Targeting Inflammation in Bronchiectasis.

Bronchiectasis: A pulmonary disease with systemic consequences.

Background and ObjectiveBronchiectasis is a chronic respiratory disease characterized by predominantly neutrophilic inflammation, recurrent infection and pathological dilatation of the airways. Current therapeutic strategies primarily target infections and improving mucus clearance. However, no current treatment can directly ameliorate neutrophilic inflammation. Recently, dipeptidyl peptidase 1 (DPP-1) inhibitors effectively abrogated neutrophilic inflammation in bronchiectasis. This narrative review aimed to analyze the structural characteristics and functional effects of DPP-1, explore the mechanism of DPP-1 inhibitors in bronchiectasis, and highlight major clinical trial findings.MethodsWe performed an online electronic search for relevant English literature on PubMed and Web of Science databases, with the keywords of “dipeptidyl peptidase 1”, “cathepsin C”, “cathepsin C structure”, “cathepsin C maturation”, “cathepsin C loss-of-function”, “neutrophil serine proteases and bronchiectasis”, “neutrophil serine proteases and cathepsin C”, “neutrophil serine proteases and DPP-1”, “DPP-1 inhibitors”, “cathepsin C inhibitors”, “DPP-1 inhibitors and bronchiectasis”, “cathepsin C inhibitors and bronchiectasis”. Two authors (R.D.T. and J.Q.Y.) independently searched and reviewed the articles.Key Content and FindingsExcessive and uncontrolled release of neutrophil serine proteases (NSPs) can lead to airway inflammatory responses and structural damage in bronchiectasis. Elevated levels of neutrophil elastase (NE) and other neutrophil markers in the airway are associated with exacerbations and lung function decline. In light of the pivotal role of DPP-1 in eliciting neutrophilic inflammation, several DPP-1 inhibitors have been developed and entered clinical trials for safety and efficacy assessment in bronchiectasis. Of these, brensocatib markedly prolonged the time to the first exacerbation and decreased the exacerbation frequency via decreasing the activity of NSPs. The phase III ASPEN trial has been completed and confirms reduced exacerbations and slower lung function decline with DPP-1 inhibitor treatment. Treatment with BI 1291583 reduced the risk of bronchiectasis exacerbations in the phase II Airleaf® trial. HSK31858 significantly decreased the exacerbation frequency and prolonged the time to the first exacerbation in the latest phase II trial among the Chinese population.ConclusionsDPP-1 inhibitors have exhibited promising effects in improving several major clinical outcomes in bronchiectasis via suppressing the activity of NSPs.

Bronchiectasis is a chronic and debilitating lung disease, characterised by irreversible dilatation of the bronchi as consequence of airway injury and remodelling due to recurrent or chronic airway inflammation and infection. The underlying aetiologies include autoimmune diseases, severe infections, genetic abnormalities and acquired disorders. The pathogenesis of bronchiectasis is poorly understood. Three distinct pathogenetic elements, namely infection, inflammation and enzymatic actions, which interact with each other, have been implicated in the pathophysiology of bronchiectasis. Some recent observations indicate that airway inflammation in bronchiectasis comes from a deregulated cytokine network independent of bacterial airway colonisation. In the present review, current knowledge about cellular and molecular inflammatory events in the dynamic process of host-pathogen interaction that are thought to play a relevant role in the pathogenic mechanisms of airway wall destruction leading to bronchiectasis are discussed.

