Implicates of PIP5K1α in asthma-related biological processes: insights into mechanisms and therapeutic potential

Abstract

PIP5K1α is a key member of the lipid kinase family, involved in several cellular processes including cell proliferation and differentiation, cytoskeletal remodeling, inositol-phospholipid signaling, intracellular vesicle transport, and protein secretion. Emerging evidence now highlights critical functions of PIP5K1α in asthma-related biological processes. In this review, we aim to consolidate existing literature on the involvement of PIP5K1α in asthma pathogenesis. We summarize PIP5K1α-related pathways that regulate airway immune homeostasis (regulating T cell/ILCs-mediated immune response, TLR4/MyD88/NF-κB signaling pathway, Let-7 miRNA biogenesis, and its regulatory modifications), airway hyper-responsiveness (modulating of calcium release, airway smooth muscle contractility, and epithelial barrier dysfunction), and airway remodeling (regulating cell migration, proliferation, epithelial remodeling, and cytoskeleton modulation) in asthma. Although clinically approved PIP5K1α inhibitors are currently unavailable, targeting this kinase present a compelling therapeutic strategy for asthma, requiring further research into develop effective treatments.

Introduction

Asthma is a chronic inflammatory airway disease characterized by variable airflow limitation and airway hyper-responsiveness, and manifests clinically as dyspnea and wheezing [1]. The pathogenesis and therapeutic responsiveness of asthma are influenced by a complex interplay between genetic and environmental factors [2]. Although the incidence of asthma has stabilized in some developed countries, it continues to increase in developing nations [3]. According to the 2024 Global Initiative for Asthma (GINA), the global prevalence of asthma has increased by 12.6% since 1990, currently affecting nearly 300 million individuals worldwide [4]. Presently, available therapeutic strategies have limitations due to side effects and drug resistance [5], highlighting the urgent need for novel therapeutics and targets, particularly for steroid-resistant and refractory asthma [6].

Type I phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are enzymes ubiquitously expressed in the membranes of eukaryotic cells and are primarily responsible for synthesizing phosphatidylinositol-4,5-bisphosphate (PIP2) [7, 8]. The PIP5Ks family has three members: PIP5K1α, PIP5K1β, and PIP5K1γ (Fig. 1A) [9]. Although the genes coding for these three members are localized in different chromosomes (Table 1), they have a highly conserved central lipid kinase core region but distinct N- and C-terminal regions (Fig. 1B) [10]. Among the three PIP5Ks family members, PIP5K1α is the most extensively studied isoform and showed the highest RNA expression level (17.3 nTPM) in the Human Protein Atlas RNA-seq data [11]. Notably, PIP5K1α is involved in regulating a variety of cellular functions, including cell proliferation and differentiation, cytoskeletal remodeling, inositol phospholipid signaling, intracellular transport and secretion [12]. The multiple roles of its product PIP2 in cellular processes also highlight the physiological relevance of PIP5K1α [13].

Fig. 1.

A 3D structure of the PIP5K family. B Comparison of PIP5Ks protein sequences using IBS 2.0

Table 1.

Different members of PIP5K family

Gene name (human)	Alternative name	Molecular weights (kDa)	Length (AA)	Exon count	Chromosomes location
PIP5K1A	PIP5KIalpha, PIPKIα	68	562	22	1q21.3
PIP5K1B	MSS4, STM7	62	540	21	9q21.11
PIP5K1C	KIAA0589, LCCS3, PIP5Kgamma	73	668	22	19p13.3

In the last decade, the role of PIP5K1α in tumor occurrence and progression has been extensively studied [14]. However, emerging evidence suggests that PIP5K1α-related pathways are also implicated in asthma [15, 16]. Thus, we summarize here its crucial role in modulating airway immune homeostasis, airway remodeling, and airway hyper-responsiveness in asthma and discuss the yet unexplored therapeutic potential of PIP5K1α inhibitors in asthma.

