Headache disorders are among the most disabling neurological conditions, affecting over 1.5 billion people globally. Despite advances in pharmacological therapies, major inequities persist due to underdiagnosis, undertreatment and limited access to effective care, particularly in low- and middle-income countries. Social determinants of health, including cultural meanings, language and health beliefs, are increasingly recognized as key drivers of disparities in burden, diagnosis and treatment outcomes. Traditional medicine, used by more than 80% of the global population, remains first-line care in many regions and continues to influence therapeutic choices in high-income settings. Major systems such as Ayurveda, Traditional Chinese Medicine, Unani and Tibetan medicine, as well as diverse indigenous traditions, emphasize holistic approaches that integrate mental and physical symptoms into diagnosis and management. Additionally, religious and spiritual practices are commonly used to relieve suffering and pain. These culturally grounded explanatory models not only strongly shape health-seeking behavior, treatment adherence and patient narratives, but also may delay biomedical care when misconceptions or unsafe practices predominate. This paper introduces Transcultural Headache Medicine as an emerging framework that integrates cultural contexts, linguistic diversity and traditional practices into headache research, clinical care and policy. We review global traditions and therapeutic modalities including herbal, physical, mental and spiritual approaches, and propose a research agenda combining ethnography, culturally adapted diagnostic tools, experimental studies and clinical trials to evaluate benefits, risks, and contextual effects. We conclude with a call to action from the International Headache Society, aiming to map and evaluate culturally embedded practices, strengthen rigorous evidence and build a global learning network that supports culturally safe integration of effective, affordable and safe headache care.

OBJECTIVE:To identify genetic and phenotypic determinants of migraine susceptibility and progression using a large-scale, hypothesis-free approach. BACKGROUND:Migraine is a common neurological disorder with a substantial individual and societal burden. While risk factors are known, hypothesis-driven approaches may overlook contributors. METHODS:We analyzed data from 502,364 UK Biobank participants (aged 37-73 years; recruited 2006-2010) to assess associations between migraine and 2824 phenotypes, including observational associations and associations with migraine polygenic risk scores. Time-dependent associations were evaluated, and causality was assessed. Follow-up extended from baseline through to November 30, 2024, with a median of ~14.7 years. RESULTS:Our analyses identified 253 phenotypes significantly associated with migraine risk, 191 phenotypes associated with migraine PRS, and 87 overlapping between the two approaches. Cox regression analysis confirmed 84 robust time-dependent associations and highlighted novel risk factors, such as oral ulcers (adjusted hazard ratio [aHR] = 1.14, 95% confidence interval [CI]: 1.02-1.28, q = 2.54 × 10-2), lower limb obesity (aHR = 1.01, 95% CI: 1.00-1.02, q = 3.52 × 10-4), and hormone replacement therapy (aHR = 1.39, 95% CI: 1.29-1.50, q = 1.95 × 10-17). MR analysis also revealed causal associations with emotional fluctuations (inverse-variance weighting odds ratio [IVW OR] 4.10, 95% CI = 1.76-9.53, q = 1.00 × 10-2), neuroticism (IVW OR = 1.12, 95% CI = 1.07-1.08, q = 1.24 × 10-5), general health ratings (IVW OR = 1.81, 95% CI = 1.43-2.29, q = 3.30 × 10-2), and fatigue (IVW OR = 1.94, 95% CI = 1.35-2.79, q = 5.73 × 10-36). However, the association with paracetamol use (IVW OR = 9.65 × 104, 95% CI = 1.67 × 104-5.57 × 105, q = 5.73 × 10-36) had uncertain directionality on Steiger testing and should be interpreted cautiously. In total, 87 genetic and phenotypic determinants of migraine were identified, offering new therapeutic targets involving inflammatory and insulin-like growth factor 1 (IGF-1) -related pathways. CONCLUSIONS:This comprehensive analysis provides new insights into the genetic and phenotypic factors that influence migraine. The findings suggest new targets for therapeutic intervention and provide a basis for the development of precision prevention and clinical management strategies.

