6–JAK–STAT3, and PI3K–Akt pathways. Machine learning biomarkers (RASD1, FCN3, and PIK3R1) exhibited diagnostic accuracy (AUC > 0.85). Drug target predictions identified ruxolitinib and celecoxib as potential immunometabolic modulators (agents predicted to modulate both immune and metabolic pathways based on gene expression signatures). Conclusions: These findings support a hypothesis that HCM may involve immunogenetic mechanisms, rather than being exclusively sarcomeric in nature, although this remains to be validated. The integration of molecular and imaging biomarkers may enable precision immunotherapy, redefining HCM from a structural cardiomyopathy to a biologically stratified condition. Full article

Iron constitutes an essential micronutrient in living organisms. All iron is absorbed into the body through dietary intake, except for exogenous therapeutic sources. Dietary iron is typically categorized as either heme or nonheme iron. Nonheme iron is essential for regulating iron in the body, as it exists in various forms, including soluble iron, storage iron within ferritin, and iron found in the catalytic centers of a wide range of proteins. Iron homeostasis is carefully managed to ensure that sufficient iron is available for critical biological processes while preventing the harmful effects that can arise from excess iron. The small peptide hormone hepcidin is the main regulator of iron homeostasis. Hepcidin and other iron regulatory molecules are regulated by various signaling pathways, such as IL-6/JAK-STAT, BMP/SMAD, and MAPK. Alterations in regulatory pathways may occur in response to iron accumulation or deficiency. Iron overload in the body can activate JAK/STAT, BMP/SMAD and MAPK pathways, leading to the initiation hepcidin synthesis. Conversely, in iron deficiency, as in hypoxic conditions or EPO-mediated signaling pathways, HAMP synthesis in the nucleus is reduced. Thus, this review provides an update on the possible regulatory pathways that play a role in iron regulation and may be potential therapeutic targets. Full article

Background/Objectives: Nickel exposure is a significant environmental and occupational risk factor associated with the onset and progression of chronic liver diseases due to its capacity to induce persistent oxidative stress, inflammation, and hepatocellular injury. This study aimed to evaluate the enhanced hepatoprotective and antioxidant/anti-inflammatory effects of naringin-loaded nanoliposomes (NRG-NLPs), a novel nanoformulation designed to improve the bioavailability of naringin, a citrus-derived flavonoid phytochemical, against nickel sulfate (NiSO₄)-induced hepatotoxicity in male Wistar rats. Methods: Ninety rats were allocated into six groups (n = 15 each): control, NRG, NRG-NLPs, NiSO₄, NiSO₄ + NRG, and NiSO₄ + NRG-NLPs. Treatments consisted of oral administration of NRG or NRG-NLPs (80 mg/kg/day) and intraperitoneal injections of NiSO₄ (20 mg/kg/day) for three weeks. Endpoints included assessment of growth performance, serum biochemistry, hepatic antioxidant status, inflammatory mediators, apoptotic gene expression, nickel tissue accumulation, and histopathological and ultrastructural liver changes. Results: NiSO₄ exposure induced marked hepatic injury, evidenced by reduced body weight, adverse serum biochemical profiles, increased hepatic enzymes and bilirubin, elevated oxidative damage markers (MDA, protein carbonyls), increased proinflammatory cytokines, and upregulation of HMGB1, PI3K, mTOR, JAK/STAT, and proapoptotic genes, accompanied by aberrant nickel accumulation and severe histopathological alterations. Co-treatment with NRG-NLPs significantly ameliorated biochemical and histological disturbances, restored antioxidant defense systems (SOD, CAT, GPx, GSH, Nrf2, HO-1), and modulated key pathways of inflammation (NF-κB, TNF-α, IL-6), fibrosis (TGF-β), cell survival, and apoptosis more effectively than crude naringin. NRG-NLPs also substantially reduced hepatic nickel deposition and preserved near-normal liver architecture. Conclusions: These findings demonstrate that nanoformulated naringin confers superior hepatoprotective benefits against nickel-induced liver injury through enhanced bioavailability and multi-pathway modulation, supporting its translational potential as a citrus-derived medicinal phytochemical and dietary bioactive for the prevention and therapeutic intervention of oxidative and inflammatory chronic liver disease. Full article

