Search Results (786)

Background: Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen that has caused repeated epidemics across Africa and the Arabian Peninsula, posing a severe and growing threat to public health and livestock. Infection in ruminants causes high neonatal mortality and catastrophic abortion storms; human disease ranges from self-limiting febrile illness to hemorrhagic fever, encephalitis, and permanent blindness. No licensed human vaccines or specific antiviral therapeutics are available, creating an urgent unmet medical need. Methods: We systematically reviewed the peer-reviewed literature on RVFV neutralizing antibodies (NAbs), extracting and synthesizing data on antibody sources, epitope specificity, in vitro neutralizing potency, in vivo protective efficacy, and molecular mechanisms of action. Results: A growing body of work has identified potent NAbs from immunized rodents, rabbits, alpacas, non-human primates, and convalescent patients. These NAbs predominantly target the Gn and Gc envelope glycoproteins. Their mechanisms include blocking host receptor (LRP1) binding, preventing the pH-dependent conformational rearrangement of the Gn–Gc complex, and directly inhibiting viral membrane fusion. Lead candidates, such as RVFV-268 and RVFV-140, achieve sub-nanogram neutralization and confer robust protection in rodent models against lethal challenge, aerosol exposure, and vertical transmission. Bispecific antibodies and combination strategies further enhance potency and the genetic barrier to viral escape. Conclusions: Substantial progress has illuminated the epitope landscape and neutralization mechanisms of RVFV, yielding promising clinical candidates. Translational challenges remain, including viral immune escape, antibody thermostability, and the need for rigorous preclinical evaluation. Future efforts should prioritize structure-guided engineering, rational antibody combinations, and testing in clinically predictive animal models. Full article

The p53 biomolecule is critical for facile antitumor response in cancer therapy. Once fully activated, p53 will kill tumor cells by activating programmed cell death (PCD), such as apoptosis and ferroptosis, and inducing immunogenic cell death. It is not surprising, therefore, that in about 50% of cancers p53 is mutated and non-functional, which induces drug resistance. Paradoxically, many cancers harboring the wild-type p53 genotype also become resistant via loss of drug-induced activation of p53. Efforts to convert loss-of-function or gain-of-function mutant p53 to the wild-type phenotype or to activate wild-type p53 through drug design have been disappointing. There is also a failure to recognize the existence of a sizeable number of mutant p53s that are phenotypically normal but cannot be functionally activated. Since such mutants and wild-type p53 retain intrinsic PCD pathways, focus on activating p53 could be more rewarding if the efforts implemented recognize and incorporate mechanistic factors that are vital for activating p53 function. This would realize a seminal goal of harnessing the true potential of p53 through more rational and effective therapeutic strategies and finally fulfill a critical unmet clinical need, particularly in the context of precision medicine. For such a vision, functional evaluation of normal (wild-type) or mutant p53 (or FENOMP) is vital and, thus, proposed herein as a conceptual assay to predict the phenotype of p53. Full article

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of oncology but are increasingly associated with cardiovascular immune-related adverse events (irAEs), including myocarditis, heart failure, arrhythmias, and vascular complications. Among these, ICI-associated myocarditis represents the most severe manifestation, often characterized by high mortality and challenging early diagnosis. Detecting subclinical myocardial injury before irreversible cardiomyocyte necrosis occurs remains a major unmet need in contemporary cardio-oncology. This narrative expert review critically examines the biological rationale, preclinical evidence, and emerging clinical data supporting the potential role of heart-type fatty acid-binding protein (H-FABP) as an adjunctive biomarker of early immune-mediated myocardial injury during ICI therapy. H-FABP is a small cytosolic lipid chaperone abundantly expressed in cardiomyocytes and rapidly released into the circulation following subtle membrane destabilization and metabolic stress, frequently preceding detectable troponin elevation in other forms of myocardial injury. Experimental studies support a mechanistic association between H-FABP release, inflammasome activation, cytokine amplification, mitochondrial dysfunction, and immune–metabolic cardiomyocyte stress. Preliminary clinical observations further suggest that H-FABP elevations may occur during ICI treatment even in the absence of overt myocarditis or concomitant increases in high-sensitivity cardiac troponins (hs-cTns). Although H-FABP cannot replace hs-cTn, which remains the cornerstone biomarker for the diagnosis of clinically significant ICI-associated myocarditis, its rapid kinetics and sensitivity to early metabolic membrane injury support its potential role as an investigational adjunctive biomarker for early surveillance and risk stratification. This approach may be particularly relevant in patients receiving high-risk combination ICI regimens or in individuals with pre-existing cardiovascular disease. However, current evidence remains limited, and large prospective multicenter studies integrating H-FABP with hs-cTns, natriuretic peptides, cardiac magnetic resonance imaging, and clinical outcomes are required before routine clinical implementation can be considered. Full article