Migraine and headache disorders are among the world’s most common yet overlooked health challenges, with profound effects on wellbeing, productivity, and equality. This multi‑regional webinar brings together experts from around the globe to explore how reframing migraine as a major global health issue can drive progress toward the UN Sustainable Development Goals (SDGs).Rational Approach to Migraine: A Brain-Capital Imperative for Global Action Migraine is far more than a headache — it is a chronic brain condition that silently affects hundreds of millions of people worldwide, particularly across the Asia–Oceania region. Despite its enormous burden, migraine remains under-recognised, underdiagnosed, and undertreated, leading to profound consequences for individuals, families, and societies. This webinar reframes migraine through a powerful new lens: brain capital — the cognitive, emotional, and creative capacity that drives human potential and economic productivity. When migraine is neglected, it erodes learning, decision-making, workforce participation, and innovation, ultimately undermining progress across multiple United Nations Sustainable Development Goals, including health, education, gender equity, and economic growth. Drawing on global clinical experience and policy engagement, this session presents a practical, scalable, and equity-focused approach to migraine care. It highlights how simple, cost-effective strategies — early diagnosis, structured care pathways, non-pharmacological interventions, and rational use of therapies — can significantly reduce disability and improve quality of life, even in resource-limited settings. Importantly, the webinar calls for a shift from fragmented, reactive care to an integrated brain-health approach, embedding migraine into primary care, workforce policy, and universal health coverage. This is not just a clinical challenge — it is a strategic, economic, and moral imperative. Addressing migraine effectively is an investment in healthier individuals, stronger communities, and more resilient societies. The time to act is now.

Objective.Foundation models have demonstrated transformative potential in medical artificial intelligence but remain underexplored in functional neuroimaging, particularly magnetoencephalography (MEG). This study aims to develop a domain-specific, self-supervised MEG clinical foundation model tailored for headache disorders to address the challenges of high-dimensional data and limited labeled datasets in clinical research.Approach. We developed a transformer-based model pretrained on a large-scale dataset comprising multi-state MEG recordings (resting-state, auditory, and somatosensory stimulation) from 416 participants (362 headache patients and 54 healthy controls). The model utilized a self-supervised masked-signal reconstruction strategy to learn latent spatiotemporal representations of neural activity. We evaluated the model's performance through signal reconstruction, visualization of attention weights, and downstream classification tasks comparing model-derived features against original MEG signals for migraine diagnosis.Main results. The pretrained model successfully reconstructed both continuous MEG signals and stimulus-specific evoked responses, effectively capturing intrinsic spatiotemporal brain dynamics. Visualization of the model's attention weights demonstrated spatial alignment with corresponding sensory brain regions, confirming its neurophysiological interpretability. Furthermore, classifiers trained on features extracted from the pretrained model significantly outperformed those using original MEG signals in identifying migraine patients, revealing distinct neural response patterns.Significance. This study introduces a scalable, data-efficient framework for clinical MEG analysis that significantly reduces reliance on manual feature extraction and labeled data. It demonstrates the efficacy of foundation models in decoding complex neural dynamics, offering promising implications for understanding neuropathology and facilitating precision diagnostics in neurology.