Dipeptidyl peptidase 1 (DPP1) exacerbates airway neutrophilic inflammation in bronchiectasis, which is characterised by airway dysfunction and dilation and chronic bacterial infection. However, little is known about the pathogenetic roles of DPP1 in obstructive airway diseases, including COPD, asthma and asthma-COPD overlap (ACO). Here, we tested the hypothesis that airway DPP1 could enhance neutrophilic inflammation and affect mucus plugging, airway dilation and the airway microbiome in patients with these diseases. Sputum DPP1, cell differential count and microbiome were cross-sectionally evaluated in patients with COPD, asthma with airflow limitation and ACO. Sputum high mobility group box 1 (HMGB1) was measured to estimate airway epithelial damage. Chest computed tomography was also performed to visually assess mucus plugs and airway dilation with the Reiff score and quantify the total airway count and wall area percentage. 68 patients were classified into high-DPP1/high-neutrophil (n=17), low-DPP1/high-neutrophil (n=37) and low-neutrophil (n=14) groups based on sputum DPP1 levels and neutrophil percentages. The rate of mucus plugging and the relative abundance of the phylum Firmicutes were significantly lower and the level of sputum HMGB1 was significantly greater in the high-DPP1/high-neutrophil group than in the low-DPP1/high-neutrophil group. Moreover, airway dilation without mucus plugging was observed only in the high-DPP1/high-neutrophil group (prevalence 29%). High sputum DPP1 levels may reduce colonisation by the phylum Firmicutes and mucus plugging, but increase airway epithelial damage, which could induce airway dilation without mucus plugging in patients with obstructive airway disease with neutrophilic inflammation.

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis (BE). Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in BE, no drug that controls neutrophilic inflammation is licensed for the treatment of BE. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of neutrophil elastase) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in BE pathogenesis, and not just neutrophil elastase. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in BE and improve disease outcomes as a result. Clinical trials for CatC inhibitors in BE have reported positive Phase III results. In this narrative review, we discuss the role of high NSP activity in BE, and how this feature drives the associated morbidity and mortality seen in BE. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the BE lung, summarising clinical trial outcomes, and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in BE.

