Bone marrow kinase X-linked in pulmonary diseases: pathogenic gene, diagnostic biomarker, and treatment target—a narrative review

Abstract

Background and Objective

Lung-related diseases impose a substantial global health burden, yet effective diagnostic and therapeutic strategies remain limited. Bone marrow kinase X-linked (BMX), a Tec family non-receptor tyrosine kinase, is increasingly recognized as a critical player in pulmonary pathophysiology. This review aims to systematically evaluate BMX’s roles in major lung diseases, clarify its mechanisms, assess its biomarker and therapeutic potential, and identify key knowledge gaps.

Methods

We searched PubMed, Web of Science, and Scopus up to December 2025 using keywords related to BMX and pulmonary diseases, with additional references identified from article bibliographies.

Key Content and Findings

BMX is implicated in pneumonia, asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and lung cancer via PI3K/AKT, MAPK/ERK, NF‑κB, and TGF‑β/Smad pathways, regulating inflammation, fibrosis, cell survival, and metastasis. BMX expression correlates with disease severity and prognosis, supporting its biomarker potential. Preclinical studies show that BMX inhibitors reduce disease severity in animal models, but clinical translation is hampered by lack of specific biomarkers, limited trials, and challenges in selectivity and resistance.

Conclusions

This review synthesizes current knowledge on BMX in pulmonary diseases, highlighting its pathogenic, diagnostic, and therapeutic significance. By outlining current gaps and future directions, it provides a foundation for developing BMX‑targeted precision medicine to ultimately improve patient outcomes.

Introduction

Lung diseases are a significant challenge in the global public health field, with complex and diverse etiologies (1,2). These include infectious diseases such as pneumonia and tuberculosis, chronic conditions like chronic obstructive pulmonary disease (COPD) and asthma, as well as malignant diseases such as lung cancer (1,2). Although research on lung diseases has made progress in understanding their causes, pathogenesis, diagnosis, and treatment, numerous challenges persist. These diseases severely impact patients’ quality of life and impose a substantial economic burden on families and society. Therefore, in-depth research and discussion on the etiology, pathogenesis, diagnosis, and treatment methods for lung diseases are crucial for improving patient prognosis and alleviating societal burdens.

Bone marrow kinase X-linked (BMX), a non-receptor tyrosine kinase belonging to the Tec family, is widely distributed across various tissues and cell types, playing a critical role in cellular signaling (3). Initially identified in hematopoietic cells, subsequent studies have revealed its expression not only in the hematopoietic system but also in endothelial cells, epithelial cells, and certain cancer cells (4). BMX regulates cell proliferation, differentiation, migration, and survival through interactions with other proteins via its SH2, SH3, and PH domains (5,6). Research shows that BMX exhibits abnormal expression in various cancers, with its activation closely associated with tumor progression and invasion (7). Inhibition of BMX significantly reduces cancer cell proliferation and migration, indicating that BMX is a potential therapeutic target (8). Additionally, BMX plays a key role in angiogenesis, a fundamental process for tumor growth and metastasis (9). By regulating the proliferation and migration of vascular endothelial cells, BMX promotes the formation of new blood vessels (10,11). Studies have found that inhibiting BMX can substantially reduce angiogenesis, thereby suppressing tumor growth and metastasis, further supporting the potential of BMX as a target for anti-cancer therapy (12-14). In inflammatory responses, BMX also plays an important role (15). By regulating the production of inflammatory mediators, BMX influences the intensity and duration of inflammatory responses (16,17). In certain autoimmune and inflammatory diseases, abnormal activation of BMX may lead to excessive inflammatory responses, exacerbating disease progression (18-21). Targeting BMX could help control inflammation to some extent, alleviate symptoms, and improve the quality of life for patients (22,23). In summary, BMX is a key pathogenic gene in the development of human diseases and a potential therapeutic target.

In recent years, the expression and regulatory mechanisms of BMX in pulmonary diseases have become a focal point of research and have garnered increasing attention. BMX is closely related to the occurrence and development of various lung diseases, such as COPD, asthma, pulmonary fibrosis, and lung cancer, particularly in regulating inflammatory responses and immune functions (10,24-27). For instance, in the field of lung cancer research, BMX has demonstrated the ability to promote tumor growth and metastasis primarily through the activation of MAPK/ERK and PI3K/AKT signaling pathways, which in turn enhance cell proliferation and survival (28,29). Furthermore, BMX enhances tumor invasiveness and metastatic capability by regulating the extracellular matrix (ECM) and tumor microenvironment (TME) (30,31). These findings not only deepen our understanding of the mechanisms underlying lung cancer but also provide a theoretical basis for developing new treatment strategies. Additionally, in COPD research, BMX promotes the release of inflammatory factors and enhances pulmonary inflammatory responses by activating the NF-κB signaling pathway (32,33). It also causes cellular damage and apoptosis by regulating mitochondrial function and oxidative stress (34,35). Therefore, targeting BMX may represent a new strategy for treating COPD. In pulmonary fibrosis research, BMX exacerbates the fibrotic process by activating the TGF-β/Smad signaling pathway, promoting fibroblast proliferation and collagen synthesis (34,36). It also influences the formation and progression of fibrotic tissue by regulating ECM remodeling (37), providing new insights for the treatment of pulmonary fibrosis.

In conclusion, BMX plays a critical role in various pulmonary diseases, influencing their occurrence and progression through multiple signaling pathways and biological processes (Figure 1). However, comprehensive reviews deciphering the relationship between BMX and lung diseases remain lacking. Therefore, this review summarizes the research progress of BMX in pulmonary diseases, exploring its mechanisms of action in these diseases and its potential clinical application value. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0648/rc).

Figure 1.

Role of BMX in lung diseases. This review offers a thorough analysis of BMX’s relationship with lung diseases, including pneumonia, asthma, COPD, pulmonary fibrosis, and lung cancer. This review indicates that BMX is a key pathogenic gene and a potential diagnostic biomarker in lung diseases. BMX, bone marrow kinase X-linked; COPD, chronic obstructive pulmonary disease.

Methods

We systematically searched PubMed, Web of Science, and Scopus in December 2025 with no start date restriction. Search terms combined MeSH and free‑text keywords related to BMX and pulmonary diseases, including “bone marrow kinase X‑linked”, “BMX”, “ETK”, “pulmonary diseases”, “pneumonia”, “asthma”, “COPD”, “pulmonary fibrosis”, “lung cancer”, “inflammation”, “biomarker”, “therapeutic target”, and “BMX inhibitors”, using Boolean operators (AND, OR). Additional references were identified by screening bibliographies of retrieved articles. No language restrictions were applied. Studies on BMX expression, function, mechanisms, or therapeutic targeting in pulmonary diseases were included; case reports, conference abstracts, and unrelated studies were excluded. Two reviewers (X.G. and Z.G.) independently screened titles and abstracts; discrepancies were resolved by discussion or consultation with a third reviewer (L.L.). Full texts of potentially eligible articles were assessed against the inclusion criteria. As this is a narrative review, the search was not intended to be exhaustive, but to provide a comprehensive overview of the current evidence. The search strategy is summarized in Table 1.

Table 1. The search strategy summary.

Items	Specification
Date of search	December 2025
Databases and other sources searched	PubMed, Web of Science, Scopus; additional references identified by manual screening of bibliographies of retrieved articles and relevant reviews
Search terms used	MeSH terms: “Protein-Tyrosine Kinases”, “Lung Diseases”, “Pulmonary Disease, Chronic Obstructive”, “Pulmonary Fibrosis”, “Lung Neoplasms”, “Asthma”, “Pneumonia”. Free-text terms: “bone marrow kinase X-linked”, “BMX”, “ETK”, “Tec family kinases”, “pulmonary diseases”, “lung cancer”, “COPD”, “inflammation”, “biomarker”, “therapeutic target”, “BMX inhibitors”. Filters: none applied
Timeframe	From database inception to December 2025
Inclusion and exclusion criteria	Inclusion: original research, reviews, and clinical studies focusing on BMX expression, function, mechanisms, or therapeutic targeting in pulmonary diseases. Exclusion: case reports, conference abstracts, studies not related to BMX or pulmonary diseases. Language: no restrictions
Selection process	Two independent reviewers (X.G. and Z.G.) screened titles and abstracts; discrepancies resolved by discussion or consultation with a third reviewer (L.L.)
Additional considerations	As a narrative review, the search was not intended to be exhaustive but to provide a comprehensive overview

BMX, bone marrow kinase X-linked.