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by frequent underdiagnosis, diverse etiologies, and limited therapeutic options. Given its complexity, artificial intelligence (AI) and machine learning (ML) offer promising avenues to decode high-dimensional, multi-modal healthcare data. This review aims to synthesize the current landscape of AI/ML applications in HFpEF, evaluating their potential to address critical unmet clinical needs. Methods: We conducted a comprehensive review of the literature focusing on AI/ML paradigms in HFpEF. Key methodological frameworks were examined, including supervised, unsupervised, semi-supervised, and reinforcement learning, alongside advanced techniques such as deep learning and natural language processing (NLP). The analysis focused on the application of these techniques across four domains: diagnosis, sub-phenotyping, risk prediction, and optimization of diagnostic modalities, with specific emphasis on studies incorporating external validation. Results: Current evidence demonstrates that AI approaches effectively enhance diagnostic accuracy and facilitate the identification of distinct HFpEF phenotypes beyond traditional classifications. These technologies show significant utility in refining prognostic assessments and optimizing diagnostic testing strategies. Furthermore, ML-driven analytics provide a robust framework for improving patient selection and streamlining clinical trial design, potentially overcoming historical barriers to drug development in this population. Conclusions: AI represents a transformative tool capable of dissecting the heterogeneity of HFpEF to enable precision medicine. While the potential to improve clinical outcomes is substantial, challenges regarding model interpretability, bias, and clinical integration persist. Future efforts must focus on rigorous external validation and prospective trials to ensure the responsible translation of these technologies into routine clinical practice. Full article

Background: Endometrial carcinoma (EC) is now classified primarily by molecular subtype—POLE-ultramutated, mismatch repair–deficient (dMMR), TP53-mutant/copy-number-high (CNH), and “no specific molecular profile” (NSMP)—a framework that has reshaped prognostic counseling and adjuvant therapy decisions. Yet several practically important questions remain insufficiently addressed in real-world cohorts: whether all four mismatch repair genes confer an equivalent favorable prognosis, whether all POLE alterations carry the same survival benefit or only specific pathogenic variants, and whether molecular subtypes retain prognostic value after adjustment for histology and tumor burden. Methods: We addressed these questions in 2901 patients pooled from the MSK-IMPACT 50K Clinical Sequencing Cohort (n = 2372; discovery) and the TCGA UCEC PanCancer Atlas (n = 529; validation)—the largest dual-cohort genomic analysis of EC reported to date. We performed individual MMR gene and combined dMMR survival stratification, multivariable Cox regression adjusted for age, histology, and sample type, and a pathogenicity-aware sensitivity analysis for POLE variants, with tumor mutational burden (TMB) compared across subgroups. Results: Across both cohorts, all four MMR gene–mutant subgroups (MLH1, MSH2, MSH6, PMS2) conferred equivalently favorable overall survival (OS) (six-group log-rank p = 7.66 × 10⁻¹² in discovery; p = 6.78 × 10⁻³ in validation), confirming dMMR as a class-level prognostic designation independent of which MMR gene is altered. Multivariable Cox regression demonstrated that POLE-ultramutated status retained an independent favorable effect (HR = 0.62, p = 0.038 in MSK; HR = 0.35, p = 0.028 in TCGA) after adjustment for age, histology, and sample type, while the favorable dMMR effect was largely accounted for by histologic context. Critically, a pathogenicity-aware sensitivity analysis revealed that the exceptional survival of the POLE subgroup is confined to canonical exonuclease-domain hotspot mutations (event rate 0.9% in MSK), whereas POLE variants of uncertain significance behave indistinguishably from NSMP-like tumors. Consistent with this finding, TMB was markedly elevated in canonical pathogenic POLE cases (median 138.7 mut/Mb in MSK; 247.4 in TCGA) but not in POLE-VUS-only cases (median 29.0 and 15.0, respectively; p < 0.001 between groups in both cohorts), confirming that the ultramutator phenotype is confined to canonical pathogenic POLE variants. We additionally characterize Uterine Clear Cell Carcinoma as a distinct histologic entity (n = 73; 3.0%) and report the POLE + TP53 co-mutant group (n = 90; 3.8%). Conclusions: These findings refine the molecular classification of EC in clinically meaningful ways: they support class-level immunotherapy eligibility based on dMMR status regardless of the specific MMR gene altered, demonstrate that POLE-ultramutated classification requires variant-level pathogenicity assessment, and identify TP53-mutant/CNH patients as the population with the most urgent unmet therapeutic need. Full article