BackgroundExcessive iron deposition is associated with migraine occurrence, disease severity, and related dysfunction. The migraine attack is a coordinated, whole-nervous-system event, while previous research has predominantly focused on discrete brain regions. This study aims to explore the associations between network-level iron deposition and both disease occurrence and clinical manifestations in migraine using the functional connectome.MethodsSeventy-three migraine patients, including 32 episodic migraine (EM) and 41 chronic migraine (CM), and 37 age- and sex-matched healthy controls (HCs) were recruited. All participants underwent magnetic resonance imaging (MRI) to acquire quantitative susceptibility mapping (QSM) data. First, individual iron deposition maps were defined by comparing iron levels in each patient versus HCs. Next, the network coupling with each patient's site of iron deposition was calculated using seed-based functional connectivity (FC) in a large (n = 1000) normative connectome, termed the iron deposition network map (IDNM). We then performed inter-group analysis to identify disease- and symptom-associated brain regions and measured the FC strength between these regions and the patients' iron deposition maps. Finally, we investigated the relationships between IDNM-derived metrics and various clinical manifestations, including headache characteristics, migraine-related symptoms, disability measures, and comorbidities.ResultsIDNM group comparisons revealed significant differences in the superior temporal gyrus (STG), insula, and cerebellum in both migraine vs. HCs and CM vs. HCs comparisons, whereas no statistically significant differences were found for EM compared to either CM or HCs. FC strength between the peak site of the regions and individual iron deposition maps showed good discriminative performance in receiver operating characteristic (ROC) analysis (AUC > 0.70), effectively distinguishing migraine patients from HCs. Moreover, we identified clinical manifestation-related networks based on the IDNMs: the cerebellum for monthly headache days (MHDs; r = 0.349, p = 0.003); the orbitofrontal cortex (OFC) and nucleus accumbens (NAC) for poor sleep quality (r = 0.604, p < 0.001); and the globus pallidus (GP) for vomiting (p < 0.001).ConclusionNetwork-level iron deposition may distinguish migraine patients from HCs and is associated with clinical manifestations including MHDs, poor sleep quality, and vomiting symptoms, suggesting that iron deposition may play a role in migraine through the functional connectome.

Migraine aura manifests as various neurological symptoms, which may occur before, during, or persist throughout the headache phase. We report a case of a 30-year-old female patient whose initial symptoms included persistent bilateral photopsia and ophthalmoplegia, accompanied by headache, with a medical history spanning over four years. The duration of her auras was up to one month. After admission, through detailed inquiry into her medical history and extensive etiological screening, the patient was diagnosed with chronic migraine (CM). Following preventive treatment for CM, her symptoms significantly improved. This case serves to encourage neurologists to expand their diagnostic thinking in clinical practice. When encountering sudden and unexplained persistent neurological symptoms, the possibility of migraine with persistent aura should be considered.

The nucleus accumbens (NAc) plays an important role in the chronic pain process and consists of core and shell subregions with distinct connectivity patterns. However, their roles in migraine progression remain unclear. This study explored static and dynamic functional connectivity (FC) patterns of NAc subregions across healthy controls (HCs), patients with episodic migraine (EM) and patients with chronic migraine (CM). 97 participants were enrolled: 70 migraine patients (24 EM, 46 CM) and 27 HCs. All underwent functional magnetic resonance imaging on a GE 3.0T system. Demographic and clinical characteristics were collected. The NAc core and shell were defined as ROIs, and static and dynamic seed-based FC analyses were performed across groups. Partial correlations between FC values and clinical variables were conducted. Significant static FC and dynamic FC were selected through multivariable logistic regression. Receiver operating characteristic curves were used to assess their diagnostic performance for distinguishing CM patients. Compared with HCs, EM showed increased sFC between the right NAc core and right supplementary motor area (SMA), whereas CM exhibited decreased sFC, particularly between the left NAc shell and the left fusiform gyrus and between the right NAc core and the left cerebellum crus II. Relative to EM, CM showed reduced sFC mainly between the left NAc shell and the bilateral precentral gyrus and right superior frontal gyrus (SFG), and between the right NAc core and right SMA, right inferior frontal gyrus, and left inferior temporal gyrus (ITG). The dFC analysis revealed decreased connectivity between the left NAc shell and left precentral gyrus and right SFG, and between the right NAc core and left SMA. Reduced sFC between the right NAc core and left ITG and dFC between the left NAc shell and right SFG effectively distinguished CM from EM. The combined FC calculated from sFC and dFC further improved discrimination (AUC = 0.919). NAc subregions in CM showed reduced connectivity with multiple brain regions, mainly in sensorimotor, executive control, and default mode networks. Significant sFC and dFC of the NAc subregions may serve as potential imaging biomarkers for CM.

