Fatty acid metabolism (FAM) plays a vital role in maintaining health by supporting energy production, cellular structure, and signaling processes. However, once this tightly regulated network becomes disrupted, it is increasingly recognized as being linked to the onset and progression of numerous chronic diseases, with cancer being one of the most prominent and clearly defined examples. In addition to the field of oncology, alterations in FAM can also lead to immune dysfunction, inflammatory responses, and metabolic disorders, including diabetes, cardiovascular disease, and neurodegenerative diseases. We examine how different cell types adapt their metabolic behavior within inflamed and tumor-rich environments, often leveraging FAM to support survival or suppress immune activity. By highlighting recent discoveries in metabolic regulation, intercellular communication, and disease-specific lipid signatures, we identify new opportunities for therapeutic intervention. These include targeted drugs, gene therapies, nanomedicine platforms, and dietary strategies aimed at restoring metabolic balance. We also discuss the emerging role of fatty acid-related biomarkers in advancing precision oncology and broader applications in personalized medicine. Together, these insights underscore the centrality of FAM in human health and disease, with particular emphasis on its growing promise as a therapeutic target in cancer and beyond.

Du T, Liu R, Zhang X, Shen L, Tang C, Wang J, Cheng Y, Yu W, Yin B, Lu S, Pan X, Peng X. Lycorine Derivative Inhibits SARS-CoV-2 Replication by Reducing −1 Programmed Ribosomal Frameshifting via Targeting ZAP. MedComm. 2026; DOI: 10.1002/mco2.70715

In the originally published version of this article, the statement indicating equal contribution among authors appeared incorrectly on the first page. The original statement read:

“Tingfu Du1, Ruixue Liu, Xintian Zhang these authors contributed equally to this work.”

This statement should have read:

“Tingfu Du, Ruixue Liu, Xintian Zhang and Longying Shen contributed equally to this work.”

We apologize for this error.

Antiangiogenic therapy remains a challenging issue in the treatment of glioblastoma (GBM). Effective therapies are in urgent need to improve prognosis of GBM patients. The high heterogeneity of GBM is both the cause of its unavoidable therapeutic resistance and the result of extensive genomic dysregulation, of which abnormal transcription factor (TF) networks are recognized to be the culprit. Herein, based on the heterogeneity of GBM, we identified the key TF serum response factor (SRF), which is closely associated with the formation of the GBM vascular microenvironment, from a large-scale dataset. Mechanistically, the 133–240aa region of SRF binds to the transcriptional cofactor P54nrb and undergoes phase separation to form a transcription complex, which upregulates OLFML3 by binding to its enhancer and promoter regions. The secreted extracellular matrix (ECM) glycoprotein OLFML3 activates endothelial cells (ECs) by degrading and remodeling the ECM, releasing proangiogenic factors, promoting intercellular adhesion, and directly acting on ECs to promote angiogenesis. The hyperplasia vasculature, in turn, promotes the infiltration of M2-polarized macrophages, leading to the formation of an immunosuppressive microenvironment. This study comprehensively elucidates the pivotal role of SRF in GBM angiogenesis. Targeting the SRF/P54nrb/OLFML3 axis holds promise for developing novel antiangiogenic strategies to improve GBM treatment outcomes.

Prostate cancer (PCa) is frequently accompanied by benign prostatic hyperplasia (BPH), highlighting the need to reassess their correlation in tumor risk, malignant progression, and immune status to improve the early diagnosis and treatment of PCa. In this study, single-cell RNA sequencing and spatial transcriptomics were used to analyze the potential association between normal, BPH, and PCa tissues. Our study revealed a continuous transformation map of luminal epithelial cells from hyperplasia to malignancy in BPH and PCa, accompanied by a persistently suppressive immune microenvironment. In the lesion nodules, T cells showed a high degree of infiltration yet showed activation retardation and functional exhaustion. Macrophages were also significantly infiltrated, exhibiting significant M2 polarization characteristics, and inflammatory signaling pathways related to immune escape were activated. Natural killer (NK) cells and B cells were partially activated, yet the low abundance of NK cells and B cells resulted in functional limitations. Our results revealed the dynamic changes of the immune landscape during the occurrence and progression of PCa. Our classification and prognostic models provide a theoretical basis for immunomodulatory and personalized therapies and provide new tools for the early diagnosis and intervention of PCa.

Scarring results in significant developmental, functional, aesthetic, and psychological challenges. Despite substantial demand from patients and healthcare providers, no drugs or biologics are currently approved specifically for preventing or reducing scarring. Our previous studies indicate that fibromodulin (FMOD) modulates adult dermal fibroblasts to adopt fetal-like characteristics, thereby improving wound appearance, reducing scar size, and enhancing tensile strength in adult skin healing. To address the high costs, variability, and safety concerns of producing FMOD through mammalian cells, a novel, chemically synthesized FMOD-derived peptide, SLI-F06, has been developed. SLI-F06 retains FMOD's essential properties, such as promoting cell migration, increasing tensile strength, and stimulating antifibrotic effects. Comprehensive animal studies using models such as mice, rats, Yorkshire pigs (the standard for normal human wound healing), and red Duroc pigs (closely mimicking human proliferative and hypertrophic scarring) demonstrate significant improvements in scar appearance, tensile strength tests, and histological outcomes with SLI-F06. Additionally, a formulation buffer has been developed to maintain physiological pH and osmolality, ensuring the stability of SLI-F06 for a suitable duration in clinical settings after removal from refrigeration. SLI-F06 exhibits no genotoxicity or local or systemic toxicity in extensive studies required by the United States Food and Drug Administration for Investigational New Drug applications.

The trends in allergic comorbidities secondary to the environmental variations in China remain unclear. We aimed to determine the variation of allergic comorbidities and polysensitization among asthma and/or rhinitis patients in the past decade. We assessed two nationally representative cross-sectional datasets from 2008 to 2009 and 2018 to 2019, which enrolled 2322 and 2353 patients, respectively. Over the present 10-year study period, the prevalence of allergic symptoms and allergen sensitivity among patients with multiple sensitivities in the 2018–2019 cohort was significantly higher than that in the 2008–2009 cohort, especially for mites, pollen, and animal allergens. The comorbidity rates of asthma, allergic rhinitis, conjunctivitis, and eczema were significantly increased in the 2018–2019 cohort. Also in that cohort, IgE polysensitization was significantly associated with the coexistence of asthma and rhinitis, and the number of IgE-reactive allergens was significantly associated with the number of multimorbidities. Use of an air-conditioner and carpet in the home, and keeping pet were linked to the risk of polysensitization. Our findings suggest an increase in the comorbidity rate and multimorbid polysensitized phenotype of allergic diseases in China. Asthma occurred in both cohorts more frequently with coexisting allergies than as a single entity.