Melanoma adjuvant therapy has substantially improved recurrence-free and distant metastasis-free survival in patients with resected high-risk disease, and more recently, these advances have extended to earlier stages. However, important unmet needs remain, including the management of stage IIIA disease, the optimal treatment strategy after relapse on adjuvant therapy, and the identification of biomarkers capable of refining patient selection. This review summarizes recent advances and unresolved questions in the adjuvant and neoadjuvant treatment of melanoma. We discuss novel systemic strategies, including immune checkpoint inhibitor combinations and personalized neoantigen mRNA vaccines, together with the expanding role of neoadjuvant approaches. We also examine prognostic and predictive tools—such as clinicopathologic models, circulating tumor DNA, serum biomarkers, tumor microenvironment features, and gene expression profiling—that may help better define recurrence risk and therapeutic benefit. Current evidence suggests that although modern therapies have changed the natural history of resected melanoma, a substantial proportion of patients are still overtreated or undertreated when treatment decisions are based on stage alone. Future progress will depend on integrating biological risk stratification with clinical staging and optimizing treatment sequencing across adjuvant and neoadjuvant settings. Full article

Background/Objectives: Vaccine development pipelines are forward-looking indicators of public health preparedness, reflecting the capacity to address unmet medical needs and emerging threats. This descriptive analysis aims to characterise the 2025 clinical-stage pipeline of infectious disease vaccines and prophylactic monoclonal antibody candidates developed by Vaccines Europe member companies, and to describe how pipeline characteristics address evolving public health priorities. Methods: A descriptive analysis was conducted using publicly available data compiled in the Vaccines Europe Pipeline Review 2025, with validation by participating companies. Candidates in clinical development or regulatory review were classified using a standardised framework by pathogen/disease, target population, public health priority, and technologies. Results: The Vaccines Europe member company pipeline comprises 91 candidates across clinical development phases, 19% of which are in Phase III and 7% undergoing regulatory review. This pipeline is predominantly targeting respiratory pathogens (75%), with a strong life-course focus (85% evaluated in adults and/or older adults), and sustained activity in bacterial pathogens relevant to antimicrobial resistance. Notably, 41% of candidates were classified as addressing diseases, disease combinations, or indications for which no licenced preventive product exists. This category includes candidates targeting diseases without a preventive solution, as well as novel combination vaccines and therapeutic approaches in areas where individual components or preventive vaccines are already available. This captures vaccines candidates in different stages of development, not necessarily first-in-disease innovation. The pipeline shows broad technological diversity (12 technologies), dominated by RNA approaches and multivalent candidates, with growing focus on climate-sensitive, zoonotic, and pandemic-prone pathogens. Conclusions: Within the pipeline of Vaccines Europe member companies, this analysis describes development activity oriented toward broader prevention, platform-based approaches, and preparedness-relevant targets. As a structured and recurring annual assessment, the Vaccines Europe Pipeline Review supports horizon scanning and evidence-based dialogue between industry and vaccine ecosystem stakeholders. In order to maximise the impact of vaccine development pipelines to public health, predictable investment, streamlined trial and regulatory pathways, strong surveillance, and real-world data systems, coordinated decision-making is required to enable timely and equitable access, and complementary incentive and procurement reforms. Full article

Breast cancer is the second leading cause of cancer death in women. Among its various subtypes, triple-negative breast cancer (TNBC) is an aggressive form characterised by the absence of hormone receptor expression and lack of HER2 amplification, which severely limits treatment options. While some targeted therapies exist, chemotherapy remains the primary treatment for TNBC. Interestingly, despite TNBC patients showing the highest initial response rates to chemotherapy, they also experience the lowest overall survival. This phenomenon is often referred to as the “TNBC paradox,” which makes achieving curative outcomes incredibly challenging due to the unpredictable nature of the disease. This highlights a significant unmet clinical need to develop tailored medicine approaches to maximise patient response. Unlike other breast cancer subtypes, TNBC is considered “immune hot,” meaning it has a higher presence of immune cells within the tumour microenvironment. This characteristic has made the development of immunotherapies a major focus of research. PD-1/PD-L1 checkpoint inhibitors have already become the standard of care for high-risk early stage TNBC patients, and other immunomodulatory therapies, such as therapeutic vaccines, are currently under investigation. Given that chemotherapy is still the cornerstone of TNBC treatment, understanding its impact on systemic and tumour immune cells is crucial for improving the effectiveness of combination therapies. This review will delve into the specific roles of TNBC chemotherapies on key immune cells during both tumour progression and regression. Full article