PIP5K1α overview: nomenclature, domains, modification sites, and expression

Some researchers have proposed a change in the nomenclature for human and mouse PIP5K1α, suggesting that human PIP5K1α corresponds to mouse β [17, 18]. However, we observed a higher degree of sequence identity between the human and murine PIP5K1α sequences (Fig. 2A) [19, 20]. Thus, we propose to maintain the prevalent use of PIP5K1α for both mouse and human based on sequence identity to avoid inconsistencies in nomenclature.

Fig. 2.

A Gene sequence comparison of PIP5K with MEGA. B Modification sites cited by multiple research groups. C Major part of PIP5K and PIP2 pathway

Structural studies on human PIP5K1α are limited, warranting further investigation. Existing research indicates that Lys-171 (within the conserved "IIK" motif), Asp-299 (in the MDYSL sequence), and Asp-378 (in the IID motif) of zebrafish PIP5K1α, based on their positions in the three-dimensional structure, suggest their involvement in ATP binding and catalysis. Furthermore, following the linker region between the N-terminal and C-terminal lobes, PIPK contains a subdomain harboring the "DLKGS" sequence motif, which is potentially a key region in determining substrate specificity [21].

Phosphorylation of PIP5K1α at Ser214 inhibits its activation and impacts its function, although the precise molecular mechanism remains to be fully elucidated [22]. However, a comprehensive mechanistic understanding of the effect of phosphorylation at different sites on PIP5K1α is currently lacking, suggesting the need for further investigation. Therefore, we retrieved and retained only those human PIP5K1α sites consistently annotated in three authoritative protein modification databases: UniProt, PhosphoSitePlus, and dbPTM to ensure the reliability of site information. This search resulted in the identification of 10 phosphorylation sites and one ubiquitination site (Fig. 2B) [23]. However, the potential functions associated with these sites remain to be explored. Notably, the PIP5K family plays a pivotal role in converting phosphatidylinositol-4-phosphate (PI4P) to PIP2. PI4P is the most abundant monophosphorylated phosphoinositide in mammalian cells, with its phosphorylation primarily occurring at the Golgi complex and plasma membrane, where PIP5K1α is located within cells [12, 24]. Owing to the acyl chain preference exhibited by PIP5Ks [25], PIP5K1α selectively phosphorylates PI4P at the 5th-position to induce PIP2 generation (Fig. 2C) [26]. PIP5K1α also exerts regulatory effects on protein phosphorylation in other signaling pathways as discussed below.

At the mRNA level, PIP5K1α is highly and ubiquitously expressed [27] (Fig. 3A). However, PIP5K1α gene is expressed in all representative cell types in the lung (Fig. 3B). In lung tissue, alveolar type I and type II cells show the highest expression levels of PIP5K1α. Considering the crucial roles of type I and type II alveolar epithelial cells in pulmonary physiology, implicates its potential involvement in lung disease pathogenesis (Fig. 3C) [11]. PIP5K1α protein expression is elevated in primary prostate cancer, colon cancer, and breast tumor tissues [28–31], further validates its role in promoting cell proliferation.

Fig. 3.

A Expression profiling of PIP5K1α in different tissues. B Expression profiling of PIP5K family in representative cell types (Data sourced from The Human Protein Atlas). C Single-cell RNA sequence (nTPM) based on the human atlas database of lung tissues

PIP5K1α participates in modulating airway immune homeostasis

The immunology of asthma is heterogeneous, and the underlying pathogenic mechanisms remain incompletely understood [32]. Immune cell infiltration is an important characteristic of asthma [33]. PIP5K1α modulates airway immune homeostasis via T cell/innate lymphoid cells (ILCs)-mediated immune responses, Toll-like receptor (TLR) 4/myeloid differentiation primary response protein 88 (MyD88) signaling pathway, miRNA biogenesis and diverse modifications of PIP5K1α (Fig. 4).

Fig. 4.