Iron (Fe) and copper (Cu) are vital micronutrients that regulate many critical physiological processes in the human body, with their homeostasis in the central nervous system (CNS) being essential for proper neuronal function. Disruptions in their metabolism and regulatory pathways have been associated with the pathogenesis of various forms of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite growing research on metal homeostasis, the intricate molecular mechanisms that link iron and copper metabolism to the initiation and progression of NDDs remain insufficiently elucidated. In this review, we provide a systematic overview of the metabolic processes of iron and copper in the body and CNS, highlighting their interactions with many metal-binding proteins, including transporters, storage proteins, and important intrinsically disordered proteins (e.g., amyloid β-protein, tau, and alpha-synuclein) involved in NDDs. We further dissect the downstream effects of metal ion dyshomeostasis on cellular redox balance, neuroinflammation, autophagy, organelle interaction network, and cell death. Additionally, we discuss current therapeutic strategies aimed at targeting iron and copper dyshomeostasis, as well as the emerging role of artificial intelligence in this field of research. By integrating metal metabolism, metal–protein interactions, the effect of metal dyshomeostasis on downstream biological processes, and potential intervention strategies, this review serves as a comprehensive reference for understanding the pathogenesis of NDDs and offers new perspectives for developing effective therapeutics. Overall, this review underscores the significance of reinstating metal balance for the treatment of neurodegeneration.

Emerging evidence highlights that N⁶-methyladenosine (m⁶A), the most prevalent internal RNA modification in eukaryotes, serves as a critical epitranscriptomic regulator of RNA metabolism. This posttranscriptional modification modulates alternative splicing, nuclear export, stability, and translation, thereby regulating various physiological processes. Notably, dysregulation of m⁶A-associated modifiers (writers/erasers/readers) is implicated in a variety of diseases, such as metabolic disorders and cancer. Despite the rapid progress of m⁶A-mediated emerging therapeutic strategies, there remains an imperative to bridge the gap between basic epitranscriptomics and clinical application. This review systematically depicts recent advances in understanding m⁶A-mediated epitranscriptomic regulation, with particular focus on its dual role in maintaining cellular homeostasis and driving disease progression upon dysregulation, provides a dedicated exploration of m⁶A-regulated mitochondrial remodeling, and outlines cutting-edge technologies for m⁶A mapping and inhibitors targeting m⁶A modifiers. Furthermore, we conduct an in-depth exploration of the existing limitations and therapeutic potential associated with targeting m⁶A modification. Acting as a pivotal link between epitranscriptomics and medicine, m⁶A modification provides novel perspectives for developing precision interventions in complex human diseases.

Organoids are three-dimensiona(3D) models derived from stem cells that closely replicate the structure and cellular complexity of human tissues, providing physiologically relevant platforms for biomedical research. This technology addresses the limitations of two-dimensional (2D) cultures, reduces species-specific discrepancies, and is particularly valuable for investigating virus–host interactions and pathogenic mechanisms under near-physiological conditions. This review systematically outlines key advancements in organoid-based virology, including the propagation of hard-to-culture pathogens such as human rhinovirus C (HRV-C) and norovirus (NoV), as well as novel insights into viral pathogenesis, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Zika virus (ZIKV) infection, and the translational utility of organoids for antiviral drug screening and preclinical assessment. It further examines the use of organoids in modeling cancer and neurological diseases, compares the strengths and limitations of different cellular sources, and discusses their potential integration with emerging technologies such as CRISPR gene editing and 3D bioprinting. In addition, it maps a translational pathway from molecular mechanisms to clinical practice to facilitate the study of disease mechanisms and accelerate drug and vaccine development. Finally, holistic strategies are proposed to address existing challenges, such as the lack of immune components and inadequate vascularization. Together, these efforts aim to promote the broader adoption of organoid technology across the life sciences and translational medicine.

Neutrophils are the most abundant innate immune cells and are pivotal first responders in host defense, playing an important role in maintaining body homeostasis and regulating pathological conditions. Growing evidence indicates that neutrophils exhibit functional heterogeneity and participate in immune regulation through processes such as neutrophil extracellular trap formation (NETosis). These findings have expanded the traditional view of neutrophils as short-lived effector cells. Nevertheless, how distinct neutrophil states are temporally coordinated during disease development, and how this coordination may be therapeutically exploited, remains insufficiently understood. In this review, we provide a comprehensive overview of neutrophil biology, focusing on functional heterogeneity, NETosis, and their roles in infectious diseases, autoimmune disorders, and cancers. We further discuss emerging therapeutic strategies targeting neutrophils, as well as advanced technologies that have enabled high-resolution characterization of neutrophil states and functions. Building on the evidence above, the concept of “neutrophil immune clock” is proposed to describe the temporal changes in neutrophil-mediated immune responses. A time-resolved perspective on neutrophil responses may offer new insights into disease progression and support the development of neutrophil-targeted strategies for disease prevention and therapy.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by targeting crucial coinhibitory pathways. Pathways involving PD-1/PD-L1 and CTLA-4 are essential for immune homeostasis but are frequently exploited by tumors to evade immune surveillance. ICIs block these interactions, unleashing a potent antitumor immune response. However, broad clinical efficacy is limited by low response rates, immune-related adverse events, and the pervasive challenge of primary or acquired resistance. This review summarizes the fundamental molecular mechanisms of key checkpoints (PD-1/PD-L1, CTLA-4, TIM-3) and highlights recent clinical progress in ICI monotherapies and combination strategies. We systematically explore multifaceted mechanisms of resistance, encompassing both tumor-intrinsic and extrinsic factors. Furthermore, we outline novel therapeutic approaches being designed to overcome this resistance. Finally, we discuss promising predictive biomarkers and precision immuno-oncology strategies. This review provides a critical framework for navigating the current landscape and offers a rationale to guide the future development of effective combination therapies to improve patient outcomes.