Bronchiectasis (BE) is an increasing global problem affecting children and adults. Historically regarded as an orphan condition, there has been an increase in both clinical and translational research in recent years. Pathophysiology of BE is understood in terms of the vicious vortex which has three key components leading to airway structural damage: impaired mucociliary clearance, airway infection and inflammation.1 While airway clearance through physiotherapy and antibiotic treatment has been the cornerstone of BE treatment for decades, there is a lack of effective therapies targeting inflammation.1, 2 Neutrophils are the most abundant inflammatory cells identified in the airways of patients with BE.1 Neutrophilic inflammation is a double-edged sword, leading on one hand to the release of harmful proteases and tissue damage, and on the other hand, contributing to immune defence. Previous clinical trials aiming to reduce neutrophil recruitment to the airway have shown similar patterns of increased infections. Understanding the mechanisms of neutrophilic inflammation is the key to unlocking new therapeutic targets. We recently conducted a series of studies with international collaborators in Spain, Italy and Australia to better understand the nature of neutrophilic inflammation in BE.1 Utilizing proteomic analysis of sputum samples, we identified that severe disease in BE was characterized by an upregulation of neutrophil and neutrophil extracellular trap (NET)-associated proteins.1 We validated these findings in two large cohort studies and found that increased sputum NET complexes were associated with disease severity, reduced quality of life, severe exacerbations and mortality. Azithromycin treatment has been proven to reduce exacerbation frequency, including in patients with Pseudomonas aeruginosa infection which is intrinsically resistant to the antibiotic effect of macrolides. Analysis of two long-term studies of azithromycin, one in BE and the AMAZES trial in asthma, demonstrated that NETs could be reduced, and clinical outcomes improved with macrolide treatment.1 This provides a potential mechanism for the beneficial effects of macrolides, particularly in patients with neutrophilic disease. Our results suggest that NETs may contribute to symptoms and exacerbations in BE and NETs are likely to be the primary mechanism by which harmful neutrophil serine proteases such as elastase are released and damage the airway. We recently reported the results of a phase 2 study of a DPP1 inhibitor in BE patients with a history of exacerbations. A total of 256 patients with BE were randomized to either two doses (10 and 25 mg) of the DPP1 inhibitor brensocatib or placebo and followed up for 6 months.2 DPP1 inhibition prevents the activation of the neutrophil proteases elastase, cathepsin-G and proteinase-3 in the bone marrow. Brensocatib treatment at both doses prolonged the time to first exacerbation and was associated with marked reductions in sputum neutrophil elastase. There were small numerical increases in skin and dental adverse effects in the phase 2 trial but no increase in infection risk. While the encouraging results need to be confirmed in a larger phase 3 trial, these data suggest the potential to directly target neutrophilic inflammation in patients with BE.2 BE is a heterogeneous disease and although neutrophilic inflammation and infection represent the most common 'endotype', clinical experience and clinical trial results suggest that there are other important contributors to disease burden and exacerbation.3, 4 Eosinophils are well-established drivers of exacerbation in asthma and chronic obstructive pulmonary disease, but until recently their role in BE was not established. Shoemark et al. recently reported the results of a pan-European cohort of 1007 patients with BE. This study showed that based on sputum eosinophil counts >3%, the gold standard for defining eosinophilic inflammation in sputum, approximately 20% of BE patients have eosinophilic inflammation after the exclusion of patients with asthma and allergic bronchopulmonary aspergillosis. Eosinophil counts in blood >300 cells/μl were shown to be a valid surrogate marker of sputum counts. In a sub-study of 144 patients, eosinophilic inflammation in blood was associated with increased risk of exacerbation.3 Oriano et al. extended these observations by also incorporating measurement of FeNO showing that a Th2-high endotype of BE was present in 31% of patients when considering a high eosinophil count (>300 cells/μl) and a raised FeNO ≥25 dpp. Patients with T2-high inflammation had more severe disease and worse symptoms.4 These studies demonstrate that BE is not exclusively a neutrophilic disease. Eosinophilic inflammation may contribute to a subset of BE exacerbations and biomarkers may be useful to target anti-eosinophil strategies such as inhaled corticosteroids or anti-IL5 therapies in future. Observational studies and post hoc analyses of randomized trials already suggest that eosinophil counts in blood may predict treatment responses in BE, although these results need to be confirmed in prospective trials.5 BE is therefore entering a new era where patients can be potentially classified into inflammatory endotypes based on the presence of neutrophilic or eosinophilic (or mixed) profiles which may require different treatments. Ongoing phase 3 trials of both anti-neutrophil (NCT04594369) and anti-eosinophil (NCT05006573) anti-inflammatory strategies represent important opportunities to transform the management of BE. Infection remains a crucial component of the vicious vortex, and targeting inflammation cannot ignore the important contribution of the airway microbiome. While much research has focused on the roles of conventional pathogens such as P. aeruginosa, which are consistently associated with poor clinical outcomes, recent research using next-generation sequencing has given us a more nuanced view of the role of bacteria in BE.6, 7 The concept of 'good bacteria' in the microbiome is well accepted in the gut but poorly defined in the airways. Commensals such as Rothia may have a beneficial effect on inflammation, as demonstrated in a recent study by Rigauts et al. Using murine models, Rothia mucilaginosa was shown to have an inhibitory effect on pathogen and LPS-induced proinflammatory responses through inhibiting nuclear factor kappa B (NF-kB) pathway activation. In sputum samples obtained from BE patients, Rothia spp. were negatively correlated with pro-inflammatory mediators, demonstrating that the presence of this organism in the lower airways may reduce inflammation.6 These studies add to evidence that the interactions between bacteria are important in determining patient outcomes7 and demonstrate that modulation of the microbiome may be a powerful tool in reducing inflammation. How to modulate the microbiome remains a challenging question. Our studies using proteomics found that antibiotic treatment in patients with dominance of Gram-negative organisms such as Pseudomonas and Haemophilus reduces neutrophilic inflammation and upregulates antiprotease defence.1 Whether the microbiome can be modified using non-antibiotic approaches such as immune modulators or probiotics requires investigation. BE therapy is entering a new era where immune-modulating therapy has a key role alongside airway clearance and antibiotics. Classifying patients into endotypes, based on neutrophilic, eosinophilic or mixed inflammatory profiles, offers a range of treatment targets under a personalized medicine approach. Targeting inflammation directly, through treatments such as DPP1-inhibition, and indirectly through modulation of the microbiome may both lead to improvements in patient outcomes in the future. Holly R. Keir and James D. Chalmers are funded by Asthma and Lung UK. Holly R. Keir declares no conflicts of interests. James D. Chalmers reports research grants and consultancy from Astrazeneca, Boehringer Ingelheim, Chiesi, Gilead Sciences, Glaxosmithkline, Grifols, Insmed, Novartis, Pfizer and Zambon.