Prostate cancer (PCa) management has evolved with biomarker-driven strategies, yet biological heterogeneity, adaptive resistance, and an immunosuppressive microenvironment limit their efficacy. Galectin-3 (Gal-3) has emerged as a central node in PCa pathobiology, influencing tumor survival, metastasis, and immune escape. This review comprehensively reviews Gal-3’s dual role as a biomarker and a therapeutic target. We first delineate the limitations of the current diagnostic, prognostic, and predictive biomarkers in PCa, establishing the unmet need. We then elucidate the multifunctional biology of Gal-3, detailing its compartment-specific roles in anti-apoptosis, angiogenesis, epithelial-to-mesenchymal transition, and, notably, its function as a master regulator of immunosuppression. The interaction between Gal-3 and prostate-specific antigen (PSA) is explored as a key regulatory interface. Furthermore, we catalog and analyze emerging Gal-3-targeted therapies, emphasizing their rationale for combination with immune checkpoint blockade to reverse therapeutic resistance. Finally, we outline a translational roadmap, advocating for standardized Gal-3 biomarker assays and biomarker-enriched clinical trials. Integrating Gal-3 into the PCa precision medicine toolkit offers a novel strategy to address heterogeneity and improve therapeutic durability. Full article

The conventional classification of multiple sclerosis (MS) into relapsing–remitting, secondary progressive, and primary progressive phenotypes has long guided diagnosis, prognosis, and therapeutic decision-making. However, accumulating evidence indicates that disability accumulation frequently occurs independently of clinical relapses, challenging relapse-centric and phenotype-based models of disease evolution. The concept of progression independent of relapse activity (PIRA) has emerged as a clinically relevant framework capturing this phenomenon across MS phenotypes. In this state-of-the-art narrative review, we propose a spectrum-based reinterpretation of MS, integrating PIRA with concepts of smouldering-associated worsening and neurologic reserve. We highlight the heterogeneity of relapse-independent worsening, distinguishing transient from persistent PIRA, and discuss how ageing-related decline in compensatory capacity contributes to the clinical unmasking of progression over time. Within this framework, secondary progressive MS is redefined as the clinically recognizable accumulation of persistent relapse-independent worsening, while primary progressive MS is conceptualized as early predominance of clinically manifest progression due to limited reserve rather than a distinct disease entity. Finally, we examine diagnostic and therapeutic implications of a spectrum-based model in the contemporary era, emphasizing the limitations of relapse-centric treatment strategies and unmet needs in addressing progression-related biology. By reframing MS as a dynamic continuum shaped by the interaction between ongoing pathology and evolving neurologic reserve, this review aims to support earlier recognition of clinically meaningful progression and to inform more biology-aware approaches to disease monitoring and therapy. Full article

This study aims to update and integrate empirical evidence on the key drivers and consistency of the appraisals of drug innovativeness in Italy by the Italian Medicines Agency (AIFA), and discuss if this evidence is supportive of the reform and requirements implemented in 2025. Appraisals from July 2017 to December 2024 were retrieved from the AIFA website. The association between the innovativeness appraisal, the innovativeness domains (unmet need/added therapeutic value/quality of evidence) and disease/drug/evidence-specific variables was assessed using odds ratios (ORs) from binary/multinomial logistic regression models. Innovativeness status was strongly associated with added therapeutic value (OR > 70). Medicines for rare diseases were more likely to receive conditional innovativeness (OR = 2.95). Full innovativeness was more frequently recognized for indications including paediatric patients (OR = 3.60). References to severe diseases and patient-reported outcomes (PROs) had a higher, not statistically significant, likelihood of innovativeness, whereas reference to indirect treatment comparisons had a lower likelihood (OR = 0.18). The appraisal process showed high internal consistency, but its regulation needs more specific guidance. The innovativeness regulation was reformed in July 2025, including specific recommendations on the criteria to identify the alternative treatments; the role and robustness of indirect comparisons; and the role and requirements for PROs. Our evidence provides an empirical rationale for this reform. Full article