Gastric cancer (GC) remains a formidable global health challenge, characterized by pronounced molecular heterogeneity, late-stage diagnosis, and limited durable responses to existing therapies. This review synthesizes recent advances in GC research through an integrated, multidisciplinary lens, spanning tumor biology, microenvironmental dynamics, and therapeutic innovation. We first consolidate updated histopathological and molecular classification systems, highlighting oncogenic programs that underpin GC development, including Hippo-YAP signaling and emerging neural–stem cell interactions. We then examine the immunosuppressive tumor microenvironment, emphasizing the dynamic crosstalk among tumor-associated macrophages, regulatory T cells, tertiary lymphoid structures, and cancer-associated fibroblasts that collectively drive metastatic dissemination and therapeutic resistance. Emerging biomarker-guided strategies, including CLDN18.2-targeted therapies, dual immune checkpoint blockade, and engineered cellular therapies, are critically discussed alongside rational combination approaches designed to overcome resistance. Beyond canonical paradigms, we highlight transformative frontiers, such as cancer neuroscience, microbiome-driven immune modulation, and spatially resolved multiomics technologies, that enable high-resolution mapping of cellular interactions. Finally, we critically assess translational barriers, including organ-specific metastatic tropism and resistance evolution, and propose that the convergence of deep molecular profiling, neural-immune modulation, and AI-enabled computational oncology will be central to advancing precision medicine for GC. This integrated framework aims to accelerate the development of mechanism-based combination therapies.

Radiomics enables high-throughput extraction of quantitative imaging features to decode tumor phenotypes and biological behaviors, representing a transformative noninvasive tool for precision oncology. In recent years, radiomics has rapidly evolved from static feature analysis to dynamic multi-dimensional assessment, and it has been widely explored in various solid tumors, yet its pan-cancer generalization, biological interpretability, and clinical translation still face prominent bottlenecks. Cancer remains the leading cause of global mortality, and solid tumors account for more than 90% of adult malignant cases, while conventional medical imaging and invasive biopsies have inherent limitations in reflecting tumor heterogeneity and dynamic evolution. This review outlines the unified technical pipeline of radiomics across solid tumors, highlights cancer-specific imaging considerations, and summarizes standardization strategies for multi-center, multi-scanner, and multi-cancer heterogeneity. We systematically review pan-cancer clinical applications covering early detection, molecular characterization, treatment response prediction, and prognostic stratification, with lung cancer as a paradigmatic example while integrating evidence from breast, colorectal, liver, glioma, and prostate cancers. We also discuss multi-omics integration, biological interpretability, and translational bottlenecks including domain shift and reproducibility crisis. Finally, we prospect cutting-edge directions including foundation models, causal inference, and federated learning to advance generalizable and clinically actionable radiomics toward routine clinical practice.

Cardiovascular diseases (CVDs) arise as the product of multiple factors, including genetic predisposition and environmental exposure, but the molecular and cellular interplays underlying such a pathogenetic process leading to sustained pathological conditions remain largely unknown. A growing body of evidence indicates that epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, noncoding RNAs, and RNA modifications, are important for cardiovascular development, adaptation, and disease. However, findings from these studies are fragmented across different genomic contexts or disease-focused scenarios, lacking systematic integration for a global view connecting epigenetic dynamics to cardiovascular phenotypes and their clinical implications. An overall picture of epigenetic modulation in CVDs is therefore provided. Common epigenetic mechanisms are described in a cell type and disease stage-specific context, and the roles of environmental and lifestyle factors in remodeling the cardiovascular epigenome are illustrated. Novel epigenetic biomarkers and therapeutic interventions are also assessed. Emphasis is placed on epigenomic plasticity, enhancer focused control, and network-level reprogramming as key concepts that drive disease remodeling. By unifying mechanistic understanding with translational evidence, this review frames CVD as a disorder of stabilized regulatory states and defines avenues for precision epigenomic manipulation.

The immune system operates within organized tissue landscapes, where spatial relationships between cells shape the nature and outcome of immune responses. Over the past decade, protein imaging-based spatial technologies have transformed how immune responses are studied within their native tissue context, enabling simultaneous high-plex detection of proteins and transcripts at single-cell resolution. Driven by advances in computational methods such as tissue image cytometry, these approaches now allow quantitative extraction of spatial metrics such as cellular neighborhoods, cell–cell distances, coexpression patterns, and tissue architecture that are emerging as next-generation spatial biomarkers of immune function and disease diagnosis and/or prognosis. This review provides a consolidated overview of immunology through the lens of imaging-based spatial proteomics and tissue image cytometry, discussing the multiplex imaging platforms, staining strategies, and computational tools that enabled this shift. We survey applications spanning tumor immunology, autoimmune and infectious diseases, immunometabolism, neuroimmunology, and transplant immunology, revealing that immune organization is not random but spatially determined and directly linked to disease outcome. We further evaluate the strengths and limitations of current approaches and explore future directions including 3D imaging, artificial intelligence-driven spatial analysis, and the clinical translation of spatial biomarkers.

X. Chen, Y. Yuan, F. Zhou, et al., “Lactylation: From Homeostasis to Pathological Implications and Therapeutic Strategies,” MedComm 6, no. 6 (2025): e70226, https://doi.org/10.1002/mco2.70226.

On Page 6, in the third paragraph, the statement ″This delayed temporal dynamic effect has been metaphorically described as a “lactate clock.” should have been supported by the following reference [1]. On Page 6, in the fourth paragraph, the statement “The level of lactylation can be influenced by various factors, including the production and transport of substrate lactate, the acyltransferases providing the lactyl group, neural excitation, gene expression, and the stimulation of certain traditional Chinese medicine components” should have been supported by the following reference [2]. On Page 6, in the fifth paragraph, the statement “Zhang et al. proposed that lactylation is derived from lactate; methods such as using gamma-interferon combined with lipopolysaccharide or bacterial stimulation can increase lactate production in cells” should have been supported by the following reference [3]. On Page 7, in the second paragraph, the statement “However, Hagihara et al. induced histone H1 lactylation in mouse neuronal cells using different methods and then treated them with the MCT2 inhibitor α-cyano-4-hydroxycinnamate (4-CIN) and the more selective MCT1/2 inhibitor AR-C155858, finding no significant changes in lactylation levels, suggesting the possible concurrent occurrence of an indirect lactylation pathway not inhibited by MCT inhibitors” should have been supported by the following reference [4]. On page 7 in the third paragraph, the statement “The acetyltransferase family has broad acyltransferase activity, utilizing different acyl-CoAs as substrates for lysine acylation of various histones.” should have been supported by the following reference [5]. On Page 8, in the third paragraph, the statement “The study of lactylation's crosstalk with other modifications is still in its early stages.” should have been supported by the following reference [6]. On page 8 in the third paragraph, the statement “Evidence shows a close relationship between lactylation and acetylation.” should have been supported by the following reference [7]. On page 8 in the third paragraph, the statement “Histone lactylation and acetylation exhibit a high degree of spatial overlap, and lactylation levels increase as acetylation decreases” should have been supported by the following reference [1]. On Page 8, in the third paragraph, the statement “Lactylation serves as an intermediary linking metabolism and epigenetics, with crosstalk phenomena present in its modification process” should have been supported by the following reference [8].