Molecular interactants of PIP5K1α associated with asthma regulation. PM plasma membrane, ER endoplasmic reticulum, LRP6 Lipoprotein receptor-related protein 6, WNT3a Wnt Family Member 3A, P53 Tumor Protein P53, Nck Non-catalytic region adaptor protein 1, Orai Calcium release-activated calcium modulator, STIM1 Stromal interaction molecule 1, TMEM16A Transmembrane protein 16A, PKC Protein kinase C, PLC-γ1 Phospholipase c gamma 1, EGFR Epidermal growth factor receptor, TLR4 Toll-like receptor 4, MyD88 Myeloid differentiation primary response 88, NF-κB Nuclear factor kappa B, IL-17 Interleukin 17, AKT Protein kinase B, IFN-γ Interferon gamma, ICAM-1 Intercellular adhesion molecule 1, RORγt Retinoic acid-related orphan receptor gamma t, XPO5 Exportin 5, Let-7 Lethal-7, NEDD4 Neural precursor cell expressed developmentally down-regulated 4, H3K9me3 Histone 3 lysine 9 trimethylation

PIP5K1α in T cell-mediated immune response

The activation of T cell receptors (TCRs) is sensed by PIP5K1α, which then enable localized secretion through the modulation of synaptic membrane composition [34]. TCR activation is closely linked to immune processes such as asthma and allergic reactions [35]. Thus, we hypothesize that PIP5K1α may play a role in immune processes such as asthma and allergic reactions by regulating T cell activation and function.

PIP5K1α-depended PIP2 was enriched in the nuclei of human T helper 17 cells (Th17) [36, 37]. PIP5K1α interacted with arsenic resistance protein 2, a nuclear cap-binding complex scaffold protein, to facilitate its binding to pro-inflammatory cytokine interleukin-17A (IL-17A) miRNA and IL-17A protein production can be inhibited by PIP5K1α inhibitor in T cells from individuals with multiple sclerosis [36]. IL-17 functions as a defense mechanism against bacterial and fungal infections. IL-17 overexpression was found to be associated with asthma [38], and inhibiting the IL-17 pathway can prevent inflammation and ferroptosis in asthma [39]. IL-17 also plays a role in irritable bowel syndrome (IBS), an epithelial-immune disorder where it participates in protecting barrier tissues from pathogenic microbes [40, 41].

PIP5K1α can stimulate tyrosine phosphorylation of the non-catalytic region of tyrosine kinase (Nck) family SH2 domain binding partner [42]. Nck, an adapter protein, is crucial for TCR signal amplification, and inhibiting its interaction with the CD3ε subunit of the TCR ameliorated inflammatory symptoms in a mouse model of asthma [43, 44]. PIP2 and PIP5K1α are both enriched at actin comets induced by Nck aggregates and PIP5K overexpression leads to significant alterations in the actin cytoskeleton [45], suggesting an important role for PIP5K1α in actin rearrangements and its subsequent involvement in the regulation of T cell-mediated inflammation.

PIP5K1α in ILCs-mediated immune response

ILCs are lymphocytes lacking the diversified antigen receptors of T and B cells, including natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells [46]. They are crucial for maintaining immune homeostasis in asthma [47]. Group 1 innate lymphocytes, including conventional NK cells and ILC1s, are characterized by their secretion of interferon gamma (IFN-γ) [48, 49]. PIP2 hydrolysis into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), is a key step in IFN-γ-induced intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells [50]. While ILC3s are a major source of IL-17A [51], and in the inflamed intestinal epithelium, ILC3s accumulate in cell aggregates positive for ICAM-1 [52], a key molecule in asthma airway inflammation and remodeling [53, 54]. Inhibition of retinoic acid-related orphan receptor gamma t (RORγt) -dependent ILC3/Th17 responses reduce IL-17 production by ILC3s and alleviates intestinal fibrosis [55]. Given the intimate functional relationship between IL-17 and PIP5K1α delineated herein, the potential roles of PIP5K1α and PIP2 in ILC-driven pathologies, particularly in asthma pathogenesis requires further investigation.