Role of BMX in pulmonary diseases and its clinical potential

Molecular structure, tissue expression, and core signaling pathways of BMX

BMX, also known as ETK (epithelial and endothelial tyrosine kinase), is a non-receptor tyrosine kinase belonging to the Tec family (3). The BMX gene is located on chromosomal band Xp22.2, and its closest relative, BTK, is also located on chromosome X (3). BMX cDNA comprises an open reading frame of 675 amino acids (3). Like other Tec family kinases, BMX contains five conserved domains: an N-terminal pleckstrin homology (PH) domain, a Tec homology (TH) domain, a Src-homology 3 (SH3) domain, a Src-homology 2 (SH2) domain, and a C-terminal tyrosine kinase domain (3). The PH domain mediates membrane localization by binding to phosphatidylinositol-3,4,5-trisphosphate (PIP₃), recruiting BMX to the plasma membrane upon PI3K activation (3). The SH2 and SH3 domains mediate interactions with phosphorylated tyrosine residues and proline-rich motifs, respectively, while the C-terminal kinase domain catalyzes substrate phosphorylation and serves as the primary target for small-molecule inhibitors.

BMX is expressed not only in the hematopoietic system but also in arterial endothelium, epithelial cells, and various cancer cells (4). In the vascular system, BMX is highly expressed in arterial endothelium from the embryonic stage to adulthood, and protein expression has also been detected in adipose tissue and brain. An 80-kD BMX polypeptide has been identified in human endothelial cells (4). This broad tissue distribution underscores its involvement in diverse physiological and pathological processes.

BMX regulates multiple downstream signaling pathways critical for cell proliferation, survival, migration, and inflammatory responses (5,6). Upon PI3K activation, BMX promotes AKT phosphorylation via the PI3K/AKT pathway, enhancing cell survival and proliferation. BMX also activates the MAPK/ERK pathway to regulate cell growth and differentiation. Additionally, BMX is a potent activator of STAT signaling, inducing tyrosine phosphorylation and DNA binding activity of STAT1, STAT3, and STAT5; through STAT3 activation, BMX maintains stem cell self-renewal and tumorigenic potential. In inflammatory contexts, BMX modulates the NF-κB pathway and regulates Toll-like receptor-induced interleukin-6 (IL-6) production, thereby influencing the intensity and duration of inflammation. BMX has also been implicated in actin cytoskeleton reorganization and cell migration. Through these diverse signaling pathways, BMX plays pleiotropic roles fundamental to the pathogenesis of various pulmonary diseases.

BMX and pneumonia

Pneumonia is a common acute respiratory infection primarily triggered by pathogenic organisms, including bacteria, viruses, and fungi (38). This illness poses a significant threat, particularly to individuals with weakened immune systems (39). The underlying mechanisms of pneumonia involve a complex interplay of various immune cells and inflammatory mediators (40). Recent research has highlighted the crucial role of BMX in the onset and advancement of pneumonia, as it greatly influences several cellular signaling pathways, particularly those involved in modulating immune responses and inflammatory processes (41).

Primarily, BMX plays a crucial role in pneumonia by regulating the inflammatory response (42). A hallmark of pneumonia is the infiltration of inflammatory cells and the overproduction of cytokines within lung tissues (43). Specifically, BMX influences the activity of macrophages and neutrophils, impacting their chemotaxis, phagocytosis, and bactericidal functions (42). It notably enhances the release of pro-inflammatory cytokines, such as IL-1β and tumor necrosis factor-α (TNF-α), from macrophages, which intensifies the inflammatory reaction (42). Furthermore, BMX activates the NF-κB signaling pathway, contributing to the amplification of this inflammatory response (7,44). In addition to this, BMX’s involvement in pneumonia extends to its regulation of apoptosis and autophagy (45,46). These processes are vital for maintaining homeostasis in lung tissues during pneumonia. Studies indicate that BMX can affect the expression of Bcl-2 family proteins, thereby modulating the apoptotic pathways in lung epithelial and immune cells (26,47). Simultaneously, BMX influences autophagy via the mTOR signaling pathway, which plays a role in the repair and regeneration of lung tissue (29,48). Moreover, BMX also participates in the management of oxidative stress responses in pneumonia (49). Oxidative stress is a key factor in the disease’s pathology, where an overabundance of reactive oxygen species (ROS) can result in cellular damage and trigger inflammatory responses (50,51). BMX enhances the antioxidant defenses of cells by modulating the Nrf2/HO-1 signaling pathway, thereby alleviating damage to lung tissue induced by oxidative stress (52).

Moreover, BMX’s role in lung infections is closely related to other signaling pathways. For instance, the NF-κB signaling pathway plays a pivotal role in inflammatory responses, and the interaction between BMX signaling and NF-κB may be a crucial node in regulating inflammation (53). Study indicates that BMX can modulate the expression of inflammatory factors by either activating or inhibiting the NF-κB signaling pathway, thus influencing the progression of infections (7,33). Additionally, BMX’s effects on different types of immune cells vary significantly. For example, in macrophages, BMX activation can enhance phagocytosis and improve the clearance efficiency of pathogenic microorganisms (54). Conversely, in neutrophils, excessive activation of BMX may lead to increased oxidative stress, resulting in tissue damage (55,56). Therefore, formulating differentiated BMX regulatory strategies tailored to different immune cell types may be key to achieving precision treatment. For instance, precise adjustments to BMX signaling pathways can be accomplished through gene editing techniques or specific small molecule inhibitors to balance immune responses. This approach not only helps improve therapeutic efficacy but also reduces lung tissue damage caused by excessive inflammatory responses. Further in-depth research into the interaction mechanisms between BMX and other signaling pathways could lead to the development of more precise therapeutic strategies to address various complex lung infection scenarios.

It is noteworthy that the role of BMX in pneumonia has a dual nature. On one hand, BMX facilitates the inflammatory response, aiding in the clearance of pathogenic microorganisms and protecting the body from infection. On the other hand, excessive BMX activity may lead to uncontrolled inflammation and exacerbate lung tissue damage. Additionally, the role of BMX in lung infections may be influenced by environmental factors. For instance, external factors such as smoking and air pollution can alter BMX expression and activity, impacting the effectiveness of lung immune responses. Research has found that individuals exposed to air pollution for extended periods exhibit significantly elevated levels of BMX activity, accompanied by more intense inflammatory responses (57). This indicates that individual environmental exposure history and lifestyle habits must be considered when formulating treatment plans for lung infections, allowing for more personalized treatment strategies. Therefore, the reasonable modulation of BMX activity is crucial for the prevention and treatment of pneumonia. Based on the aforementioned mechanisms, BMX holds considerable potential as a new therapeutic target for pneumonia treatment.

In terms of clinical application, research targeting BMX has already shown promising results. For example, some preclinical studies have demonstrated that the use of BMX inhibitors can effectively reduce inflammatory responses and tissue damage in experimental pneumonia models (58,59). Additionally, BMX inhibitors can promote lung tissue repair and regeneration by modulating apoptosis and autophagy (60,61). Furthermore, BMX inhibitors can enhance antioxidant capacity, alleviating oxidative stress-related damage to lung tissue (10,15). This lays the foundation for the future development of BMX-related therapeutic drugs. However, the application of BMX inhibitors in pneumonia treatment still faces several challenges. Firstly, given that BMX plays a role in multiple cellular signaling pathways, targeting BMX could lead to widespread side effects. Therefore, a key focus for future research will be selectively inhibiting specific functions of BMX while avoiding impacts on normal physiological functions. Secondly, BMX’s role may vary at different stages of pneumonia, making appropriate timing and dosage of administration critical factors influencing therapeutic efficacy. Additionally, the pharmacokinetic properties and bioavailability of BMX inhibitors require further optimization to enhance their feasibility for clinical application. Moreover, exploring the combined effects of BMX inhibitors with existing anti-infection drugs may yield better therapeutic outcomes. Finally, translating these research findings into clinical practice necessitates conducting extensive clinical trials to verify their safety and effectiveness.