The omission does not affect the overall conclusions of the paper. The authors apologize for this oversight.

Xiulin Jiang's current contact details: xiulinjiang17@163.com, UF Health Cancer Center, University of Florida, Gainesville, FL, USA.

Natural products, owing to their unique biological activities, possess the ability to interact with specific target proteins or regulatory networks, representing a valuable source of innovative drug candidates. However, target identification remains a major bottleneck in natural product-based drug discovery, largely because of the chemical complexity of natural products and the heterogeneity of biological systems. To address these challenges, various complementary strategies have been developed, including experimental strategies such as chemical proteomics, and computational methods such as artificial intelligence-driven methods. Nevertheless, reliably advancing a candidate protein hit to a therapeutically relevant and physiologically validated target remains a critical challenge. Focusing on technologies for natural product target discovery, this review systematically summarizes the principles, methodologies, and practical applications of current approaches. Through representative case studies, we further propose a reusable integrated experimental–computational workflow and illustrates how key targets and their modes of action can be identified in real-world research scenarios. In addition, we discuss common technical and conceptual bottlenecks encountered during target discovery and proposes potential countermeasures. The review provides an actionable reference framework for natural product target identification, with the goal of reducing false-positive findings and fragmented evidence, thereby improving the robustness of mechanism-oriented studies and facilitating subsequent translational research.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), remain critical conditions with persistently high mortality. The failure to develop effective pharmacotherapies stems largely from reductionist approaches focused on isolated linear pathways. This review synthesizes recent breakthroughs redefining ALI as dysregulation of integrated pathological networks spanning immunity, metabolism, and cell death. We systematically analyze three interconnected core circuits: cGAS–STING as a central danger signal integrator, immunometabolic reprogramming as fuel for sustained inflammation, and the programmed cell death network—particularly PANoptosis—as executor of tissue damage. We further elucidate how ALI manifests as a multiorgan communication disorder, with the brain and gut actively shaping pulmonary inflammation. The convergence of single-cell technologies, multiomics profiling, and computational modeling has deconstructed ARDS heterogeneity into clinically actionable endotypes (hyperinflammatory C1, hypoinflammatory C2) with differential treatment responses. This network-based understanding is catalyzing a therapeutic shift toward rationally designed poly-pharmacology, precision immunotherapies, and advanced platforms integrating smart nanomaterials with endogenous systems. By embracing this holistic perspective, we chart a course toward mechanism-based, personalized interventions that move beyond supportive care to genuine disease modification.

The wider application of posttransplant cyclophosphamide (PTCY) and granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocols has revolutionized haploidentical hematopoietic stem cell transplantation (haplo-HSCT) by decreasing graft-versus-host disease and facilitating engraftment. In this study, we compared the clinical outcomes and the immune reconstitution of propensity score-matched (1:1:1) patients receiving PTCY (n = 45), ATG (n = 45), or PTCY plus ATG (n = 45). Patients in the ATG group had significantly higher overall survival (OS) (p = 0.029) and leukemia-free survival (LFS) (p = 0.034). CD3⁺ (p < 0.01) and CD8+ T-cell counts (p = 0.02) were greater at 3 months after transplantation in the ATG group. After adjustment for relevant covariables, Cox models revealed a significant association between CD8⁺ T-cell reconstitution and OS in all patients (p = 0.008); CD8+ T-cell recovery and LFS showed a similar trend (p = 0.034). Sensitivity analysis revealed stable results. Restricted cubic spline curve analysis to visualize the relationship between immune reconstitution and outcomes revealed that the CD8⁺ T-cell count at 3 months post-HSCT strongly correlated with survival prognosis. These findings demonstrate that conditioning regimens profoundly impact immune reconstitution, which may contribute to differences in survival prognosis. Moreover, increasing the probability of CD8⁺ T-cell reconstitution after HSCT may become an important strategy for improving outcomes.

Crocin shows cardioprotective potential against chemotherapy-related cardiotoxicity, but clinical evidence for cycle-synchronized intervention remains limited. This randomized, double-blind, placebo-controlled trial investigated whether crocus total glucosides tablets (CTGT) administered synchronously with chemotherapy could prevent cancer therapy-related cardiac dysfunction (CTRCD) in breast cancer patients. A total of 120 patients were randomly assigned (1:1) to receive either CTGT or placebo for 8 days/cycle, starting 1 day before chemotherapy. Primary endpoints were 6-month relative decline in left ventricular global longitudinal strain (ΔLVGLS%) and change in left ventricular ejection fraction (ΔLVEF); secondary endpoints included 3-month measures, LVEF and LVGLS, CTRCD incidence [LVEF<50% or ΔLVGLS%>15% or elevated high-sensitivity cardiac troponin I (hs-cTnI)/N-terminal pro-B-type natriuretic peptide (NT-proBNP)], and severe arrhythmias. Based on the intention-to-treat analysis, CTGT significantly attenuated the 6-month ΔLVGLS% compared with placebo (−6.55 ± 10.85 vs. −12.63 ± 13.49%, p = 0.009), whereas ΔLVEF did not differ significantly (−3.67 ± 5.75 vs. −2.40 ± 5.47%, p = 0.220). Similar results were observed at 3 months (ΔLVGLS%: −3.91 ± 10.18 vs. −7.76 ± 10.64%, p = 0.047). CTGT also reduced the proportion of patients with ΔLVGLS%>15% (18.3 vs. 40.0%, p = 0.009) and the incidence of CTRCD (21.7 vs 46.7%, p = 0.004). An 8-day, cycle-synchronized CTGT regimen attenuates LVGLS decline and reduces CTRCD incidence, highlighting its cardioprotective effect during breast cancer chemotherapy (NCT05504148).