PIP5K1α in TLR4/MyD88/NF-κB signaling pathway

PIP5K1α interacts with and modulates TLR4, MyD88, and nuclear factor kappa-B (NF-κB). The TLR4/MyD88/NF-κB signaling pathway plays a critical role in the pathogenesis of asthma, including the regulation of neutrophilic airway inflammation [56, 57]. Studies have indicated that MyD88 and PIP5K interact directly in skin dendritic cells (DCs) [58]. Additionally, PIP5K1α facilitates NF-κB activation in brain tissue, as evidenced by the fact that PIP5K1α knockdown inhibited ganglioside-activated NF-κB signaling, including suppressing ganglioside-induced phosphorylation and nuclear translocation of NF-κB [59].

TLR4 stimulates NF-κB translocation via MyD88 [60, 61]. TLR4 is also involved in the modulation of allergic airway inflammation elicited by ovalbumin-lipopolysaccharide (OVA-LPS), cockroach allergen (CRA) [62], and house dust mite (HDM) [63], as well as occupational asthma induced by toluene diisocyanate (TDI) [64, 65]. PIP2 has been recognized for its role in facilitating plasma membrane localization of the Toll/IL-1 receptor domain-containing adaptor protein (TIRAP), which is essential for the MyD88/TLR4 signaling pathway [66]. PIP5K1α mediates TIRAP by recruiting PIP2 to promote TLR4-associated microglial inflammation in plasma membrane [67]. Studies have shown that reducing the expression of TLR4 and MyD88 in corpus cavernosum smooth muscle cells leads to reduced inflammation [68]. Besides, the protective effect of geniposide against LPS-induced injury in pulmonary arterial smooth muscle cells can be enhanced by inhibiting TLR4/MyD88 signaling and downregulating NF-κB expression [69].

PIP5K1α in Let-7 miRNA biogenesis

PIP5K1α is not just involved in protein-level regulation, but also in miRNA biogenesis. Kinase-independent PIP5K1α interacts with the nuclear export protein exportin 5 (XPO5) to regulate let-7 miRNA biogenesis [70]. Let-7 miRNA is an ancient and evolutionarily conserved family of non-coding RNAs [71, 72]. Let-7 miRNA is highly expressed in human pulmonary tissue, and its expression is significantly altered under asthmatic conditions [73, 74]. In lung tissues, age-associated downregulation of XPO5 expression is related to the severity of N protein-induced pneumonia [75]. XPO5 expression is significantly associated with immune cell infiltration in hepatocellular carcinoma [76]. PIP5K1α is probably intricately involved in the age-related and immune cell infiltration concerns observed in asthma, via Let-7 miRNA biogenesis.

Diverse modifications of PIP5K1α

PIP5K1α is also regulated by the ubiquitin–proteasome system. The ubiquitin ligase neural precursor cell expressed, developmentally down-regulated gene 4 (NEDD4) interacts with PIP5K1α in the C-terminal region in the absence of NEDD4‐binding P(L)PXY motifs and ubiquitinates the N-terminal lysine 88, mediating ubiquitination and proteasomal degradation of PIP5K1α, consequently reducing plasma membrane PIP2 level. PIP5K1α-dependent PIP2 pool is negatively controlled by NEDD4 in breast cancer cell proliferation [77]. NEDD4 is closely related to NEDD4-2 [78], and is expressed ubiquitously [79]. NEDD4-2 is known to participate in cold-induced asthma exacerbation including proteolysis and airway epithelial barrier disruption [80]. NEDD4-2 has an important negative regulatory function in IgE-dependent mast cell activity such as in asthma [81].

In addition to ubiquitination, PIP5K1α is also modulated by other post-translational modifications, including small ubiquitin-like modifier (SUMO)ylation. In normal cells, nuclear PIP5K1α is modified by SUMO-1. The level of this SUMO-1-conjugated PIP5K1α is enhanced in the nuclear pool, and PIP5K1α modified by distinct poly SUMO chains, comprising SUMO-1 and SUMO-2, is also increased during apoptosis [82]. PIP5K1α is associated with chromatin silencing complexes composed of histone H3 at lysine 9 (H3K9me3) and heterochromatin protein 1α at multiple ribosomal DNA loci. SUMOylation of PIP5KIα at lysine 490 facilitates its interaction with components of the chromatin silencing machinery, including H3K9me3 and heterochromatin protein 1α [83].