Background/Objectives: Uveal melanoma (UVM), the leading primary intraocular cancer in adults, is driven by GNAQ/GNA11 mutations, encoding the active forms of Gαq proteins. While local treatments like surgery or radiation can control primary tumors, nearly half of patients die from metastasis. Our aim was identifying potential pathways involved in resistance to targeted therapy in UVM. Methods: Here, we screened 100 pathway-activating mutant complementary DNAs by lentiviral overexpression to identify those that enhance the survival of cancer cells in the presence of clinically relevant targeted therapies, using BAP1 wild-type UVM cells and validated the most significant results in BAP1-mutant cells. Results: This revealed JAK/STAT activation, overexpression of anti-apoptotic BCL2/BCL-XL, and dysregulated PI3K/mTOR or Hippo pathways as escape routes under MEK-ERK or FAK inhibition. Bioinformatic analysis of UVM transcriptome in TCGA further showed that high expression of the hallmark PI3K/AKT/mTOR pathway and IL6/JAK/STAT signaling correlates with poor prognosis. A similar correlation was shown by YAP and anti-apoptotic signatures. The analysis of individual representative genes from these signatures revealed that MTOR, BCL2L1 (BCL-XL), and TEAD4 gene expression are linked to poorer survival, underscoring the potential clinical impact of these adaptive pathways. Proliferation and apoptosis assay demonstrated that aberrant activation of AKT and YAP promotes resistance to FAK and MEK inhibitors. Conclusions: These findings support the adaptability of UVM lesions and suggest rational combination therapies targeting both primary GNAQ/GNA11-driven oncogenic signals and their compensatory networks as a more effective, personalized treatment approach for advanced UVM. Full article

Argininosuccinate synthetase 1 (ASS1) expression and arginine availability are key metabolic determinants that influence tumor fitness and regulate immune interactions within the tumor microenvironment (TME). Using an orthotopic triple-negative breast cancer (TNBC) model, we demonstrate that arginine deprivation heightens tumor dependence on the TME for survival. Mechanistically, fibroblasts sustain tumor viability by supplying arginine, whereas macrophages cooperate with stromal cues to activate Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, thereby enhancing tumor survival. Concordantly, a JAK-STAT gene-expression signature correlates with ASS1 levels in human TNBC datasets. Translationally, combined pharmacological inhibition of JAK signaling with arginine deprivation markedly suppresses tumor growth. Together, these findings reveal a TME-driven, targetable stromal–immune circuit that enables tumors to withstand arginine deficiency-induced metabolic stress. Broadly, our work highlights that mapping and strategically inducing metabolic dependencies can reveal actionable compensatory pathways, offering opportunities to improve cancer therapy. Full article

Obesity and air pollution are two pervasive and increasingly prevalent risk factors for neurodegenerative diseases, like Alzheimer’s disease. Both independently disrupt brain homeostasis through overlapping mechanisms, including chronic neuroinflammation, oxidative stress, and insulin resistance. Recent evidence highlights the Wnt/β-catenin signaling pathway as a critical integrator of these insults, mediating neuroprotective processes such as synaptic plasticity, blood–brain barrier integrity, and neuronal survival. In this review, we synthesize emerging data on how obesity-driven metabolic dysfunction and air pollution-induced oxidative injury synergize to impair brain metabolism and accelerate cognitive decline. We describe the roles of pathways such as JAK-STAT, NF-κB, and TLR4 signaling cascades, as well as leptin and adiponectin imbalances, in modulating glial reactivity and neuroimmune signaling. Particular attention is given to the suppression of Wnt/β-catenin signaling in obese and pollution-exposed brains, and its consequences for Alzheimer’s disease pathology, including β-amyloid accumulation and tau hyperphosphorylation. Finally, we examine the translational implications, highlighting the Wnt pathway as a potential therapeutic target that offers neuroprotection in the context of dual metabolic and environmental stress. Together, these insights provide a mechanistic framework that links systemic dysfunction to central nervous system vulnerability, offering pathways for intervention in at-risk populations. Full article