Chronic periodontitis (CP) is a common chronic oral infectious disease. This study evaluated the clinical significance of differentially expressed OIP5-AS1 and miR-223-3p in CP patients and investigated the biological function of the OIP5-AS1/miR-223-3p axis in a cell model induced by LPS. One hundred and eighteen CP patients were enrolled to provide clinical samples and data. OIP5-AS1 and miR-223-3p expression were detected by reverse transcription quantitative PCR, and their clinical application in diagnose CP was evaluated by receiver operative curve (ROC) analysis. Bioinformatics prediction and dual-luciferase reporter assay confirmed the interaction between OIP5-AS1 and miR-223-3p. Human periodontal ligament cells (HPLCs) were treated with LPS to establish disease cell model, and the effects of OIP5-AS1/miR-223-3p on cell viability and inflammation were examined using CCK-8 and ELISA. In CP patients, OIP5-AS1 expression was lower and miR-223-3p expression was higher than in the control group (both P < 0.001). Serum OIP5-AS1 and miR-223-3p showed considerable ability to diagnose CP from healthy controls (AUC = 0.816, sensitivity = 70.34%, specificity = 81.97% for OIP5-AS1; AUC = 0.837, sensitivity = 80.51%, specificity = 72.13% for miR-223-3p). Cell experiments showed OIP5-AS1 improved LPS-induced impaired cell proliferation by sponging miR-223-3p. Additionally, OIP5-AS1 targets miR-223-3p and inhibits the inflammatory response induced by LPS, while promoting osteogenic differentiation of HPDLCs. Serum upregulated OIP5-AS1 and downregulated miR-223-3p serve as potential diagnostic biomarkers for CP, and OIP5-AS1 might be involved in CP progression by sponging miR-223-3p.

Chronic migraine (CM) is a debilitating neurological disorder characterized by persistent trigeminovascular sensitization and neuroinflammation. While FK506-binding protein 51 (FKBP5) modulates spinal neuroinflammation in chronic pain, its specific role in trigeminovascular nociceptive processing and CM pathogenesis remains largely unknown. We used a nitroglycerin (NTG)-induced CM mouse model. Following RNA-sequencing (RNA-seq) of total RNA isolated from trigeminal nucleus caudalis (TNC) tissue lysates, target expression was validated via reverse transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence. To establish causality, we used a neuron-specific CRISPR-Cas9 editing system for Fkbp5 knockout within the TNC, alongside pharmacological interventions using the specific FKBP5 antagonist SAFit2 and the nuclear factor kappa B (NF-κB) inhibitor PDTC. Migraine-like behaviors were evaluated using von Frey filaments, coupled with biochemical analyses of NF-κB cascade activation and trigeminovascular neuroinflammation. RNA-seq, RT-qPCR, Western blotting, and immunofluorescence consistently confirmed a marked upregulation of Fkbp5 mRNA and FKBP5 protein in the TNC of NTG-treated mice, predominantly localized to neurons. Concurrently, significant microglial and astrocytic activation was observed in the TNC. Both neuron-specific Fkbp5 knockout and pharmacological inhibition with SAFit2 significantly attenuated NTG-induced periorbital and hind paw mechanical allodynia. Furthermore, FKBP5 deficiency blunted the NTG-triggered phosphorylation of p65 and IκBα, effectively suppressing the downstream release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as the upregulation of calcitonin gene-related peptide (CGRP) and c-Fos. Crucially, targeted blockade of the NF-κB cascade with PDTC recapitulated the protective behavioral and biochemical effects of FKBP5 deficiency. We demonstrate that neuronal FKBP5 is significantly associated with CM pathogenesis. FKBP5 sustains mechanical allodynia by activating the NF-κB-mediated neuroinflammatory cascade. Consequently, targeting FKBP5 represents a promising therapeutic strategy for CM.