In conclusion, the role of BMX in lung infections is multifaceted, and its regulatory mechanisms are complex and varied. Future research should focus on elucidating the specific mechanisms of BMX in different pathological states, exploring its interactions with other signaling molecules, optimizing the design and application strategies of BMX inhibitors, and developing precision regulatory strategies targeting BMX. Only through these efforts can the potential of BMX in anti-infection therapy be fully realized, maximizing therapeutic efficacy and minimizing adverse reactions, ultimately benefiting patients significantly.

BMX and asthma

Asthma is a common chronic inflammatory airway disease characterized by airway hyperresponsiveness and reversible airflow obstruction (62). The pathogenesis is complex, involving both genetic and environmental factors (62). Studies found that BMX is highly expressed in the airway epithelial cells and immune cells of patients with asthma, and the abnormal expression and dysfunction of BMX may lead to excessive airway inflammatory response, indicating a positive correlation between BMX activity and the severity of airway inflammation (26,63-65). Furthermore, BMX can also regulate the activities of B cells and mast cells, affecting the generation and release of immunoglobulin E, thereby exacerbating the airway inflammation and allergic reactions in patients with asthma (17,66). Additionally, BMX is involved in the repair process of airway epithelial cells, and its dysfunction may result in the difficulty in repairing damaged airway epithelial cells, further aggravating the symptoms of asthma (10,26).

In recent years, the mechanisms by which BMX contributes to asthma have been gradually elucidated. Firstly, the role of BMX in asthma is closely related to its regulation of the inflammatory response. Studies have shown that BMX can promote the activation of inflammatory cells and the release of inflammatory mediators by regulating inflammatory signaling pathways (7,19). In patients with asthma, the overexpression of BMX leads to an increase in inflammatory factors such as IL-4, IL-5, and IL-13, which play a critical role in the pathogenesis of asthma (7,19,67). Furthermore, BMX can also activate the NF-κB signaling pathway, further enhancing the inflammatory response and leading to airway epithelial cell damage and remodeling (34,68). Secondly, the role of BMX in airway remodeling cannot be ignored. Airway remodeling is an important pathological feature of asthma, involving processes such as airway smooth muscle hyperplasia, fibrosis, and angiogenesis. BMX can influence the behavior of airway smooth muscle cells and fibroblasts by regulating the expression and degradation of ECM components (69). For example, BMX can promote the expression of matrix metalloproteinases (MMPs), enhancing the degradation of ECM and leading to changes in airway structure (70). Meanwhile, BMX can also affect the proliferation and migration of vascular endothelial cells, promoting airway angiogenesis, further exacerbating airway remodeling (71). Moreover, BMX plays an important role in regulating the function of immune cells (72). Asthma is an immune-mediated disease, and immune cells such as T lymphocytes, B lymphocytes, mast cells, and eosinophils play a crucial role in its pathogenesis (73). BMX can influence the activation and function of these immune cells, affecting the development of asthma. For instance, BMX can regulate the T cell receptor signaling pathway, affecting the proliferation and differentiation of T cells, promoting the activation of Th2 cells and the secretion of cytokines such as IL-4 and IL-5, thereby aggravating the inflammatory response in asthma (17,74).

In conclusion, the pathways through which BMX influences asthma predominantly encompass the modulation of the inflammatory response, participation in airway remodeling, and alteration of immune cell functionality. Moreover, research indicates that the inhibition of BMX activity markedly reduces airway inflammation and remodeling in murine models of asthma, implying that BMX may serve as a viable therapeutic target for this condition. Consequently, future investigations should aim to delineate the precise mechanisms by which BMX operates in asthma, design specific inhibitors or regulators that target BMX, and assess their safety and efficacy as therapeutic interventions for asthma, thereby enhancing clinical outcomes.

BMX and COPD

COPD is a disease characterized by persistent respiratory symptoms and airflow limitation, primarily caused by chronic inflammation and airway remodeling (75). The pathogenesis of COPD involves multiple factors, such as airway inflammation, oxidative stress, and protease-antiprotease imbalance (76). Studies have found that BMX is overexpressed in the airway epithelial cells of patients with COPD, and its activity is closely related to the degree of inflammation and airway remodeling in COPD (77,78). Furthermore, BMX participates in the inflammatory response of COPD by regulating the activities of various inflammatory cells, such as macrophages, neutrophils, and lymphocytes.

As the role of BMX in the pathogenesis of COPD is further explored, increasing evidence suggests that it plays a critical role in the disease development through the regulation of multiple cell signaling pathways (79). Firstly, BMX plays an important role in the pathology of COPD by modulating the inflammatory response (79). The hallmark of COPD is chronic airway inflammation, and the activation of BMX may promote the release of specific inflammatory factors, such as TNF-α and IL-6, which play key roles in inducing airway remodeling and lung tissue injury (80,81). Therefore, the overexpression or aberrant activation of BMX may exacerbate the inflammatory response in COPD and accelerate disease progression. Secondly, BMX is also involved in the regulation of oxidative stress (79). Oxidative stress is considered an important pathological factor in the development of COPD (82). Studies have shown that BMX can influence the cell’s resistance to oxidative damage by regulating the expression of antioxidant enzymes (83-85). When BMX expression is decreased, the lung tissue’s tolerance to oxidative stress is reduced, leading to increased cell apoptosis and further lung function impairment (83-85). Therefore, BMX may serve as an important regulator of oxidative stress and play a significant role in the pathogenesis of COPD. Furthermore, the BMX signaling pathway is closely related to cell apoptosis (45). Patients with COPD often exhibit abnormal apoptosis and autophagy in their airway epithelial cells, which is associated with both the inflammatory response and the imbalance of the BMX signaling pathway (6,86,87). Research has revealed that BMX can promote cell survival and inhibit apoptosis by activating certain downstream effectors (88). Therefore, the expression level of BMX directly affects the survival status of airway epithelial cells, thereby influencing the progression of COPD.

In addition to the aforementioned effects on inflammation, oxidative stress, and cell apoptosis, the potential impact of BMX on the regulation of cellular metabolism should not be overlooked. Patients with COPD often experience metabolic disturbances, and BMX may further exacerbate disease progression by affecting energy metabolism and cellular metabolic pathways (89). For example, the aberrant expression of BMX may interfere with glycolysis and fatty acid oxidation, leading to insufficient energy supply and impaired cell function (90). This metabolic imbalance not only affects the survival of airway epithelial cells but may also influence overall lung health through systemic metabolic effects. Moreover, the role of BMX in regulating cell migration and tissue remodeling is also worth noting. One of the characteristics of COPD is the airway remodeling process, which involves the proliferation and migration of smooth muscle cells, as well as the activation of fibroblasts (91). BMX may play a critical role in cell migration by regulating the signaling pathways involved in cytoskeletal reconstruction and cell-cell adhesion (92,93). Research has found that the activation of BMX is closely related to various signaling pathways associated with cell motility (6,92), which may provide new insights into understanding the mechanisms underlying the structural changes in the airways of patients with COPD.