The composition of the gut microbiota changes throughout life and is shaped by various external influences, particularly major physiological stressors such as surgery. The extent of these changes and their impact remain poorly understood. This prospective cohort study aimed to investigate changes in the gut microbiota following colorectal surgery and to identify factors that modify these alterations. Paired pre- and postoperative stool samples from 59 patients at the University Medical Centre Freiburg were analyzed using 16S rRNA and ITS2 gene sequencing. Analyses included alpha and beta diversity, LEfSe differential feature analysis, network analysis with Louvain clustering, KEGG pathway annotation, and correlation with clinical parameters. Bacterial diversity significantly decreased postoperatively (Shannon index: p < 0.001), while fungal diversity remained largely unchanged (p > 0.05). Beta diversity revealed increased inter-patient variability in bacterial communities after surgery (PERMANOVA p = 0.001). Preoperative network analyses identified 18 microbial network clusters and interkingdom associations between bacteria and fungi. KEGG pathway mapping showed cluster-specific metabolic profiles, including enrichment in degradation pathways, antimicrobial resistance mechanisms, and bacterial secretion systems. The contrasting responses of bacterial and fungal communities highlight the importance of considering the entire gut microbiome in perioperative care and suggest a central role for interkingdom interactions in maintaining gut homeostasis during surgical recovery.

Inducible T cell costimulator ligand (ICOSLG) regulates T cell functional states, yet its role in small cell lung cancer (SCLC) remains poorly characterized. By integrating multiple cohorts, we found that high tumor-intrinsic ICOSLG was associated with poor overall survival (OS) in the TU-SCLC cohort (p = 0.010) and the Wang et al. cohort (p < 0.001), and was associated with inferior efficacy to chemo-immunotherapy (hazard ratio [HR] = 2.66, p = 0.008). Consistently, the ICOSLG high subgroup exhibited significantly reduced functional CD8⁺ T cell infiltration, elevated exhausted CD8⁺ T cells, decreased effector molecules such as GZMK and IFNG, and enrichment of malignant pathways, including hypoxia, epithelial–mesenchymal transition, and others. Meanwhile, the correlation between ICOSLG and NEUROD1 expression was observed. On the contrary the subgroup high in ICOS, the main ICOSLG receptor, harbored NOTCH pathway mutations, showed an inflamed tumor microenvironment, better prognosis, and prolonged OS with chemo-immunotherapy (HR = 0.52, p = 0.003). Dual ICOSLG and ICOS stratification revealed that the ICOSLG low and ICOS high subgroup derived the greatest benefit from chemo-immunotherapy (median OS: 17.2 vs. 9.8 months; p < 0.001). Collectively, this dual-stratification strategy refined patient selection for chemo-immunotherapy, unveiled actionable targets, and ultimately advanced precision immunotherapy in SCLC.

Three-dimensional (3D) bioprinting offers a suitable in vitro preclinical model system to reduce or replace animal experiments; however, published studies are difficult to compare. In this study, we characterized growth dynamics, tissue architecture, and mammalian target of rapamycin (mTOR) pathway activity in a 3D bioprinted breast carcinoma model of T47D cell line and compared these features with conventional two-dimensional (2D) monolayer cultures. Tissue-mimetic structures (TMSs) were generated by 3D bioprinting and analyzed for cell viability, proliferation, autophagy, and apoptosis, as well as the expression of cell–cell and cell–extracellular matrix (ECM) adhesion proteins. In addition, mTOR pathway activity and responsiveness to mTOR inhibitors (rapamycin and ipatasertib) and chemotherapeutic agents (cisplatin) were assessed. The bioprinted TMSs remained viable for up to 3 weeks and developed a tissue-like architecture characterized by heterogeneous marker expression (β-catenin, E-cadherin, N-cadherin, fibronectin, and syndecan) and complex cellular organization. Compared with 2D monolayer cultures, 3D TMSs exhibited reduced mTOR signaling activity, which led to significantly decreased sensitivity to mTOR inhibition. These findings indicate that 3D bioprinted breast cancer models recapitulate key structural and signaling features of in situ tumors more accurately than 2D systems, highlighting their potential value for preclinical drug testing and mechanistic studies.

Preeclampsia, a severe pregnancy-induced disorder unique to humans, affects ∼2%–8% of pregnancies globally. Strong evidence supports placental dysfunction as central to preeclampsia; however, there is inadequate understanding of the precise pathogenesis of preeclampsia. In this study, we present a comprehensive multi-omics analysis of early pregnancy placental biopsies (chorionic villus samples) from pregnancies that later developed preterm/term preeclampsia, compared to normotensive controls. Using an integrative multivariate approach, we uncovered distinct molecular signatures associated with preeclampsia. Preterm preeclampsia was strongly associated with dysregulated lipoprotein metabolism, while term preeclampsia exhibited alterations in inflammatory pathways, Notch/Kit signaling, and ribosome assembly. These results challenge the prevailing notion that term preeclampsia is unrelated to early placental pregnancy dysfunction. To validate our findings, we focused on melanophilin, a gene downregulated in the early pregnancy placenta of term preeclampsia. Melanophilin expression was reduced during cytotrophoblast syncytialization; however, excessive loss disrupted syncytiotrophoblast function, triggering the production of factors known to drive preeclampsia. Our study provides critical insights into the early pregnancy aberrations underlying preterm and term preeclampsia, paving the way for the development of predictive biomarkers and targeted preventative treatments. This work represents a significant step toward unraveling the complex etiology of preeclampsia and improving maternal and perinatal health outcomes.