Intercellular mitochondrial transfer has recently emerged as an important concept in bone biology, providing a new framework for understanding immune–metabolic cross-talk within the bone microenvironment. This microenvironment is a dynamic system that is both metabolically active and immunologically complex, and its homeostasis relies on finely tuned communication among multiple cellular populations. Increasing evidence suggests that mitochondrial transfer is a key mechanism integrating these diverse signaling networks. In this review, we systematically summarize recent advances in mitochondrial transfer among osteolineage cells, immune cells, and vascular-associated cells, and we further discuss its multiple roles in bone remodeling, tissue repair, and the pathogenesis of osseous diseases. At the mechanistic level, special emphasis is placed on the Mitochondrial Rho GTPase 1 (MIRO1)-mediated mitochondrial transport pathway, through which mitochondria are transferred from osteolineage cells to myeloid cells, thereby driving metabolic reprogramming and modulating susceptibility to ferroptosis, ultimately helping to suppress excessive osteoclastogenesis. From a pathological perspective, dysregulated mitochondrial transfer is increasingly recognized as a common feature across a range of skeletal disorders. In glucocorticoid-induced osteoporosis (GIOP), impairment of MIRO1-dependent mitochondrial transport promotes ferroptosis resistance in osteoclast precursors. In osteoarthritis, aberrant mitochondria accelerate cartilage degeneration by disrupting coenzyme A (CoA) metabolism through Nudix Hydrolase 8 (NUDT8) and subsequently activating the cGAS–STING signaling pathway. In bone metastasis, inflammatory signals triggered by mitochondrial deoxyribonucleic acid (mtDNA) release exhibit both pro-tumorigenic and anti-tumorigenic regulatory effects. Based on these mechanisms, this manuscript also critically evaluates the translational potential of several therapeutic strategies, including mesenchymal stem cell-derived mitochondrial transplantation, nanocarrier delivery systems, and the modulation of tunneling nanotubes. Overall, targeting intercellular mitochondrial transport may offer new therapeutic opportunities for metabolic intervention and immunomodulation in bone diseases.

Intervertebral disc degeneration (IDD) is a major contributor to chronic low back pain, with its pathological mechanisms closely linked to an imbalance in macrophage polarization within the immune microenvironment. Macrophages are broadly categorized into two phenotypes: pro-inflammatory M1 and anti-inflammatory/restorative M2. The dynamic equilibrium between these subsets profoundly influences IDD progression. M1 macrophages exacerbate disc degeneration by secreting pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and activating NF-κB and MAPK signaling pathways, thereby amplifying inflammatory responses, apoptosis, matrix degradation, and oxidative stress. Conversely, M2 macrophages promote tissue repair and extracellular matrix (ECM) remodeling through anti-inflammatory mediators such as IL-10 and TGF-β. Emerging therapeutic strategies, including pharmacological interventions (e.g., ROS scavengers, COX-2 inhibitors), biomaterials (e.g., smart hydrogels, engineered exosomes), and multimodal therapies (e.g., gene editing combined with immune-metabolic modulation), demonstrate significant translational potential. However, challenges persist, including the impact of the disc-specific microenvironment (hypoxia, nutrient deprivation, mechanical stress) on polarization efficiency, drug delivery limitations, and fibrosis risks. Future research should focus on resolving macrophage subpopulation heterogeneity, achieving precise polarization regulation, and optimizing clinical translation to advance immunometabolic therapies for IDD.

The persistent headaches characteristic of chronic migraine may stem from the activation and sensitization of primary afferent neurons within the trigeminovascular pathway. However, the underlying molecular mechanisms remain unclear. This study shows a SET-domain bifurcated histone lysine methyltransferase, SETDB2, in trigeminal ganglion (TG) neurons as a key mediator of migraine-like pain. In a mouse model of chronic migraine induced by nitroglycerin (NTG), SETDB2 is significantly upregulated in TG neurons, a finding mirrored in cerebrospinal fluid from patients with migraine. Reversing this upregulation reduces levels of the repressive histone mark H3K9me3 and alleviates migraine-like pain behaviors in mice, whereas mimicking it induces hypersensitivity. Mechanistically, SETDB2 upregulation impedes transcription factor KLF4 from binding to the promoter of the insulin-degrading enzyme (Ide) gene, thereby suppressing IDE expression and impairing degradation of calcitonin-gene-related peptide (CGRP) in TG neurons. Targeting the sensory SETDB2-KLF4-IDE transcriptional axis may present therapeutic opportunities for treating migraine.