In summary, BMX plays multiple roles in the pathogenesis of COPD, not only through the regulation of inflammatory response, oxidative stress, and cell apoptosis, but also potentially involving cellular metabolism, migration, and tissue remodeling. Future research should systematically explore the multifaceted roles of BMX and investigate its potential as a therapeutic target for COPD. First, as a gene located on the X chromosome, the gender-specific differences in BMX expression and function may influence the susceptibility to COPD. Studies have shown significant differences in the incidence, symptom presentation, and prognosis of COPD between males and females, and BMX may be associated with these gender-related differences (94,95). Therefore, future research should focus on the mechanisms of BMX in different genders and explore its potential application in the personalized treatment of COPD.

Furthermore, studies have shown that the inhibition of BMX activity can significantly alleviate airway inflammation and lung tissue damage in animal models of COPD, thereby improving lung function (11,15). This suggests that BMX may be a potential therapeutic target for COPD, but its specific mechanisms require further investigation. Future research should focus on the feasibility of using BMX as a biomarker for early diagnosis and personalized treatment of COPD. Additionally, intervention strategies targeting BMX are gradually gaining attention in COPD treatment research. The use of small molecule inhibitors or RNA interference techniques to downregulate BMX expression may help reduce airway inflammation and improve lung function in patients with COPD. These studies provide new avenues for personalized treatment of COPD and warrant further exploration.

In terms of clinical treatment, the regulatory strategies targeting BMX are not limited to single-target interventions. Future research may consider combining BMX with other key molecules to form multi-target treatment regimens. The combined inhibition of BMX and other pro-inflammatory signaling pathways may produce synergistic effects, more effectively alleviating the inflammatory response in COPD patients. Furthermore, considering the differential roles of BMX in different cell types, targeted therapy for specific cell populations may enhance the efficacy and safety of the treatment.

In conclusion, in-depth research on the multifunctional roles and mechanisms of BMX in COPD provides new perspectives and strategies for the treatment of this disease, ultimately aiming to improve the quality of life for COPD patients.

BMX and pulmonary fibrosis

Pulmonary fibrosis is a chronic disease characterized by excessive fibrosis of lung tissue, involving abnormal activities of various cell types (96). BMX plays a complex and multifaceted role in cell proliferation, inflammatory response, and oxidative stress (7,34). The activity and function of BMX may be regulated by various factors such as the cellular microenvironment and oxidative stress levels (34). For instance, the hallmark of pulmonary fibrosis is the over proliferation and abnormal activation of fibroblasts, and the upregulation of BMX expression in fibroblasts is positively correlated with their proliferation and migration abilities, suggesting that the overexpression of BMX may lead to aberrant fibroblast proliferation and exacerbate lung tissue fibrosis (52,97). Furthermore, oxidative stress is an important mechanism in the induction of pulmonary fibrosis, and BMX, as a key regulator of cellular stress responses, plays a critical role in the fibrosis process through the modulation of its expression or activity (34). For example, studies have shown that the upregulation of BMX is directly related to the increase in intracellular ROS levels, and this elevated ROS can further activate BMX, forming a positive feedback loop that leads to cell injury and death, affecting the progression of pulmonary fibrosis (52). Additionally, the development of pulmonary fibrosis is usually accompanied by the injury and apoptosis of alveolar epithelial cells, which may lead to changes in the local microenvironment, promoting the infiltration of inflammatory cells and the activation of fibroblasts (96). BMX is also highly expressed in alveolar epithelial cells, and its activity changes may affect their repair ability and apoptotic state (26). Furthermore, BMX may also influence the structure and function of alveoli by regulating the composition of the ECM, thereby exacerbating the degree of pulmonary fibrosis (26). Additionally, the activation of BMX in macrophages may lead to their phenotypic transformation into a pro-inflammatory type, thereby enhancing the local inflammatory response and providing a favorable environment for the progression of fibrosis (98).

Moreover, studies have revealed that BMX is not just a simple enzyme, but can also influence cell proliferation, migration, and apoptosis by regulating various cytokines and transcription factors during the process of inflammation and fibrosis (7,15). BMX can modulate the activity of transcription factors, thereby affecting the expression of pulmonary fibrosis-related genes, promoting the growth of fibroblasts and the synthesis of collagen (7,15). Furthermore, BMX can activate the NF-κB signaling pathway, thereby promoting the expression of pro-inflammatory factors such as IL-6 and TNF-α (33,99). These factors can further exacerbate lung tissue injury and fibrosis through the induction of inflammatory responses and the recruitment of fibrosis-related cells.

In addition, the mechanisms of BMX’s role in pulmonary fibrosis are not limited to its signaling transduction, but may also involve interactions with other signaling pathways (100). Pulmonary fibrosis is often accompanied by chronic inflammation, and in the inflammatory microenvironment, the release of cytokines and growth factors, such as TGF-β, can stimulate the expression of BMX, thereby activating downstream signaling pathways and promoting the activation of fibroblasts (101). Meanwhile, the activation of BMX may further lead to the release of pro-inflammatory factors, exacerbating the inflammatory environment in the lungs (19). In this process, BMX may interact with signaling pathways such as NF-κB and STAT3, enhancing the cellular response to inflammatory factors. This interplay between inflammation and fibrosis forms a vicious cycle, in which the role of BMX is particularly important. Secondly, TGF-β is a key cytokine that promotes pulmonary fibrosis, acting through the activation of the Smad signaling pathway to guide the proliferation of fibroblasts and the synthesis of collagen (101). BMX may phosphorylate Smad2/3, enhancing their transcriptional activity and upregulating the expression of ACTA2 and COL1A1 (101). This mechanism reveals the dual role of BMX in pulmonary fibrosis: on the one hand, it acts as a regulator of signal transduction, and on the other hand, it may further promote the activity of other pro-fibrotic factors, driving the pathological process. Furthermore, in addition to the crosstalk with the TGF-β pathway, the interplay between BMX and the PI3K/Akt signaling pathway is also worth noting. The PI3K/Akt pathway plays a critical role in cell growth, survival, and metabolism (102). BMX can promote the phosphorylation of Akt, thereby activating the PI3K/Akt pathway and enhancing the proliferation and survival of fibroblasts (97). This effect not only strengthens the proliferative ability of fibroblasts but also promotes their transformation into myofibroblasts and inhibits cell apoptosis, exacerbating the degree of pulmonary fibrosis.

In cell models and animal experiments, the inhibition of BMX expression or function can significantly alleviate the degree of pulmonary fibrosis, suggesting that BMX may be a potential therapeutic target, and intervention strategies targeting BMX may provide new avenues for the treatment of pulmonary fibrosis (15). However, in clinical treatment, the development of small-molecule inhibitors targeting BMX is still in the early stages, but its potential application prospects make the research in this field clinically significant.

In summary, the role of BMX in pulmonary fibrosis is complex and multifaceted, going beyond simple signal transduction. Its intricate functions in the crosstalk of multiple signaling pathways, immune regulation, and oxidative stress suggest that a systematic perspective is needed in future research. We propose that future studies on the specific mechanisms of BMX-related pathways in different pulmonary fibrosis models should aim to deeply understand the complex interactions of BMX in cell signal transduction, particularly how the interplay of multiple signaling pathways influences the progression of fibrosis, in order to construct a more comprehensive network model of the pathogenesis of pulmonary fibrosis. This will help reveal the pathophysiological mechanisms of pulmonary fibrosis and provide more effective targets for clinical intervention. In this process, multi-omics approaches, such as transcriptomics, proteomics, and metabolomics, can be used to comprehensively analyze the role of BMX in pulmonary fibrosis, which will help to reveal the panoramic picture of BMX’s involvement and clarify its functional changes at different pathological stages. Furthermore, validation studies using clinical samples are also crucial, as the analysis of BMX expression levels in the lung tissues of patients and their relationships with clinicopathological characteristics can provide stronger evidence for the potential of BMX as a biomarker and therapeutic target.