Serine incorporator 5 (SERINC5) restricts the infectivity of various enveloped viruses, including HIV-1 and severe acute respiratory syndrome coronavirus 2. However, these pandemic viral pathogens have evolved mechanisms to counteract this restriction. Here, we examined the impact of all five human SERINC family members on the seasonal human coronaviruses (hCoVs) 229E and OC43, which account for up to 15% of global mild respiratory infections and can cause severe disease in vulnerable individuals. Our data show that both exogenous and endogenous SERINC1, SERINC3, and SERINC5 significantly reduce OC43 infectivity in human lung and liver cells but have little, if any, effect on 229E. Functional analyses revealed that both the 130-amino-acid ORF4a protein encoded by most laboratory 229E strains and the full-length 219 amino acid ORF4 protein encoded by clinical 229E isolates antagonize SERINC5 by promoting its relocalization to lysosomes and subsequent degradation. Finally, we show that endogenous SERINC5 expression in primary human lung cells inhibits infection by ORF4-deficient but not wild-type hCoV-229E. In conclusion, several SERINC proteins restrict hCoV-OC43, whereas hCoV-229E efficiently counteracts SERINC-mediated restriction by its ORF4/4a accessory proteins to ensure efficient production of fully infectious viral particles.

Determining the link between fibrosis-4 index (FIB-4) score, which serves as a noninvasive metric for identifying liver cirrhosis, and mortality risks from all causes and cardiac causes in individuals with diabetes or prediabetes and confirmed cardiovascular disease remains ambiguous. This study seeks to explore the impact of FIB-4 on all-cause and cardiac mortality within this high-risk clinical group. Two large-scale patient cohorts were utilized for evaluation: patients from Fuwai Hospital (N = 20,133) and the UK Biobank (N = 5678). Multivariable Cox regression analysis was employed to estimate hazard ratios (HRs) along with the associated 95% confidence intervals (CIs). In the fully adjusted models, the elevated FIB-4 category showed a significant association with elevated hazards of all-cause death (Fuwai Cohort: HR 2.58, 95% CI 1.95–3.42; UKB Cohort: HR 1.26, 95% CI 1.06–1.50) and cardiac mortality (Fuwai Cohort: HR 2.99, 95% CI 1.92–4.66; UKB Cohort: HR 1.41, 95% CI 1.08–1.84). Consistent findings were observed in subgroups based on glucose levels, age, sex, and body mass index. Liver fibrosis, assessed via FIB-4, showed a significant association with elevated mortality hazards and ought to be incorporated into risk stratification among individuals with coronary heart disease concomitant with either diabetes or prediabetic states.

Lung cancer (LC) is a leading cause of cancer mortality worldwide, frequently complicated by malignant pleural effusion (MPE). This study aimed to investigate volatile organic compounds (VOCs) in pleural effusion to identify metabolic biomarkers for LC. A total of 107 LC-related MPE and 112 benign pleural effusion (BPE) patients were enrolled and divided into discovery (MPE: n = 75; BPE: n = 78) and validation (MPE: n = 32; BPE: n = 34) cohorts. Paired tumor and adjacent nontumor tissues from 14 LC patients formed an independent cohort. Differential VOCs were identified using criteria of q < 0.05, |log₂ fold change| > 1, and VIP > 1.5 in both the pleural effusion discovery cohort and the tissue cohort. Hexanal was identified as the only LC-associated VOC present across both compartments. In the validation cohort, hexanal demonstrated strong diagnostic performance in distinguishing MPE from BPE (AUC = 0.8339; sensitivity 75.00%; specificity 65.71%). Single-cell analysis indicated that hexanal accumulation is linked to fatty acid metabolism reprogramming. This study supports pleural effusion-based gas biopsy as a promising LC diagnostic approach.

Aortic dimensions differ between ethnic groups. To correct the ethnicity-related differences in aortic dimensions, Ao-a, Ao-s, and Ao-asc were measured by echocardiography in a total of 1820 Chinese and Italian healthy adults. The correction equations based on an optimized multivariate allometric model (OMAM) were constructed and tested, and the correction efficacies of the two approaches of body surface area (BSA) and OMAM were compared. The aortic dimensions were found to vary with physiological variables and ethnicities (all p < 0.05). Correction using BSA eliminated neither the differences in aortic dimensions across study populations nor the residual correlations with physiological variables (all p < 0.05). In contrast, indexation with OMAM equations eliminated both the ethnicity-related differences and residual correlations (all |r| < 0.20 and p > 0.05). The success rate of the BSA approach was 0%, while that of the OMAM approach was 100% for correcting all aortic dimensions in Chinese, Italian, and combined populations, respectively. In conclusion, the OMAM approach is superior to BSA approach in correcting the variations in aortic dimensions. Using OMAM as a novel indexing tool may facilitate establishing universal cutoffs between normal and abnormal aortic dimensions among different ethnic populations in the world.

Apolipoprotein E (ApoE) is classically recognized for its role in lipid trafficking and the coordination of lipoprotein metabolism, yet its influence extends well beyond these pathways. While the contribution of ApoE isoforms to neurodegenerative disorders, most notably Alzheimer's disease, has been described in considerable detail, their impact on peripheral physiology is far less clearly defined. Evidence accumulated over the past decade suggests that variation in ApoE may shape traits such as adiposity, fat and lean mass distribution, bone density, muscle function, and cardiovascular risk, although the findings are often inconsistent across studies and populations. This review brings together current knowledge on how ApoE interfaces with several key biological processes, including inflammatory signaling, glucose and insulin responses, mitochondrial and redox homeostasis, senescence, and regulated cell death. These pathways lie at the core of many chronic disorders, yet their links to ApoE genotype remain insufficiently defined. Moreover, translation of these findings, including the use of ApoE genotyping for risk stratification, therapeutic choices, and personalized prevention is also discussed. By reframing ApoE as a systemic regulator rather than a brain-restricted factor, this review offers a cohesive roadmap for interdisciplinary research and improved clinical interpretability of ApoE-associated risk.

Aging is a complex biological process characterized by the functional decline of multiple cellular organelles, with mitochondrial dysfunction emerging as a predominant hallmark. Alterations in mitochondria within senescent cells primarily encompass two interrelated aspects: intrinsic mitochondrial dysfunction and compromised mitochondrial quality control systems, including mitophagy, dynamics, and biogenesis. However, a comprehensive synthesis that bridges mechanistic insights into mitochondrial dysfunction with an analysis of therapeutic obstacles remains lacking. Here, we systematically summarized the pathways leading to mitochondrial dysfunction in aging and deeply analyzed how this dysregulation, including mitochondrial DNA instability and mitochondria driving inflammation through the cGAS–STING pathway, contributed to the etiology of aging-related diseases, including muscle, bone, neurodegeneration, cardiovascular, and metabolic diseases. Additionally, we analyzed a series of mitochondrial targeted treatment strategies, from metabolism and kinetic regulation to disease-specific intervention and emerging technologies, such as mitochondrial transplantation and mitochondrial DNA base editing. Finally, we emphasized the key obstacles that must be overcome for clinical transformation, including tissue-specific mitochondrial heterogeneity. By combining the basic mechanism with the development of treatment and its potential challenges, this review provides a key perspective for promoting the emerging field of mitochondrial medicine to intervene in aging-related pathology more accurately and effectively.

Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge, and the aggressive basal-like/mesenchymal subtype is particularly refractory to chemotherapy, underscoring the need for novel therapies. Leveraging genetic screens, we identified protein phosphatase 2A (PP2A) catalytic subunit PPP2CA as a target. Pharmacological PP2A inhibition selectively impaired the growth of mesenchymal PDAC cells. To delineate the mechanisms underlying sensitivity to the PP2A inhibitor LB100, we employed a dual-pronged strategy. Functional characterization revealed metabolic reprogramming coupled with endoplasmic reticulum (ER) stress and cell death induction. Genome-wide genetic screens identified key modifiers of LB100 sensitivity, implicating transcriptional regulators, mRNA processing, translation, and metabolism. Based on expression data linking PP2A to splicing and transcriptional regulation, we prioritized these processes for validation. Mesenchymal PDAC cells exhibited enhanced splicing following PP2A inhibition. Notably, we identified enhanced transcriptional elongation upon LB100 treatment, particularly of short genes, driven by cyclin-dependent kinase 9 (CDK9). Our findings support a reciprocal regulatory relationship between PP2A and CDK9 that connects to the activation of ER stress response factors, including activating transcription factor 4 (ATF4). These results establish PP2A as a druggable target in mesenchymal PDAC cells and reveal a role of LB100-induced transcriptional elongation and splicing, providing a mechanistic basis to guide future therapy development.

Liver failure remains a life-threatening syndrome where the available therapeutic options are extremely limited beyond transplantation. This study addresses critical cell source and mechanistic challenges by developing a novel bioartificial liver (BAL) system. We utilized CRISPR/Cas9 technology to knockout the GGTA1 gene in primary porcine hepatocytes to reduce immunogenicity. These hepatocytes were co-cultured with R-spondin1-overexpressing human umbilical vein endothelial cells (R-HUVECs) to form functionally stable liver organoids. In ex vivo study using plasma from patients with acute-on-chronic liver failure (ACLF), the BAL system demonstrated superior detoxification, significantly reducing ammonia and bilirubin levels compared to traditional non-bioartificial liver (NAL) support. Multi-omics analyses revealed that BAL treatment actively restored metabolic homeostasis by promoting branched-chain amino acid (BCAA) metabolism and upregulating lysophosphatidylcholine (LPC) species associated with membrane repair and anti-inflammatory signaling. Significantly, this research demonstrates that unlike the passive physical filtration of NAL, BAL serves as an active biological regulator of systemic metabolism. These findings provide a robust theoretical and practical foundation for the clinical translation of BAL technology, offering a promising strategy to improve outcomes for liver failure patients by modulating systemic metabolism.

Betel nut chewing is a major etiological factor for oral squamous cell carcinoma (OSCC), yet its mechanistic underpinnings remain poorly defined. Here, we performed single-cell RNA sequencing and spatial transcriptomics from six OSCC patients to comprehensively dissect the tumor microenvironment (TME) dynamics and cellular heterogeneity associated with betel nut-induced oral mucosal carcinogenesis. We identify a fibrotic, immunosuppressive TME characterized by expanded cancer-associated fibroblasts (CAFs) and B/plasma cells, alongside depletion of cytotoxic T/NK cells and macrophages. CAFs, particularly antigen-presenting CAFs, are spatially enriched at the invasive front and drive epithelial plasticity and malignant transformation. Notably, we uncover a malignant epithelial subpopulation, LAMC2⁺ EpiC6, enriched for epithelial–mesenchymal transition (EMT) programs, angiogenesis, and metastasis-associated pathways, which engaged in extensive crosstalk with CAFs and other nonmalignant components. Clinically, LAMC2 expression was significantly elevated in OSCC tissues from betel nut chewers, and arecoline treatment of OSCC cell lines induced LAMC2 upregulation, EMT, and enhanced migratory and invasive capacities in vitro. Collectively, our study delineates a malignant trajectory of epithelial cell progression, highlighting LAMC2⁺ EpiC6 as a key aggressive subpopulation orchestrated by EMT-related transcriptional regulators and extracellular matrix remodeling. These findings offer mechanistic insights and identify potential therapeutic targets to disrupt tumor–stroma interplay and mitigate disease progression.

Protein secretion is a fundamental biological process essential for cellular communication, matrix remodeling, and overall homeostasis across all domains of life. While the classical endoplasmic reticulum (ER)-to-Golgi pathway has long been recognized as the primary route for eukaryotic protein export, decades of research reveal that numerous cytosolic and membrane proteins bypass this canonical route. This alternative paradigm, termed unconventional protein secretion (UcPS), encompasses direct transmembrane translocation, vesicle-mediated release, and Golgi-bypass mechanisms. Simultaneously, prokaryotes utilize highly specialized secretion machineries to deliver effector proteins. Despite these established frameworks, the precise molecular regulation, cargo sorting mechanisms, and dynamic crosstalk between these diverse pathways remain incompletely understood. Here, we comprehensively review the molecular mechanisms of UcPS and prokaryotic secretion systems, synthesizing their evolutionary adaptations and operational frameworks. By mapping nonvesicular pores, extracellular vesicles intermediates, and complex bacterial nanomachine assemblies, we delineate how cells rapidly mobilize proteins under stress. Furthermore, we highlight the dual role of these pathways in driving physiological adaptation versus fueling pathological dissemination. Abnormalities in these secretory nodes are now recognized as primary drivers of neurodegeneration, inflammatory disorders, and cancer metastasis. Consequently, manipulating UcPS mechanisms offers promising, multidimensional therapeutic opportunities for future medicine.