Asthmatic human airway smooth muscle cells (ASMC) hypersecrete vascular endothelial growth factor (VEGF), which contributes to bronchial vascular remodeling and chronic inflammation. In non-asthmatic ASMCs, the recruitment of H3K9 methyltransferase G9A, trimethylation of H3K9me3, and a consequent decrease in RNA polymerase II at the VEGF promoter are critical for the repressing of VEGF secretion [84, 85].

PIP5K1α regulates airway hyper-responsiveness

The pathophysiology of asthma encompasses a diverse array of complex disease mechanisms. Airway hyperresponsiveness (AHR) is a key pathophysiological hallmark of asthma, primarily resulting from excessive contraction of airway smooth muscle, accompanied by the release of inflammatory mediators that further exacerbate airway inflammation and remodeling [86, 87]. PIP5K1α affects airway hyper-responsiveness through calcium (Ca²⁺) release, ASMC contraction and relaxation, and epithelial barrier dysfunction as discussed below.

PIP5K1α in calcium release

Ca²⁺ signaling plays an important role in airway remodeling by controlling ASMC migration and hypertrophy/proliferation. The frequency of oscillations in intracellular Ca²⁺ concentration determines the strength of muscle contraction [88]. PIP5K1α is the key enzymes responsible for PIP2 synthesis [89]. PIP2 itself can be hydrolyzed into IP3 and DAG upon the action of phospholipase C (PLC) [15], which can directly increase intracellular Ca²⁺ level [90]. Increased PIP2 causes contraction of asthmatic airway smooth muscle [91], due to prolonged intracellular Ca²⁺ flux and protein kinase C (PKC) activation [92]. PKC regulates ASMC contraction and proliferation [15].

Plasma membrane PIP2 also exerts a significant influence on calcium release-activated calcium modulator 1-stromal interaction molecules 1 (Orai1-STIM1) interaction [93]. Orai1 is a ubiquitously expressed plasma membrane Ca²⁺ channel involved in store-operated Ca²⁺ entry (SOCE), a fundamental biological process that regulates the contraction of airway smooth muscles [94, 95]. PIP2, involved in coordinating actin remodeling within endoplasmic reticulum—plasma membrane (ER-PM) junction, influences the assembly of Orai1 with STIM proteins. This dynamic actin reorganization is essential for the regulation of SOCE and downstream Ca²⁺-dependent effector functions [93]. Orai1 channel is recruited and activated by STIM1 and STIM2 in ER-PM [96]. Orai and STIM proteins are expressed in airway smooth muscles and modulate the Ca²⁺ release-activated Ca²⁺ current [97].

Anoctamin 1 (ANO1)/Transmembrane protein 16A (TMEM16A) is a widely expressed Ca²⁺-activated Cl⁻ channel that regulates airway smooth muscle contraction [98, 99]. PIP2 binding stabilizes the activated state of TMEM16A [100, 101]. TMEM16A antagonism can relax β-agonist-desensitized airway smooth muscle in murine and human [102]. Inhibition of the PIP5K1A/PIP2 pathway might act to destabilize the activated state of TMEM16A.

PIP5K1α in ASMC contraction and relaxation

The pH of exhaled breath condensate (EBC) of adults with asthma is lower than that of healthy subjects during acute exacerbation [103]. The interaction between PIP5K1α kinase and PIP2 is also pH-dependent [104]. The distinct pH microenvironments present in the respiratory system of individuals with asthma compared to healthy controls, can potentially modulate the kinase activity of PIP5K1α, thereby impacting its interaction with PIP2 and catalytic efficiency.