Background: The absence of disease-modifying treatments for Parkinson’s disease (PD)—a neurodegenerative condition with escalating global incidence—represents a critical unmet medical need. Traditionally utilized for both dietary consumption and medicinal preparations, the fruit derived from Rosa roxburghii Tratt demonstrates a remarkably rich profile of biologically active compounds, with flavonoids, triterpenoids, and organic acids representing the predominant classes. Experimental evidence indicates that these compounds elicit robust antioxidative, anti-inflammatory, and neuroprotective effects, making them promising candidates for neurodegenerative disease modulation. This study aimed to systematically evaluate the neuroprotective effects of Rosa roxburghii Tratt juice concentrate powder (RRJCP) across the preventive, interventional, and therapeutic stages of PD and to elucidate its underlying molecular mechanisms. Methods: Rosa roxburghii Tratt juice was subjected to rotary evaporation concentration and vacuum freeze-drying to obtain the juice concentrate powder. C57BL/6 mice were randomly assigned to three main groups (prevention, intervention, and treatment), each containing subgroups including a normal control, an MPTP model group, low-, medium-, and high-dose RRCJP groups (50, 100, and 200 mg/kg), and a positive control Madopar group, totaling 18 subgroups. A chronic MPTP-induced PD mouse model was established. Motor function was assessed via the open field test, pole test, and wire hang test. Substantia nigra neuronal morphology was examined by hematoxylin and eosin staining. The area of tyrosine hydroxylase (TH)-positive regions was measured by immunohistochemistry. The levels of oxidative stress indicators in serum were measured using biochemical kits. Network pharmacology was employed to predict core targets, and the expression of PI3K/AKT pathway and apoptosis-related proteins was determined by Western blotting. Results: Compared with the MPTP model group, RRCJP (200 mg/kg) significantly increased the total distance traveled in the open field, shortened the pole climbing time, and improved the wire hang score. It attenuated the morphological disorganization and nuclear pyknosis of substantia nigra neurons, increased the TH-positive area and TH protein expression, reduced serum MDA content, and elevated the activities of SOD and GSH-Px. Network pharmacology analysis indicated that the PI3K/AKT signaling pathway was among the core targets. Western blotting results further showed that the juice concentrate powder upregulated the expression of p-PI3K, p-AKT, and Bcl-2, while downregulating Bax and Cleaved Caspase-3 levels, which was consistent with the network pharmacology prediction. Conclusions: RRCJP exerts neuroprotective effects across the preventive, interventional, and therapeutic stages in PD model mice, the mechanisms of which may be associated with activation of the PI3K/AKT signaling pathway, attenuation of oxidative stress, and inhibition of neuronal apoptosis. Full article

Background: High-risk cytogenetic multiple myeloma (HRMM) confers inferior outcomes despite significant therapeutic advances. Real-world data characterizing contemporary treatment patterns across lines of therapy in this population are limited. Methods: We conducted a multicenter retrospective study of 205 patients with HRMM diagnosed between January 2009 and January 2024. High-risk cytogenetics were defined according to the International Myeloma Working Group (IMWG) and Revised International Staging System (R-ISS) criteria as the presence of del(17p), t(4;14), t(14;16), t(14;20), and/or gain/amplification of 1q21. Treatment regimens were categorized by the number of agents (doublet, triplet, quadruplet), mechanism of action (proteasome inhibitor [PI]-based, immunomodulatory drug [IMiD]-based, and anti-CD38 monoclonal antibody-based), and specific regimen composition. Treatment patterns were analyzed across three treatment eras and stratified by age (<70 vs. ≥70 years). Results: The cohort included 205 patients (median age, 62 years [interquartile range [IQR], 54–68 years]; 78.5% aged <70 years). Double-hit and triple-hit cytogenetics were present in 60.0% and 7.3% of patients, respectively. For first-line induction, triplet therapy predominated (81.0%, n = 166), followed by quadruplet (8.8%, n = 18), doublet (5.9%, n = 12), and multi-agent chemotherapy (2.9%, n = 6). By mechanism of action, PI + IMiD combinations were the most common (63.4%, n = 130), followed by PI-based (19.0%, n = 39), anti-CD38-based (10.2%, n = 21), and IMiD-based (2.9%, n = 6) regimens. Era-stratified analysis revealed a significant increase in quadruplet utilization from 3.2% in Era 1 (2009–2015) to 20.3% in Era 3 (2020–2024), with anti-CD38-containing frontline regimens administered to 26.6% of patients in the contemporary era (p < 0.001). Second-line induction was required in 50 patients (24.4%), with anti-CD38-based triplets comprising the most common approach (30.0%). Autologous stem cell transplantation (ASCT) was performed in 75.1% of patients overall, with significantly higher utilization in those aged <70 years (83.9% vs. 43.2%). Maintenance therapy was administered to 71.7% of patients (n = 147), with IMiD-based regimens predominating (53.1%), followed by PI + IMiD combinations (27.9%) and anti-CD38-containing regimens (10.2%). Despite intensive therapy, 69.4% of patients on maintenance experienced disease relapse, with higher rates observed in younger patients (74.8% vs. 41.7%). Conclusions: In this real-world HRMM cohort, the PI + IMiD triplet regimen remained the predominant induction approach, with a significant shift toward quadruplet and anti-CD38-containing regimens in the contemporary era. However, substantial relapse rates during maintenance underscore the continued unmet need in HRMM and support the early integration of novel therapeutic strategies, including quadruplet induction and BCMA-directed agents, in this population. Full article