BackgroundAbnormal interoception is increasingly recognized as a key feature of migraine. The dorsal anterior insula (dAI) is hypothesized to play a central role in interoceptive processing, yet the neural mechanisms underlying this abnormality remain unclear. We aimed to investigate interoceptive disturbances in migraine and to clarify the role of insula dysfunction, specifically dAI functional connectivity, in underlying these interoceptive alterations and potentially contributing to the pathophysiology of migraine.MethodsWe recruited 29 patients with migraine without aura and 32 matched healthy controls. All participants completed evaluations of interoceptive accuracy and resting-state functional magnetic resonance imaging scans. We applied a multivariate seed-based connectivity approach to examine the direct connectivity of the bilateral dAI and its link to interoceptive awareness in migraine patients. We conducted a simple mediation analysis to determine whether specific dAI connectivity mediated variations in interoceptive awareness across groups. Finally, serial multiple mediation analysis was applied to explore whether these effects were conveyed via subjective or objective accuracy metrics.ResultsMigraine patients showed significantly enhanced interoceptive accuracy awareness compared with controls. Across all participants, this awareness was positively associated with functional connectivity from the right dAI to the bilateral precentral gyrus (PreCG). Crucially, this specific right dAI-bilateral PreCG connectivity was markedly enhanced in migraine patients. Simple mediation results indicated that increased dAI connectivity substantially mediated the group difference in interoceptive accuracy awareness. Serial multiple mediation analysis revealed that this effect was predominantly driven by objective interoceptive processing.ConclusionsThe observed altered dAI connectivity and its relationship with interoceptive awareness suggest that dysfunctions in interoceptive processes, particularly within the dAI-PreCG network, may be integral to the neuropathology of migraine.

BACKGROUND Migraine is increasingly recognized as a network disorder involving distributed structural and functional brain alterations. However, regional changes in the relationship between resting-state activity and white-matter organization remain unclear. We used the structural decoupling index (SDI), a graph signal processing measure of structure–function alignment, to characterize regional coupling alterations in migraine. METHODS After quality control, 108 participants (41 with episodic migraine [EM], 31 with chronic migraine [CM], and 36 healthy controls [HCs]) underwent resting-state functional, diffusion, and T1-weighted MRI. Regional SDI was computed for 246 Brainnetome regions using individual RD-weighted structural graphs. Group differences were tested by age- and sex-adjusted ANCOVA with Benjamini–Hochberg FDR correction. Partial Spearman correlations examined associations between clinical measures and SDI in regions differing between EM and CM, adjusting for age, sex, and migraine subtype. Exploratory classification used class-weighted linear SVMs with repeated nested fivefold cross-validation. PLS regression related the unthresholded migraine–HC SDI t-map to Allen Human Brain Atlas gene-expression data, followed by enrichment analysis of genes with positive and negative PLS1 weights. RESULTS Compared with HCs, patients with migraine had lower SDI in the left superior frontal gyrus and higher SDI in the right inferior temporal gyrus. Three-group analyses additionally identified differences in the left lateral occipital cortex, where CM showed lower SDI than EM; lower values were associated with more monthly migraine days. Regional SDI features showed preliminary discrimination, strongest for CM versus HCs (AUC = 0.866). Positive PLS1-weighted genes were enriched in chromatin regulation, transcriptional control, and RNA metabolism, whereas negative-weighted genes were enriched in mitochondrial energy metabolism, oxidative phosphorylation, ribosome-associated quality control, and calcium signaling. CONCLUSIONS This first application of SDI to migraine revealed bidirectional hierarchical structure–function disruptions across prefrontal, temporal, and occipital regions. Lower lateral occipital SDI was associated with more monthly migraine days, while regional SDI features showed preliminary within-sample discrimination, strongest for CM versus HCs (AUC = 0.866). Transcriptomic enrichment implicated chromatin regulation and mitochondrial energy metabolism. SDI may provide a useful framework for characterizing hierarchical brain network dysfunction in migraine.