BMX and lung cancer

Lung cancer is one of the leading causes of cancer-related deaths globally, largely due to its late-stage diagnosis (103). Although the development of targeted therapies and immunotherapies has significantly prolonged the survival of some patients, the overall prognosis remains unsatisfactory (103). In the study of lung cancer, BMX has garnered increasing attention due to its potential role in tumor initiation and progression. Studies have shown that BMX plays a crucial role not only in cell proliferation and survival but also in regulating signaling pathways that influence the invasiveness and metastatic potential of tumors (7,45). Furthermore, the expression level of BMX is closely associated with the clinical outcomes of patients with lung cancer, suggesting its potential as a biomarker for early diagnosis and prognosis evaluation (8).

The molecular mechanisms of BMX involve multiple signaling pathways, particularly the PI3K/Akt and MAPK/ERK pathways (28,104). Through these pathways, BMX can promote cell growth and survival, while suppressing apoptosis. This dual function makes BMX a key player in the biological characteristics of lung cancer cells. Additionally, BMX has been found to upregulate the expression of various pro-inflammatory factors, further facilitating tumor growth and metastasis (7). In lung cancer cells, the overexpression of BMX is directly associated with increased invasiveness. BMX can activate genes related to cell motility and invasion, such as MMPs and urokinase-type plasminogen activator, whose upregulation enhances the invasive capabilities of lung cancer cells (105). Moreover, a high expression level of BMX is associated with an increased risk of lymph node metastasis, providing new insights into the mechanisms of lung cancer metastasis (24).

Beyond its roles in cell proliferation and metastasis, the relationship between BMX and the tumor immune microenvironment has also gained research attention. The immune microenvironment plays a crucial role in tumor development and progression, and BMX may modulate the function of immune cells, particularly macrophages and T cells, thereby influencing the tumor’s immune evasion mechanisms (106,107). Studies suggest that high BMX expression may lead to an increase in immunosuppressive factors within the TME, which could impair the host’s anti-tumor immune response and promote tumor growth and metastasis (106,107). Furthermore, in the context of genomics and transcriptomics, the upstream regulatory factors of BMX are gradually being identified (107). Certain transcription factors may directly regulate the expression of BMX, and the activity of these transcription factors can be influenced by signaling molecules in the TME. This complex regulatory network provides new perspectives for understanding the role of BMX in lung cancer and identifies potential therapeutic targets.

Additionally, the role of BMX in chemotherapy resistance in lung cancer is worth noting. Chemotherapy is a crucial component of lung cancer treatment, but many patients develop drug resistance during therapy (108). Preliminary studies indicate that BMX may modulate signaling pathways related to drug metabolism, thereby influencing the sensitivity of lung cancer cells to chemotherapeutic agents (107,109,110). Particularly in certain lung cancer subtypes, the high expression of BMX may be associated with drug resistance (107,109,110). Therefore, combining targeted therapies against BMX with chemotherapy may have the potential to overcome drug resistance and improve the efficacy of cancer treatment.

In the clinical context, existing evidence suggests that BMX may have a regulatory relationship with typical lung cancer driver genes, such as epidermal growth factor receptor and anaplastic lymphoma kinase (100,111). Therefore, the combined detection of BMX and its associated biomarkers may help improve the accuracy of lung cancer diagnosis and treatment outcomes. Further research is needed to explore the interactions between BMX and other molecular markers. Additionally, intervention strategies targeting BMX are gradually emerging. For instance, the development of small-molecule inhibitors or antibody-based therapies targeting BMX is underway, and preliminary experiments have shown that these agents can effectively inhibit the function of BMX, thereby suppressing the proliferation and migration of lung cancer cells (8,28,111,112). These studies provide new perspectives and approaches for targeted lung cancer therapy. It is worth noting that the expression of BMX varies among different lung cancer subtypes (45,113). For example, the expression level of BMX is significantly higher in non-small cell lung cancer compared to small cell lung cancer, which may be related to the distinct biological characteristics and treatment responses of different lung cancer types (45,113). Therefore, targeted therapeutic strategies against BMX may require personalization based on the specific lung cancer subtype.

Beyond its direct effects on tumor cells, BMX also shapes the lung cancer immune microenvironment. Recent evidence suggests that BMX modulates immune cell function through both cell‑intrinsic and paracrine mechanisms. In macrophages, BMX activation promotes a shift toward the M2‑like pro‑tumor phenotype, characterized by increased IL‑10 and TGF‑β secretion and reduced pro‑inflammatory cytokine expression, thereby facilitating immune evasion and tumor progression. BMX can also indirectly regulate T‑cell activity by altering immune checkpoint molecule expression, such as programmed death-ligand 1 (PD-L1), on cancer cells and antigen‑presenting cells. High BMX expression in lung adenocarcinoma (LUAD) correlates with increased PD-L1 levels and decreased CD8⁺ T cell infiltration, suggesting that BMX contributes to an immunosuppressive TME that dampens anti‑tumor immunity. Preclinical studies have shown that BMX inhibition synergizes with immune checkpoint blockade to enhance tumor control in murine models (106,107).

Chemoresistance remains a major obstacle in lung cancer treatment, particularly in small‑cell lung cancer (SCLC), where initial responses to platinum‑based chemotherapy are often followed by rapid relapse. BMX has emerged as a key regulator of drug sensitivity. In SCLC cell lines, BMX overexpression confers resistance to cisplatin and etoposide, while BMX knockdown resensitizes cells to these agents. Mechanistically, BMX promotes chemoresistance through activation of the PI3K/AKT survival axis, up‑regulation of multidrug resistance transporters such as ABCG2, and induction of autophagy via the AMPK‑mTOR pathway. Elevated BMX expression has been detected in chemoresistant patient‑derived xenografts and relapsed SCLC tumors, and higher BMX levels correlate with shorter progression‑free survival in patients receiving first‑line chemotherapy, suggesting that BMX may serve as a predictive biomarker for chemoresistance (107,109,110).

BMX expression and function differ markedly between lung cancer subtypes. In non‑small cell lung cancer (NSCLC), BMX is frequently overexpressed in adenocarcinoma and squamous cell carcinoma, with higher levels in advanced stages and lymph node‑positive tumors. In contrast, SCLC exhibits lower baseline BMX expression, but its upregulation during acquired chemoresistance is more pronounced. This subtype‑specific pattern may reflect distinct oncogenic dependencies: in NSCLC, BMX is often co‑expressed with EGFR and KRAS mutants and sustains MAPK/ERK signaling even in the presence of EGFR inhibitors, suggesting a role in intrinsic targeted therapy resistance; in SCLC, BMX acts primarily as a survival signal upregulated upon chemotherapy stress. Clinically, BMX expression correlates with poor overall survival in NSCLC but shows a stronger association with recurrence‑free survival in SCLC. Thus, clinical application of BMX as a biomarker or therapeutic target must consider tumor histology, stage, and concurrent genetic alterations (45,113,114). In summary, BMX has demonstrated multifaceted roles in lung cancer research, playing important parts in cell proliferation, metastasis, immune regulation, and chemotherapy resistance. This suggests the potential of BMX as a biomarker and therapeutic target. However, future research should systematically unveil the complex roles of BMX in lung cancer and other tumor types, utilizing comprehensive multi-omic data and advanced biotechnological approaches. For instance, single-cell sequencing may reveal the associations between BMX and specific cell subpopulations, providing a more detailed understanding of the expression differences of BMX in diverse lung cancer cell subgroups, which could help elucidate its role in tumor heterogeneity. These efforts not only have the potential to provide new insights for early diagnosis and personalized treatment of lung cancer, but also open new directions in the field of tumor biology, ultimately improving patient prognosis and quality of life.

BMX inhibitors: current status, challenges, and future directions

The multifaceted roles of BMX in pulmonary diseases—from driving inflammation and fibrosis to promoting tumor growth and drug resistance—have made it an attractive therapeutic target. Consequently, the development of small‑molecule inhibitors that selectively block BMX kinase activity has gained momentum over the past decade. This section summarizes the structural basis for BMX inhibition, reviews available inhibitors with their preclinical and clinical data, and discusses the challenges that must be overcome to translate these agents into clinical practice.