Deuterium, the heavy isotope of hydrogen, has unfolded as a cornerstone in modern drug discovery due to its potential to influence metabolic stability and pharmacokinetic behavior. The deuterium kinetic isotope effect (KIE), which strengthens carbon–deuterium bonds, make it possible to improve therapeutic efficacy while maintaining pharmacological activity. Although some deuterated drugs, notably donafenib and deutetrabenazine, have demonstrated clinically significant efficacy, their limited use is an effect of ongoing challenges with metabolic switching and species-specific variation, as well as inadequate mechanistic understanding. This review presents a systematic discussion of the recent innovations in site-selective deuteration, the principles that underpin the KIE process, and the effects of deuterium substitution on drug metabolism, toxicity, and blood–brain barrier penetration. It illustrates novel implications in oncology, rare diseases, and central nervous system disorders, as well as the integration of deuterated chemistry with modalities such as proteolysis-targeting chimaeras, peptides, and nucleic acid therapeutics. Furthermore, the review's discussion includes the current challenges, synthesis, analytical limits, and regulatory considerations that influence further development. Overall, the review offers a strategic roadmap for utilizing deuterium-enabled molecular engineering to accelerate the development of next-generation precision medicine, guiding rational design, innovation toward safer, longer-lasting, and more effective treatments.

Cancer-associated metabolic reprogramming profoundly reshapes the tumor microenvironment (TME), emerging as a central driver of immune evasion and therapeutic resistance. Increasing evidence indicates that metabolic enzymes function not only as bioenergetic regulators but also as active modulators of immune signaling, immune cell fate, and immune checkpoint expression. To elucidate these complex immunometabolic networks, this review utilizes fructose-1,6-bisphosphatase 1 (FBP1)—a key gluconeogenic enzyme—as a paradigmatic metabolic gatekeeper to illustrate how metabolic dysregulation drives tumor progression. By examining both the canonical metabolic effects and noncanonical signaling mechanisms of such enzymes, we synthesize recent advances demonstrating how metabolic rewiring promotes glycolytic reprogramming, immune suppression, and resistance to immunotherapy. Specifically, we explore broad mechanisms of immune evasion, including STAT3–PD-L1 regulation, modulation of innate immune surveillance, T cell exhaustion, and remodeling of stromal and fibrotic tumor niches. Furthermore, we discuss emerging therapeutic strategies targeting these immunometabolic pathways, encompassing small-molecule modulators, vitamin- and gene-based interventions, nanotechnology-enabled delivery systems, and metabolism-informed combination immunotherapy. Finally, we highlight key challenges, including metabolic heterogeneity and context-dependent enzyme function, emphasizing the need for biomarker-guided precision strategies to translate fundamental immunometabolic insights into durable and safe cancer therapies.

Encephalopathy refers to diffuse brain dysfunction caused by various systemic pathological processes such as systemic infections, metabolic disorders, and organ failure. This condition poses a formidable challenge in neurocritical care, with major subtypes encompassing sepsis-associated encephalopathy, hepatic encephalopathy, hypoxic–ischemic encephalopathy, diabetic encephalopathy, uremic encephalopathy, and toxic encephalopathy. The current therapeutic landscape reveals a critical deficiency in effective neuroprotective interventions, highlighting an urgent need for novel treatment strategies. Small-molecule compounds, particularly those derived from natural products, offer a promising therapeutic paradigm due to their multitarget capabilities and potential for network-level modulation of pathogenic processes. However, advancement in this field remains constrained by several fundamental limitations: fragmented mechanistic insights, ill-defined target networks, and insufficient clinical translation. To address these challenges, this review systematically synthesizes contemporary evidence to delineate the etiopathogenesis of these encephalopathies, with particular emphasis on the molecular mechanisms and cellular targets of small molecule drugs (especially natural products). Through a critical assessment of current research limitations, this review aims to establish a robust framework and provide forward-looking perspectives to guide the development of targeted neuroprotective strategies and their clinical translation.

This study was designed to provide prospective evidence for the combination of hepatic arterial infusion chemotherapy (HAIC) and toripalimab, which had suggested encouraging antitumor activity and safety in advanced hepatocellular carcinoma (HCC) previously. This single-center, non-comparative, randomized phase II study (NCT04135690) recruited locally advanced HCC participants (1:1) to receive HAIC plus either toripalimab (TorHAIC) or sorafenib (SoraHAIC) per 3 weeks. The primary endpoint was the progression-free survival (PFS) rate at 6 months. Seventy-two participants were randomly assigned to received TorHAIC (n = 36) or SoraHAIC (n = 36). The 6-month PFS rate was 63.9% in the TorHAIC group and 61.1% in the SoraHAIC group. The median OS was 20.9 months in the TorHAIC group and 16.4 months in the SoraHAIC group, while the median PFS was 9.1 and 7.2 months, respectively. There were 12 participants (33.3%) developed grade 3–4 adverse events (AEs) in the TorHAIC group and 16 participants (44.4%) in the SoraHAIC group. Serious AEs were reported in two participants in the TorHAIC group and five participants in the SoraHAIC group. Our study suggested that the TorHAIC regimen had a favorable safety and efficacy profile in locally advanced HCC. However, these findings warrant validation in a phase III trial.

Distinguishing characteristics have been found in the left-sided and right-sided colorectal cancer (CRC), which have different embryonic origins, molecular and clinical features. These result in differences in the efficacy of targeted therapy and immunotherapy. Multi-omics characterization, predicated upon tumor laterality, may facilitate a more precise and personalized approach to the treatment of patients with CRC. Encompassing whole-exome, proteomics, and phosphoproteomics sequencing, we conducted a comprehensive investigation of tumor and matched normal adjacent tissues from a total of 80 pairs of patients with CRC. Results revealed that the pathogenesis of left-sided CRC was predominantly associated with chromosomal instability, while right-sided CRC was primarily linked to microsatellite instability. Regarding the tumor microenvironment, left-sided CRC exhibited predominant microvascular endothelial cell proliferation, while right-sided CRC displayed enhanced MHC Class II-associated antigen presentation mediated by M1 macrophages. Additionally, the proportion of deficient mismatch repair that developed into microsatellite instability-high was observed to be lower in the left-sided CRC compared to the right-sided, indicating divergent DNA damage repair systems between laterality subtypes that contribute to differential immunotherapy efficacy. This integrated proteogenomic study provides a comprehensive and nuanced understanding of the molecular heterogeneity between left- and right-sided CRC, offering opportunities for optimizing these patients' treatment outcomes through tailored therapeutic strategies.