PIP2 lipids interacts very strongly with Cofilin [105, 106], a major actin depolymerizing factor, is associated with various respiratory diseases [107]. Cofilin has a common binding sequence for actin and PIP2 [108], and the pH-dependent interaction occurs through a specific binding pocket [109, 110]. The actin-severing capacity of cofilin plays a pivotal role in stretch-induced fluidification of the cytoskeleton. Upon activation, cofilin can trigger relaxation of human ASMCs [111].

PIP5K1α in epithelial barrier dysfunction

A dysfunctional epithelial barrier is a common feature of allergic diseases that allows allergens and microbes to penetrate, leading to the release of type II cytokines that drive inflammation [112]. Through the differentiation process, keratinocytes form the physical barrier of the skin [113], and are essential for preventing allergen or microbial invasion [114]. Epithelial dysregulation is a characteristic feature of asthma [112]. Evidence indicates that skin allergen sensitization during epicutaneous exposure to S. aureus-induced IL-36 responses that triggered the development of allergen-specific lung inflammation [115].

PIP5K1α mediates the role of extracellular calcium in inducing differentiation in human keratinocytes. This is critical for extracellular calcium-induced generation of the second messengers IP3, intracellular calcium, and keratinocyte differentiation [116]. Activation of PIP5K1α leads to phospholipase C-gamma1 (PLC-γ1) activation and subsequent keratinocyte differentiation [117]. This suggests the potential of PIP5K1α to participate in allergic asthma due to epithelial barrier dysregulation through modulation of keratinocyte differentiation. Additionally, binding of PIP5K1α to circSPAG16 inactivates protein kinase B (AKT) and suppresses cadmium-induced transformation of human bronchial epithelial cells [118].

Interleukin-33 (IL-33), along with other epithelial-derived alarmins like TSLP and IL-25, is at the forefront of precision medicine approaches for asthma and allergic diseases [119, 120]. PIP2, within the context of allergic responses, plays a vital role in PKC-mediated vesicular secretion, serving as a key link between allergen signaling (via the P2Y2 receptor) and downstream IL-33 release [121].

PIP5K1α regulates airway remodeling

Airway remodeling is a complex pathological process of asthma that involves long-term alterations in airway structure and potentially occurring early in the disease course [122]. Airway remodeling manifests as a combination of pathological alterations, including subepithelial fibrosis, basement membrane thickening, mucosal edema, and airway smooth muscle hypertrophy, collectively leading to airflow obstruction. Furthermore, disruption of the airway epithelial barrier function enhances the inflammatory response to both specific and non-specific triggers [123]. PIP5K1α regulates airway remodeling through cell migration, proliferation, epithelial remodeling and cytoskeleton modulation.

PIP5K1α in cell migration, and proliferation

PIP5K1α and its product PIP2 regulate the stability of tumor protein 53 (P53), and the inhibition of PIP5K1α and PIP2 binding leads to the destabilization of P53 [124]. In asthma, P53 is involved in regulating ASMC proliferation by promoting apoptosis and autophagy [125]. In obstructive airway disease, P53 induced the autophagy, thereby significantly delaying apoptosis [126]. P53 ubiquitination is involved in regulating multiple aspects of ASMC, including cell division, proliferation, migration, viability and inflammatory responses [127]. In vivo studies have shown that asthma increased inflammatory cell infiltration and influenced airway structure by promoting P53 ubiquitination [128]. In older individuals with asthma the isolated ASMCs shows increased expression of phospho-P53 [129]. Aging increases airway remodeling and causes irreversible cell cycle arrest, which induces senescence [130].

PIP5K1α is indispensable for Wnt3a-induced phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6) at Ser1940, acts in the cellular function of Wnt signaling [21, 131]. Phosphorylation of LRP6, a key event in Wnt/β-catenin signaling that promotes β-catenin stabilization, involved in cell differentiation, proliferation, and migration, is implicated in airway remodeling and asthma development [132, 133].

In addition to its involvement in airway remodeling through P53 stabilization and LRP6 phosphorylation, PIP5K1α also contributes to extracellular matrix (ECM) remodeling, thereby linking to both the structural and inflammatory pathologies of asthma [134]. Mechanistically, PIP5K1α drives cell–matrix adhesion formation and ECM degradation, and is essential for invadopodia formation in cancer cells [135]. The STIM1/Orai1-mediated SOCE, previously discussed in the context of calcium release, is also implicated in ECM protein deposition in ASMCs [136].