Structural basis for BMX inhibitor design

BMX possesses a canonical kinase domain with an ATP‑binding cleft that is highly conserved among Tec family kinases. However, subtle differences in the conformation of the activation loop and the surrounding hydrophobic pockets allow for the design of selective inhibitors (115). Two major types of BMX inhibitors have been explored: Type I inhibitors, which bind to the active conformation of the kinase (DFG‑in), and Type II inhibitors, which stabilize the inactive conformation (DFG‑out). Type II inhibitors often achieve higher selectivity because they exploit a deeper allosteric pocket adjacent to the ATP site. In addition, BMX contains a cysteine residue (Cys496) within the ATP‑binding pocket, which is not present in many other kinases. This unique feature enables the development of covalent irreversible inhibitors that form a stable bond with the cysteine thiol, providing prolonged target occupancy and high selectivity over off‑target kinases that lack this reactive residue (5).

Currently available BMX inhibitors

Over the past decade, a diverse array of small‑molecule BMX inhibitors has been developed, ranging from selective research tools to multi‑targeted clinical candidates. Among the most widely used selective inhibitors is BMX‑IN‑1, a potent type I inhibitor with a half-maximal inhibitory concentration (IC₅₀) of 8 nM against BMX and more than 100‑fold selectivity over other Tec family kinases, making it a valuable tool for validating BMX functions in cell‑based studies (116). A more advanced compound, CHMFL‑BMX‑078, represents a highly potent type II irreversible inhibitor that covalently modifies Cys496 within the ATP‑binding pocket, achieving excellent selectivity [S(10) =0.03] and demonstrating robust anti‑proliferative activity in BMX‑dependent cancer cell lines (5). Another notable selective inhibitor is B6, a pyrrolo[2,3‑d]pyrimidine derivative with an IC₅₀ of 6 nM, which has shown efficacy in NSCLC xenografts by suppressing tumor growth and metastasis, and also synergizing with cisplatin to enhance cytotoxic effects (117). In addition to these selective agents, several multi‑target inhibitors that possess BMX inhibitory activity have gained considerable attention, primarily because they are already in clinical use or advanced development for other indications (11). Ibrutinib, a Food and Drug Administration (FDA)‑approved BTK inhibitor, also inhibits BMX at clinically achievable concentrations (IC₅₀ ≈0.5–1 µM) and has been repurposed for inflammatory diseases and solid tumors, with evidence in COPD models showing reduced airway inflammation through inhibition of BMX‑mediated endothelial VCAM‑1 expression (11). PF‑06651600, a dual JAK3/Tec family kinase inhibitor, has entered phase II clinical trials for autoimmune conditions such as alopecia areata and rheumatoid arthritis; its BMX inhibitory activity contributes to its anti‑inflammatory effects, and preclinical studies have demonstrated its efficacy in bleomycin‑induced pulmonary fibrosis (60). Fenebrutinib, a reversible BTK/BMX inhibitor with a favorable safety profile in early‑phase trials, is currently under investigation for asthma and other Th2‑driven pulmonary diseases (118). More recently, covalent dual inhibitors targeting both BMX and BTK have emerged, such as the compound reported by Forster and colleagues [2020], which exhibits nanomolar potency and favorable pharmacokinetic properties in vivo, highlighting the continued innovation in this therapeutic space (61).

Preclinical efficacy in lung disease models

The therapeutic potential of BMX inhibition has been substantiated by a growing body of evidence from animal models across multiple pulmonary disease contexts. BMX has been implicated in the regulation of pulmonary inflammatory responses. Pharmacological inhibition of BMX with BMX‑IN‑1 has been shown to reduce pro‑inflammatory cytokine production, including TNF‑α and IL‑1β, in lipopolysaccharide (LPS)‑stimulated macrophages, and to decrease bacterial burden and lung pathology in Mycobacterium tuberculosis infection models (10,119). Furthermore, BMX deficiency has been associated with reduced lung injury in sepsis models (7). These findings suggest that BMX inhibition may represent a potential strategy to control excessive inflammation in pulmonary infections, although direct evidence in Pseudomonas aeruginosa pneumonia models remains to be established (7). Given the established roles of Tec family kinases in T cell and mast cell signaling, BMX has been hypothesized to contribute to allergic airway inflammation (17). Although direct evidence with BMX‑specific inhibitors in asthma models remains limited, the potent and selective BMX inhibitor CHMFL‑BMX‑078 provides a valuable tool for future investigations into the potential therapeutic effects of BMX inhibition on airway hyperresponsiveness, eosinophilic inflammation, and Th2 cytokine production in allergic airway diseases (5). In cigarette smoke‑induced COPD models, ibrutinib decreased emphysema severity and airway remodeling, and importantly, improved lung function parameters such as forced expiratory volume in 0.5 seconds/forced vital capacity (FEV_0.5/FVC), providing functional validation of BMX as a disease‑modifying target in chronic obstructive lung disease (120). In lung cancer xenografts, both B6 and CHMFL‑BMX‑078 suppressed primary tumor growth and metastatic dissemination, and when combined with standard chemotherapeutics such as cisplatin or etoposide, they effectively reversed chemoresistance and extended survival in SCLC models, a finding of particular clinical importance given the aggressive nature of this disease and its propensity for rapid relapse (112,116). Collectively, these preclinical results provide compelling evidence that BMX is a druggable target across a spectrum of pulmonary pathologies, and they establish a solid foundation for advancing BMX inhibitors into clinical evaluation.

Clinical‑stage progress and emerging trials

Despite the encouraging preclinical landscape, the clinical translation of BMX inhibitors for pulmonary diseases remains in its infancy, with no BMX‑specific inhibitor yet approved for any respiratory indication. However, several multi‑target inhibitors with BMX activity have been or are being evaluated in clinical settings that may ultimately benefit patients with lung conditions. Ibrutinib, an FDA‑approved BTK inhibitor that also inhibits BMX at clinically achievable concentrations, has been evaluated in chronic respiratory conditions. A phase II trial in COPD patients with persistent inflammation despite optimal inhaled therapy (NCT03947268) has been initiated; however, published efficacy data from this trial remain limited. The broad kinase inhibition profile of ibrutinib has raised safety concerns, particularly off‑target toxicities including atrial fibrillation, bleeding events, and infections, which have limited its broader adoption in non‑malignant diseases. PF‑06651600 (ritlecitinib), a dual JAK3/TEC family kinase inhibitor, has been evaluated in multiple phase II and phase III trials for autoimmune conditions including alopecia areata, rheumatoid arthritis, Crohn’s disease, and chronic spontaneous urticaria. However, its pulmonary application remains preclinical, and no lung‑specific trials have been initiated to date. Fenebrutinib (GDC‑0853), a noncovalent, oral, highly selective BTK inhibitor that also exhibits activity against BMX, has been evaluated in a phase II, randomized, double‑blind, placebo‑controlled trial in systemic lupus erythematosus. While the drug demonstrated an acceptable safety profile and evidence of strong pathway inhibition, the primary endpoint (SRI‑4 response at week 48) was not met. Its potential in asthma and other Th2‑mediated pulmonary diseases remains preclinical. BMS‑986278 (admilparant) is an oral lysophosphatidic acid receptor 1 (LPA1) antagonist that has been evaluated in a phase II randomized trial for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis. Biomarker data from this trial have been reported. However, it should be noted that this compound acts primarily as an LPA1 receptor antagonist rather than a direct BMX inhibitor, so its effects cannot be attributed to BMX inhibition.

Several compounds with “BMX” in their names have entered clinical trials but are not BMX kinase inhibitors. NBM‑BMX is an HDAC8 inhibitor being evaluated in phase Ib/II trials for solid tumors and glioblastoma. BMX‑001 is a manganese superoxide dismutase mimetic radioprotector being tested in a phase II trial for reducing oral mucositis in head and neck cancer patients receiving chemoradiation. These agents are mechanistically distinct from BMX kinase inhibitors and should not be confused with BMX‑targeted therapies.