Patient-derived organoid (PDO) is a kind of three-dimensional models constructed through in vitro three-dimensional culture systems that can highly mimic the characteristics of patients' tumors, often referred to as "mini-organs". These models can not only recapitulate the genetic, phenotypic and metabolic diversity of patient tumors but also effectively simulate the tumor microenvironment (TME) and heterogeneity. They provide an ideal platform for fundamental research, including exploring tumor drug resistance mechanisms, studying the dynamic processes of disease initiation and progression and discovering and functionally validating novel drug targets. In the era of precision medicine, PDO demonstrates significant potential in guiding clinical medication decisions, optimizing new drug development pathways and reshaping the design of clinical trials. The core of precision medicine lies in moving beyond the traditional "one-size-fits-all" diagnostic and treatment model, instead formulating personalized treatment plans based on individual patient differences in genetics, environment and lifestyle. With advances in genomics and sequencing technologies, next-generation sequencing (NGS)-based testing has become version 1.0 of precision medicine. However, the high heterogeneity of tumors, the complexity of the TME and the limitations of existing detection technologies-such as sample homogenization and insufficient tumor cell content-hinder their precise clinical application. PDO, as a class of high-fidelity in vitro three-dimensional models, has opened a new chapter-version 2.0 in precision medicine. PDO serves not only as a powerful basic research platform for studying the TME, drug resistance mechanisms and discovering new biomarkers, but also exhibits tremendous potential in clinical translation. In preclinical research, PDO is widely used for high-throughput drug screening, exploring combination therapy strategies and assessing drug safety. They enable efficient prediction of drug efficacy, differentiation between synergistic and antagonistic effects, and evaluation of toxicity risks to normal tissues. In clinical research, the potential applications of PDO span the entire process of drug development and individualized treatment, including assisting in the selection of lead indications, dose estimation, patient screening, sample size calculation and expanding new drug indications. Furthermore, PDO demonstrates unique value in predicting the efficacy of cell therapies ［such as chimeric antigen receptor T (CAR-T) cell therapies］, assessing radiosensitivity and co-culturing with other immune cells to develop novel therapeutic approaches. Multiple expert consensus statements have been established both domestically and internationally, dedicated to promoting the standardization and clinical application of organoid drug sensitivity testing. The concept of "one organoid equals one patient" is gradually becoming a trend, aiming to overcome the limitations of genomic information by directly testing drugs on PDO as "in vitro avatars" of patients, thereby achieving more precise guidance for individualized treatment. Since its inception in 2009, organoid technology has evolved from building basic models to deep integration with technologies such as single-cell sequencing, microfluidic chips and gene editing. The complexity and application breadth of these models continue to expand. Today, organoid technology plays an increasingly vital role in precision medicine, drug development and regenerative medicine. Looking ahead, with model optimization, standardization and the accumulation of clinical evidence, PDO is expected to play an even more central role in personalized cancer therapy and new drug development. We are on the verge of entering a new “organoid era”.