Background/Objectives: Heart failure (HF) is associated with substantial morbidity, impaired quality of life (QOL), and reduced functional capacity. In selected patients with symptomatic HF despite Optimal Medical Therapy (OMT), Cardiac Contractility Modulation (CCM) may be a therapeutic option. Identifying patients most likely to benefit from CCM remains an unmet need. The Predict-CCM study aims to evaluate long-term clinical and objective outcomes after CCM therapy and to assess the predictive value of pre-implant low-dose dobutamine stress echocardiography (LDDSE). Methods and Results: Predict-CCM is an independent, non-profit, multicenter, observational cohort study conducted in Italy, with both retrospective and prospective enrollment. The primary endpoint is the proportion of subjects with a clinical response to CCM at 12 months, defined as a ≥1-class reduction in NYHA class. Secondary clinical endpoints include reductions in HF-related hospitalizations, changes in QOL assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and changes in NT-proBNP levels from baseline to follow-up. Outcomes will be evaluated in the overall cohort and in two subcohorts stratified by pre-implant LDDSE response: (1) reduction in left ventricular end systolic volume (LVESV) ≥ 15% (DeltaLVESV ≥ 15%); and (2) reduction in LVESV < 15% (DeltaLVESV < 15%). Assuming a 70% clinical response rate at 12 months, the estimated sample size is 120 patients. The study was approved by the Ethics Committee in March 2025. Enrollment will continue for 2 years, with a 12-month follow-up period after implant for each subject. Conclusions: This study may provide new criteria for patient selection and outcome assessment in CCM therapy. Left ventricular contractile reserve assessed by stress echocardiography may be a promising predictor of response. Full article

Microbiome-based therapies are reshaping the therapeutic landscape for ulcerative colitis (UC), offering new avenues for disease management beyond conventional immunomodulatory and biologic treatments. UC remains a chronic, relapsing condition with significant unmet clinical needs, as many patients fail to achieve sustained remission or experience adverse effects with current therapies. The gut microbiome has emerged as a central contributor to UC pathogenesis, influencing epithelial barrier integrity, immune homeostasis, and metabolic signaling. Interventions such as fecal microbiota transplantation (FMT) and defined microbial consortia have demonstrated proof-of-concept efficacy in early-phase clinical trials, each leveraging distinct mechanistic strategies. FMT, as a broad ecological intervention, restores microbial diversity and functional redundancy, potentially addressing multiple pathogenic mechanisms simultaneously. In contrast, defined consortia enable precise targeting of specific metabolic and immunological pathways, including short-chain fatty acid production, bile-acid remodeling, epithelial barrier reinforcement, immune modulation, and succinate degradation. Recent clinical evidence suggests that consortia with broader mechanistic coverage may achieve more consistent biological activity than narrowly focused designs. This review synthesizes mechanistic and clinical insights across broad and defined microbial consortia, integrates evidence from randomized controlled trials and early-phase LBP studies, and outlines a precision-medicine framework to guide therapy selection. We highlight the importance of aligning therapeutic mechanisms with patient-specific microbial, metabolic, and immune profiles, and discuss future directions including biomarker-guided stratification, hybrid consortia, and adaptive trial designs. Advancing both broad and defined approaches, while incorporating ecological principles, mechanistic understanding, and patient stratification, will be essential to realizing the full therapeutic potential of microbiome-based therapies in UC. Full article