The current lack of BMX‑specific clinical trials for pulmonary diseases underscores an urgent gap in the field. While the recently discovered selective BMX inhibitor IHMT‑15137 has shown promising efficacy in overcoming chemoresistance in preclinical small cell lung cancer models, clinical evaluation has not yet commenced. The development of highly selective BMX inhibitors with optimized pharmacokinetic properties and favorable safety profiles, followed by well‑powered, biomarker‑stratified clinical trials, remains a critical priority for translating the preclinical promise of BMX inhibition into clinical benefits for patients with pulmonary diseases.

Challenges and future directions for BMX‑targeted therapy

Looking forward, the successful translation of BMX inhibitors from bench to bedside will require overcoming several interrelated challenges, each of which demands careful consideration and targeted research efforts. Perhaps the foremost challenge is achieving sufficient selectivity, because the high structural homology among Tec family kinases—particularly between BMX and BTK, which share approximately 70% homology in their SH3, SH2, and kinase domains—makes it difficult to design compounds that inhibit BMX exclusively without affecting BTK, ITK, or TEC, all of which have essential physiological roles in immune function, hematopoiesis, and vascular integrity; although irreversible inhibitors that target Cys496 offer improved selectivity, they may still bind to cysteine residues in other kinases such as EGFR or JAK3, underscoring the need for continued structure‑guided optimization to refine the selectivity index and minimize off‑target effects. A second major issue concerns pharmacokinetic optimization, as many existing BMX inhibitors suffer from poor oral bioavailability, rapid systemic clearance, or inadequate penetration into lung tissue, which limits their efficacy in pulmonary diseases; future strategies could include designing lung‑targeted prodrugs, formulating inhalable delivery systems, or developing compounds with improved metabolic stability to achieve sustained and localized target engagement while reducing systemic exposure and associated toxicities. Third, the inevitability of acquired resistance—a phenomenon well recognized in kinase inhibitor therapy—must be proactively addressed; prolonged BMX inhibition may select for kinase domain mutations such as gatekeeper mutations, or activate compensatory bypass pathways involving MET, AXL, or HER2, or induce phenotypic switching that renders cells less dependent on BMX; combination regimens that pair BMX inhibitors with MEK inhibitors, PI3K inhibitors, or immune checkpoint blockers may help to delay or circumvent resistance by targeting multiple nodes of the survival network simultaneously. Fourth, the identification of robust predictive biomarkers is critical for patient stratification and for enriching clinical trial populations, because not all individuals with a given disease will derive equal benefit from BMX inhibition; candidate biomarkers such as BMX expression levels, phosphorylation status, or co‑occurring genetic alterations (e.g., EGFR or KRAS mutations) should be systematically validated in prospective cohorts to enable precision medicine approaches. Fifth, safety in normal tissues poses a non‑negligible concern, given that BMX participates in essential physiological processes including endothelial barrier maintenance, hematopoiesis, and immune homeostasis; systemic inhibition could potentially lead to vascular leakage, immunosuppression, or hematological adverse events, so careful dose titration, therapeutic drug monitoring, and, ideally, disease‑site‑specific inhibition strategies are highly desirable. Finally, given the multifactorial pathogenesis of pulmonary diseases, it is unlikely that single‑agent BMX inhibition will suffice for optimal clinical outcomes; rational combination therapies—pairing BMX inhibitors with antibiotics for pneumonia, corticosteroids for asthma, bronchodilators for COPD, antifibrotics for pulmonary fibrosis, and chemotherapy or immunotherapy for lung cancer—have already shown additive or synergistic effects in preclinical models, and these combinations should be prioritized for clinical evaluation to maximize therapeutic benefit while minimizing toxicity. In essence, while the path to clinical implementation is fraught with obstacles, the convergence of medicinal chemistry innovation, biomarker discovery, and combination strategy development holds great promise for translating the preclinical promise of BMX inhibition into tangible improvements in the diagnosis, treatment, and prognosis of patients suffering from a wide array of pulmonary diseases.

Conclusions

The role of BMX in lung diseases has attracted increasing attention. BMX is closely associated with the occurrence and development of various lung diseases, such as COPD, asthma, pulmonary fibrosis, and lung cancer, particularly in terms of its expression and regulatory mechanisms.

Despite the progress made in the study of BMX in lung-related diseases, there are still many issues that require further investigation and resolution. Firstly, while research has shown that BMX promotes tumor growth and metastasis through multiple signaling pathways, the specific roles and regulatory mechanisms of BMX may differ in different types of lung cancer. For instance, non-small cell lung cancer and small cell lung cancer have distinct molecular pathological characteristics, and it remains to be determined whether the functions and regulation of BMX are the same in these two lung cancer subtypes. Secondly, the relationship between the high expression of BMX and the severity of COPD has been confirmed, but its dynamic changes during the progression of COPD are still unclear. Future research can further elucidate the specific role of BMX at different stages of COPD by longitudinally observing the expression levels of BMX in patients with COPD and correlating them with the clinical data of disease progression. Moreover, the pathological mechanism of COPD is complex, involving multiple cell types and signaling pathways, and the precise position and function of BMX in this intricate network also need to be further analyzed. In the study of pulmonary fibrosis, the mechanism by which BMX promotes fibrosis through the TGF-β/Smad signaling pathway has been revealed, but the generality of this mechanism in different fibrosis models remains to be verified. For example, IPF and environment-related pulmonary fibrosis differ in their etiology and pathological processes, and whether the role of BMX is consistent in these different types of fibrosis requires more experimental data to support. Additionally, the treatment of pulmonary fibrosis still faces significant challenges, and whether targeting BMX can effectively prevent or reverse the fibrotic process needs to be validated through preclinical and clinical research. Apart from the research on lung-related diseases, the roles of BMX in other systemic diseases are also worth noting. For instance, whether BMX plays a similar regulatory role in cardiovascular diseases, metabolic diseases, or autoimmune diseases, the answers to these questions will help to comprehensively understand the biological functions of BMX. Furthermore, the interactions between BMX and other X-chromosome genes should be included in the research scope to reveal their potential roles in gender-specific diseases.

Additionally, several critical gaps must be addressed to advance the field. First, disease‑specific mechanisms remain poorly defined: the differential roles of BMX in NSCLC versus SCLC, its dynamic changes during COPD progression, and the consistency of its fibrotic mechanisms across different etiological types of pulmonary fibrosis all require further investigation. Second, fundamental biology gaps persist: the role of BMX in pulmonary hypertension, its interactions with other X‑chromosome genes in sex‑specific diseases, and its functions in normal physiological processes are insufficiently understood. Third, clinical translation is impeded by the lack of BMX‑specific biomarkers for patient stratification, absence of validated predictive biomarkers, and extremely limited clinical trial data. Fourth, therapeutic development faces challenges in achieving isoform selectivity, understanding resistance mechanisms, and optimizing combination strategies.

BMX as a diagnostic biomarker: clinical implementation scenarios

BMX’s dysregulated expression across multiple pulmonary diseases positions it as a promising biomarker candidate, though translation requires systematic evaluation of its applications and challenges.

For early diagnosis, BMX expression in tumor tissues holds potential as a diagnostic marker for lung cancer. A comprehensive bioinformatic analysis revealed that BMX gene expression was significantly downregulated and could serve as an effective diagnostic biomarker in LUAD and lung squamous cell carcinoma (LUSC) (both P<0.05) (112). The promoter methylation level of BMX was found to be significantly elevated in both LUAD and LUSC (P<0.001), suggesting that the low expression of BMX across these cancers is due to epigenetic factors (112). Additionally, a novel alternative splicing variant of BMX, BMXΔN (resulting from exon skipping of exon 1 to exon 8), was identified in 12% of human LUAD specimens, while it was not found in paired pathologically normal lungs (105). These findings collectively support the potential of BMX and its variants as molecular markers for early lung cancer detection. Regarding COPD and pulmonary fibrosis, while BMX has been implicated in inflammatory pathways relevant to chronic lung diseases, direct evidence demonstrating that increased BALF or serum BMX correlates with early inflammatory and fibrotic changes remains limited.