Neutrophilic airway inflammation is a key pathogenic driver of bronchiectasis, sustaining a vicious cycle of infection, mucus obstruction, recurrent exacerbations and progressive airway damage. The growing knowledge on the neutrophilic bronchiectasis endotype has led to increasing interest in host-directed approaches targeting neutrophilic mediators. Long-term macrolide therapy currently represents the reference anti-inflammatory treatment for patients with bronchiectasis at high risk of exacerbations and is supported by randomized controlled trials and extensive clinical experience. However, its use is limited by antimicrobial resistance, drug-to-drug interactions, safety concerns in selected populations and uncertainty regarding optimal dosing and duration. More recently, inhibition of Cathepsin C (CatC), an upstream regulator of neutrophil serine protease activation, has emerged as a novel therapeutic strategy aimed at reducing protease-driven airway injury. This manuscript presents a focused review of the literature that critically examines and compares long-term macrolides and CatC inhibitors with respect to their mechanisms of action, clinical evidence, safety profiles and potential roles within future treatment algorithms. We summarize data from Phase II and III trials of CatC inhibitors, particularly brensocatib, highlighting their effects on exacerbation risk, lung function trajectories and biomarkers of neutrophilic inflammation. We also discuss the limitations of the current evidence base, including restricted trial populations, limited long-term data and the lack of validated biomarkers to guide treatment selection in clinical practice. Finally, we discuss future perspectives for integrating these therapies into individualized, biomarker-informed management of bronchiectasis. Together, these developments support a shift towards more mechanism-based and personalized anti-inflammatory treatment strategies in bronchiectasis, in which treatment selection is guided by underlying inflammatory pathways. This review aims to translate current clinical evidence into practical considerations for patient selection and future therapeutic positioning, thereby helping bridge the gap between research and clinical implementation.

Noncystic fibrosis bronchiectasis, hereafter referred to as bronchiectasis, is a chronic, progressive lung disease that can affect people of all ages. Patients with clinically significant bronchiectasis have chronic cough and sputum production, as well as recurrent respiratory infections, fatigue and impaired health-related quality of life. The pathophysiology of bronchiectasis has been described as a vicious vortex of chronic inflammation, recurring airway infection, impaired mucociliary clearance and progressive lung damage that promotes the development and progression of the disease. This review describes the pivotal role of neutrophil-driven inflammation in the pathogenesis and progression of bronchiectasis. Delayed neutrophil apoptosis and increased necrosis enhance dysregulated inflammation in bronchiectasis and failure to resolve this contributes to chronic, sustained inflammation. The excessive release of neutrophil serine proteases, such as neutrophil elastase, cathepsin G and proteinase 3, promotes a protease-antiprotease imbalance that correlates with increased inflammation in bronchiectasis and contributes to disease progression. While there are currently no licensed therapies to treat bronchiectasis, this review will explore the evolving evidence for neutrophilic inflammation as a novel treatment target with meaningful clinical benefits.

There is an unmet need for therapies targeting chronic neutrophilic inflammation in bronchiectasis. In the Phase II, dose-finding AIRLEAF® study, the dipeptidyl peptidase 1 (cathepsin C) inhibitor verducatib (BI 1291583) reduced the pulmonary exacerbation risk in people with bronchiectasis and demonstrated a similar safety profile to placebo; these results support the investigation of verducatib in a Phase III study. Here, we describe the design of the Phase III, randomised, double-blind AIRTIVITY™ study (ClinicalTrials.gov identifier NCT06872892 ), assessing the efficacy, safety, and tolerability of verducatib in people with bronchiectasis. In AIRTIVITY™, approximately 1680 adults and 75 adolescents (aged 12–<18 years) with bronchiectasis with a broad range of aetiologies are randomised 2:1 to receive oral verducatib 2.5 mg or placebo for at least 52 weeks and up to 76 weeks. Unlike previous studies of bronchiectasis, people with cystic fibrosis-related bronchiectasis are included. The primary objective is to demonstrate the superiority of verducatib compared with placebo on the annualised rate of pulmonary exacerbations up to 76 weeks. The main secondary objective is to demonstrate a reduction in lung function decline, an improvement in respiratory symptoms, a prolongation in time to first pulmonary exacerbation and a reduction in annualised rate of severe pulmonary exacerbations for verducatib versus placebo. All pulmonary exacerbations are adjudicated. If the efficacy of verducatib is demonstrated and there is a favourable benefit–risk ratio, the AIRTIVITY™ results will provide confirmatory evidence for the use of verducatib 2.5 mg in a large and broad bronchiectasis population, independent of underlying aetiology.