Chronic migraine (CM) severely affects patients’ work and daily life, imposing a significant economic burden. However, the underlying neural mechanisms of migraine chronification remain unclear. This study aimed to characterize temporal neural dynamics patterns of migraine via magnetoencephalography (MEG) combined with dynamic network mode (DyNeMo), providing further neuroimaging evidence for migraine chronification. This cross-sectional study recruited patients with episodic migraine (EM), CM, and healthy controls (HC). MEG data were acquired during resting and somatosensory stimulation states. The DyNeMo model was applied to source-reconstructed MEG data to quantify temporal neural dynamics metrics, including mean lifetime, mean interval, switching rate and fractional occupancy. Permutation-based analysis of covariance (ANCOVA) with Bonferroni correction and Spearman correlation with false discovery rate (FDR) correction were applied. Six distinct brain modes were identified: visual network (VN), anterior and posterior default mode networks (aDMN/pDMN), right and left sensorimotor networks (rSMN/lSMN), and auditory network (AN). During resting state, EM showed prolonged mean lifetime and decreased switching rate of the VN vs. HC; CM showed increased switching rate of the VN vs. EM; CM showed prolonged mean lifetime and decreased switching rate of the AN vs. HC. During somatosensory stimulation state, both EM and CM showed prolonged mean lifetime and decreased switching rate of the AN vs. HC. In CM patients, longer duration of disease was correlated with shorter mean lifetime and higher switching rate of the AN during somatosensory stimulation state. This study identifies distinct alterations in the temporal dynamics of VN and AN in EM and CM. Abnormalities in AN were observed during both resting and somatosensory stimulation states, while disease duration in CM was associated with altered temporal metrics of the AN. These cross-sectional findings support the involvement of altered sensory and cross-modal network processing in migraine and warrant longitudinal validation.

Chronic migraine is characterized by recurrent trigeminovascular activation, cutaneous allodynia, and central sensitization. Mitochondrial dysfunction and impaired calcium handling may contribute to migraine chronification, but whether these processes are modified by Yangxue Qingnao (YXQN), a traditional Chinese medicine used for headache disorders, remains unclear. Here, a chronic migraine mouse model was induced by intraperitoneal nitroglycerin (NTG) injections on alternate days for 9 days. Migraine-like behaviors, trigeminal nucleus caudalis (TNC) neuropeptide expression, neuronal activation, proteomic profiling, mitochondrial function, and electrophysiological properties were assessed. YXQN attenuated migraine-like phenotypes, reduced TNC calcitonin gene-related peptide (CGRP) levels and c-Fos neuronal activation in TNC region. Proteomic analysis identified exploratory changes in mitochondrial- and calcium-transport-related pathways. YXQN treatment was accompanied by improvements in selected mitochondrial structural and functional measures, reduced calcium-associated fluorescence signals, and attenuated TNC neuronal hyperexcitability. These findings support further investigation of mitochondrial calcium handling and TNC neuronal excitability as potential contributors to the effects of YXQN.

PURPOSE. Mitochondrial dysfunction is increasingly recognized as a pivotal factor in cancer pathogenesis. We thus explored the causal role of mitochondrial-related genes (MRGs) in uveal melanoma (UM) and the underlying mechanisms. METHODS. We performed Mendelian randomization (MR) analysis using 1693 cis-expression quantitative trait loci (cis-eQTLs) of MRGs as instrumental variables and genome-wide association data (GWAS) of UM. Colocalization analysis assessed whether gene expression and UM risk shared a common causal variant. Further, mediation MR and in vitro functional assays were used to validate key findings and explore their biological relevance. A molecular docking-based virtual screening strategy, followed by experimental validation, was used to identify potential therapeutic compounds. RESULTS. MR analysis identified 57 MRGs significantly associated with UM risk after Bonferroni correction (P < 0.05/1693). Among them, MTG2 or GTPBP5, encoding a mitochondrial ribosome-associated GTPase, showed strong colocalization with UM susceptibility (PP.H4 = 75%). Silencing MTG2 in UM cell lines induced PARP cleavage and markedly suppressed cell proliferation and colony formation. Mediation analysis revealed that mitochondrial DNA (mtDNA) heteroplasmy at chrM:567 (A:ACCCCCC) partially mediates MTG2's effect on UM (4%). Moreover, both genetically driven analysis and qPCR confirmed a positive association between MTG2 expression and mtDNA copy number. Notably, dimercaptosuccinic acid (DMSA), identified as a potential MTG2 inhibitor, reduced MTG2 levels and promoted apoptosis in UM cells. CONCLUSIONS. Our integrative genomic and experimental approach uncovers MTG2 as a causal contributor to UM pathogenesis, potentially through modulation of mtDNA heteroplasmy and copy number. DMSA emerges as a promising therapeutic agent targeting mitochondrial dysregulation in UM.