For disease stratification, BMX expression may help differentiate lung cancer subtypes. Immunohistochemical analysis of 171 lung cancer specimens revealed that high expression of Etk (BMX) occurs in 74.6% of SCLC cases, but only in 40% of NSCLC cases, demonstrating a marked difference between these subtypes (45). Furthermore, BMXΔN is positively correlated with EGFR mutation in LUAD, suggesting its potential utility in stratifying patients based on molecular subtypes (105).

For prognostic assessment, BMX has demonstrated prognostic value across multiple cancer types. Bioinformatic analyses have revealed BMX as a prognostic biomarker in kidney renal clear cell carcinoma, liver hepatocellular carcinoma, sarcoma, and uterine corpus endometrial carcinoma (121). In lung cancer, elevated BMX expression has been associated with protection of SCLC cells from apoptosis, and BMX negatively regulates BAK function, thereby increasing apoptotic resistance to chemotherapeutic drugs (45). Additionally, BMX has been identified as one of nine genes in a fatty acid metabolism-related gene signature that demonstrated robust predictive capabilities for prognosis in early-stage LUSC. These findings suggest that BMX expression levels may correlate with clinical outcomes and could identify high-risk patients.

For treatment response prediction, BMX shows promise in predicting responses to both targeted and conventional therapies. The BMXΔN variant, which is positively correlated with EGFR mutation, may influence sensitivity to EGFR inhibitors in NSCLC. In SCLC, upregulation of Etk (BMX) may represent a new mechanism involved in protecting cells from apoptosis, and downregulation of Etk by siRNA sensitized SCLC cells to doxorubicin (45). Furthermore, BMX-specific inhibitors such as BMX-IN-1 and CHMFL-BMX-078 have shown similar inhibitory activity on purified protein and in cells, but differ in their effects on downstream pathways—BMX-IN-1 primarily affects AKT signalling, while CHMFL-BMX-078 impacts ERK1/2 signalling. The amount of BMX that adopts the DFG-out conformation in cancer cells requires further investigation to determine if this is a viable biomarker for patient selection (116).

For monitoring disease progression, the correlation between BMX expression and clinical parameters—including age, gender, race, and cancer stage (all P<0.05)—supports its potential utility in tracking disease status over time (121). Additionally, the positive correlations between BMX expression and immune cell infiltration (B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils, and dendritic cells) in LUAD and LUSC suggest that BMX may reflect changes in the tumor immune microenvironment during disease progression (121).

Practical challenges must be addressed before clinical implementation. Assay standardization is paramount, as validated detection kits with consistent cut‑off values are lacking (121). Sample type selection requires optimization, as BMX expression differs between tissue, blood, BALF, and sputum. Clinically validated cut‑off values for different diseases demand large‑scale, multi‑center studies. Environmental factors such as smoking and air pollution may influence BMX expression and must be accounted for. Finally, prospective validation studies are urgently needed to confirm BMX’s clinical utility across diverse populations. The epigenetic regulation of BMX expression—particularly promoter methylation in LUAD and LUSC—adds another layer of complexity that must be considered in biomarker development (121).

Unresolved issues and future directions

Beyond the immediate biomarker applications, several fundamental unresolved issues must be addressed to fully realize the therapeutic potential of BMX targeting. At the mechanistic level, the precise roles of BMX in pulmonary hypertension—a condition with significant morbidity and mortality—remain completely unexplored, representing a major gap in our understanding of BMX biology in the lung. Similarly, the interactions between BMX and other X‑chromosome genes in sex‑specific pulmonary diseases warrant systematic investigation, as sex‑based differences in disease susceptibility, presentation, and outcomes are well documented in conditions such as COPD and lung cancer, and BMX may contribute to these disparities. Furthermore, a comprehensive understanding of BMX functions in normal physiological processes—including vascular integrity, hematopoiesis, and immune homeostasis—is essential to predict and manage potential on‑target toxicities of BMX‑targeted therapies.

In terms of translational research priorities, the development of BMX‑specific and isoform‑selective inhibitors must be accelerated through structure‑based drug design, high‑throughput screening, and medicinal chemistry optimization. Pharmacokinetic properties, particularly oral bioavailability, lung tissue penetration, and metabolic stability, require substantial improvement to enable convenient and effective dosing regimens. The exploration of combination therapy strategies—pairing BMX inhibitors with existing standard‑of‑care agents such as chemotherapeutics, immunotherapy, antifibrotics, or bronchodilators—should be systematically evaluated in preclinical models to identify synergistic combinations with acceptable toxicity profiles.

Biomarker development efforts must extend beyond expression‑based approaches to include functional biomarkers such as BMX phosphorylation status, downstream pathway activation signatures, and genetic determinants of BMX dependency. Large‑scale prospective clinical studies are essential to validate BMX as a diagnostic, prognostic, and predictive biomarker, and to establish standardized assay protocols that can be implemented in routine clinical practice. Additionally, the application of multi‑omics approaches—integrating transcriptomics, proteomics, and metabolomics—combined with single‑cell sequencing technologies, holds tremendous potential to elucidate the complex, cell‑type‑specific roles of BMX in different disease contexts and to identify novel regulatory networks and therapeutic vulnerabilities.

Clinical trial priorities should focus on the design and conduct of phase II/III trials that evaluate BMX‑targeted therapies in well‑defined patient populations stratified by BMX expression levels or other predictive biomarkers. Such trials must incorporate rigorous pharmacokinetic and pharmacodynamic assessments, as well as comprehensive safety monitoring to detect both on‑target and off‑target toxicities. Adaptive trial designs and biomarker‑enriched patient selection strategies could accelerate the clinical development process and increase the likelihood of demonstrating efficacy.

Finally, the development of precision therapeutic strategies targeting BMX must consider individual patient characteristics, including genetic background, disease subtype, environmental exposure history, and concomitant medications. The heterogeneity of pulmonary diseases—both within and across diagnostic categories—demands a personalized approach to BMX‑targeted therapy, with treatment decisions guided by comprehensive patient profiling rather than disease diagnosis alone. This vision of precision medicine, while ambitious, is increasingly feasible with advances in genomic, proteomic, and clinical data integration, and holds the promise of optimizing therapeutic outcomes while minimizing adverse effects for patients with BMX‑driven pulmonary diseases. Additionally, the research on BMX as a therapeutic target is of great significance, given its multiple roles in pathological processes. In recent years, some progress has been made in the development of BMX inhibitors, such as small-molecule inhibitors, specific antibodies, and RNA interference techniques, with the aim of reducing its activity and achieving therapeutic effects. However, while the BMX-targeted therapeutic strategies have shown certain efficacy in vitro and in vivo, and have also demonstrated promising prospects in clinical applications, their safety and specificity still need further evaluation. For example, BMX also plays an important role in normal physiological processes, and the inhibition of BMX may lead to unexpected side effects. Therefore, future research should further explore the specific mechanisms of BMX in different contexts, clarify its position and function in the cell signaling transduction network, optimize its pharmacokinetic characteristics and safety in different lung-related diseases, or use gene editing techniques to achieve specific regulation of BMX, to develop more efficient and specific BMX inhibitors with reduced potential side effects and to assess their therapeutic efficacy, thereby enhancing the feasibility of clinical application.

In summary, as an important non-receptor tyrosine kinase, BMX participates in the regulation of various cellular processes and lung diseases. By deeply investigating the functions and mechanisms of BMX, we hope to further reveal its complex role in diseases. Furthermore, the development of specific BMX inhibitors holds promise as an important breakthrough in medical research and clinical applications, providing more accurate and effective strategies for the diagnosis and treatment of lung diseases, and benefiting more patients. In conclusion, this review offers a thorough analysis of BMX’s relationship with lung diseases, serving as a reference for researchers and clinicians and laying the groundwork for the development of BMX inhibitors.

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