IntroductionThe relationship between neutrophilic inflammation and microbiome dysbiosis, two central features of bronchiectasis pathophysiology, is not fully understood. We used novel full length 16s rRNA sequencing, which provides detailed characterisation...

BackgroundElevation of systemic inflammatory markers were found to correlate with increased disease extent, reduced lung function and higher risk of future severe exacerbations in patients with bronchiectasis. Although a significant correlation of circulating hs-CRP levels with HRCT scores and resting oxygen saturation in patients with stable-state non-cystic fibrosis (CF) bronchiectasis was suggested, there is little data on the relationship between hs-CRP and the prognosis of bronchiectasis and a lack of data on the role of hs-CRP in predicting bronchiectasis exacerbation.MethodsA prospective study was conducted on Chinese patients with non- CF bronchiectasis from 1st October to 31st December 2021. Baseline serum hs-CRP were obtained at stable-state. The follow-up period lasted for one year. Co-primary endpoints were the development of any bronchiectasis exacerbation and hospitalized bronchiectasis exacerbation.ResultsTotally 123 patients were included. Higher hs-CRP was associated with increased risk to develop any bronchiectasis exacerbation, adjusted odds ratio (aOR) of 2.254 (95% CI = 1.040–4.885, p = 0.039), and borderline significantly increased hospitalized bronchiectasis exacerbation with aOR of 1.985 (95% CI = 0.922–4.277, p = 0.080).ConclusionBaseline serum hs-CRP level at stable-state can predict risk of bronchiectasis exacerbation, which is reflecting chronic low-grade inflammation in bronchiectasis.

Bronchiectasis is a chronic airway disease characterized by dysbiosis, persistent inflammation, and permanent structural airway damage. Neutrophilic inflammation is a key pathogenic feature, as indicated by enhanced neutrophil-derived proteases and formation of neutrophil extracellular traps (NETs), associated with poor prognosis. However, recent studies have identified an eosinophilic endotype in up to 30% of patients, characterized by higher levels of type 2 (T2) cytokines and fractional exhaled nitric oxide (FeNO). The role of T helper (Th) cells in the dysregulated inflammatory environment of bronchiectasis remains unclear. Evidence suggests that persistent bacterial infection can skew adaptive immunity from Th1 toward Th2 response, while the airway microbiome-IL-17 axis is also a critical regulator of chronic inflammation. T regulatory (Treg) cells have been shown to play a protective role against excessive chronic inflammation by modulating the function of several types of effector cells, including the Th17 subset. However, the capacity of this subset to delay or prevent disease progression remains to be determined Microbial dysbiosis, with loss of diversity and increased quantity of bacterial pathogens, may also be important for disease progression, and emerging evidence indicates that distinct inflammatory endotypes associate with specific microbiota alterations, especially in severe disease. In this review, we provide an overview of the immune cells and cytokine signaling that are involved in the pathogenesis of bronchiectasis. Additionally, we present the main endotypes of bronchiectasis and explore the relationships between the type of inflammation and alterations in microbiota, as well as the potential benefits of targeting specific pathophysiological mechanisms for the management of bronchiectasis. This review also examines how bacterial infection can shift adaptive immunity from Th1 toward Th2 responses, the role of the airway microbiome-IL-17 axis in chronic inflammation and the potential protective role of Treg cells against excessive inflammation. Novel therapeutic strategies are highlighted, with focus on targeting specific cytokine signaling pathways and restoring Th17/Treg balance These developments underscore a shift toward precision medicine in bronchiectasis, emphasizing the importance of identifying specific inflammatory endotypes to tailor treatment strategies effectively.

Bronchiectasis is a heterogeneous chronic lung disease, characterised by irreversible dilatation of the airways and attributed to a wide spectrum of other underlying conditions, usually underdiagnosed and inadequately treated with a high burden for both the patients and the healthcare system. The way bronchiectasis is viewed by physicians has drastically changed over the last decades, with the topic of eosinophilia in the context of the disease being one of the substantially highlighted. Eosinophilia was traditionally considered as a means for distinguishing bronchiectasis from asthma, whereas bronchiectasis was primarily associated with neutrophilic inflammation. However, eosinophilic bronchiectasis is nowadays identified as a distinct disease endotype and is associated with a specific clinical course and response to treatment. Further research is needed to better characterise this endotype and improve its personalised investigation and management in daily clinical practice.

PurposeInfections from the oral microbiome may lead to exacerbations of chronic obstructive pulmonary disease (COPD). We investigated whether advanced dental cleaning could reduce exacerbation frequency. Secondary outcomes were disease-specific health status, lung function, and whether the bacterial load and composition of plaque microbiome at baseline were associated with a difference in outcomes.Patients and MethodsOne-hundred-one primary and secondary care patients with COPD were randomized to intervention with advanced dental cleaning or to dental examination only, repeated after six months. At baseline and at 12 months, data of exacerbations, lung function, COPD Assessment Test (CAT) score, and periodontal status were collected from questionnaires, record review, and periodontal examination. Student’s t-test and Mann–Whitney-U (MWU) test compared changes in outcomes. The primary outcome variable was also assessed using multivariable linear regression with adjustment for potential confounders. Microbiome analyses of plaque samples taken at baseline were performed using Wilcoxon signed ranks tests for calculation of alpha diversity, per mutational multivariate analysis of variance for beta diversity, and receiver operating characteristic curves for prediction of outcomes based on machine learning models.ResultsIn the MWU test, the annual exacerbation frequency was significantly reduced in patients previously experiencing frequent exacerbations (p = 0.020) and in those with repeated advanced dental cleaning (p = 0.039) compared with the non-treated control group, but not in the total population including both patients with a single and repeated visits (p = 0.207). The result was confirmed in multivariable linear regression, where the risk of new exacerbations was significantly lower in patients both in the intention to treat analysis (regression coefficient 0.36 (95% CI 0.25–0.52), p < 0.0001) and in the population with repeated dental cleaning (0.16 (0.10–0.27), p < 0.0001). The composition of microbiome at baseline was moderately predictive of an increased risk of worsened health status at 12 months (AUC = 0.723).ConclusionAdvanced dental cleaning is associated with a reduced frequency of COPD exacerbations. Regular periodontal examination and dental cleaning may be of clinical importance to prevent COPD exacerbations.

Bronchiectasis is a highly heterogeneous chronic respiratory disease. This review aims to summarize recent advancements in pathogenesis and therapeutic strategies within the precision medicine framework, focusing on how individualized approaches to diagnosis and management are replacing conventional “one-size-fits-all” treatments to improve patient clinical outcomes. We synthesized high-level evidence from global registries, such as EMBARC and the BE-China National Prospective Registry, alongside findings from multi-omics research and recent clinical trials. The review evaluates quantifiable biomarkers for endotype-based stratification and assesses mechanism-oriented interventions, including novel targeted therapies and pathogen eradication strategies. Pathogenesis is now conceptualized through the “vicious vortex” model involving persistent infection, dysregulated inflammation, and structural damage. Specific biomarkers, including sputum neutrophil elastase (NE) activity and blood eosinophil counts, allow for the identification of distinct inflammatory endotypes. Notably, the August 2025 Food and Drug Administration (FDA) approval of brensocatib, a dipeptidyl peptidase 1 inhibitor, represents a major milestone in targeted therapy for non-cystic fibrosis bronchiectasis. Furthermore, advancements in understanding the airway resistome and managing multidrug-resistant Pseudomonas aeruginosa have provided robust tools for molecular classification and risk stratification in clinical practice. Bronchiectasis management has shifted from descriptive phenotyping to biomarker-driven endotyping. Transitioning toward mechanism-oriented interventions enables precise clinical decision-making, which is essential for modifying disease progression and reducing the global healthcare burden in the precision medicine era.