PIP5K1α in epithelial remodeling

Elevating PIP2 levels by modulating the level of PIP5K1α led to enhanced epidermal growth factor receptor (EGFR) tyrosine phosphorylation [137]. EGFR controls aberrant epithelial remodeling and mucus obstruction in the airway epithelium of chronic airway diseases [138]. Reduced EGFR phosphorylation inhibited bronchial inflammation, fibrosis, goblet cell hyperplasia/metaplasia, and airway hyperreactivity in asthmatic mice. HDM-induced eosinophilic asthma is also characterized by EGFR activation in mice [139, 140].

PIP5K1α in cytoskeleton modulation

PIP2 is a pivotal modulator of actin dynamics and cytoskeletal homeostasis, and interacts with Rho GTPases (RhoA, Rac, and Cdc42) [141, 142]. PIP5K1α is also directly and indirectly implicated in actin dynamics and the maintenance of cytoskeletal homeostasis.

PIP5K1α contribute to the recruitment and binding of the actin anchoring protein ezrin to sodium-iodide symporter, promoting its localization and function at the plasma membrane [143]. Ezrin, an actin-binding protein, serves as an integral connection organizing the cortical cytoskeleton and plasma membrane during cell migration, adhesion, and proliferation [144]. The diverse functions of ezrin extend beyond the cytoskeleton, and is directly implicated in multiple cellular dynamics including signal relay, inflammation, and the stress responses [145]. Ezrin expression is correlated with asthma severity in bronchial epithelial cells injury [146]. Ezrin is also involved in the repair of the bronchial epithelium [147]. Extensive phosphorylation of ezrin is closely associated with asthma in airway smooth muscle contraction, airway inflammation and remodeling [148–150]. Ezrin bridges PIP2 and F-actin, its N-terminal FERM domain specifically binds to PIP2, whereas its C-terminal ERM-associated domain interacts with F-actin [151]. PIP2 is required for ezrin-mediated cytoskeleton-membrane interactions [152]. PIP2 similarly promotes the unfolding and activation of the ezrin, leading to increased formation of microvilli, filopodia and stress fibers [153]. Therefore, the functional interplay between the PIP5K1α pathway and ezrin suggests a coordinated regulatory mechanism, with consequences for a range of cellular processes in asthma.

Emerging developments of PIP5K1α inhibitors

Common medications for asthma treatment include inhaled corticosteroids (ICS), biologics, and leukotriene receptor antagonists, etc. However, existing drugs for asthma treatment face issues related to safety and drug resistance [5]. Prolonged glucocorticoid exposure often leads to metabolic disruption, endocrine disruption, and immunosuppression [154]. ICS is also been associated with an increased risk of heart failure and other cardiovascular diseases [155]. The leukotriene receptor antagonist (LTRA) montelukast is associated with increased neuropsychiatric events [156, 157]. Approved biologic therapies for asthma, including anti-IgE, anti-IL-5, anti-IL-5 receptor, anti-IL-4/IL-13, and anti-TSLP agents, are primarily indicated for moderate-to-severe uncontrolled asthma [158], and these therapies exhibit limited efficacy in T2-low, neutrophilic, or steroid-resistant asthma [159, 160]. Moreover, it’s worth noting that biologics targeting type 2 inflammation in severe asthma (such as omalizumab, dupilumab, and mepolizumab) may be associated with rheumatic adverse effect [161, 162].Therefore, asthma treatment requires novel therapeutic targets and drugs [6]. The prominent role of PIP5K1α in airway remodeling and airway hyperresponsiveness, beyond its involvement in immune regulation, may hold the key to overcoming the current limitations of asthma therapy, warranting further investigation.

Therapeutic strategies that focus on inhibiting PIP5K1α may represent a promising approach for treating asthma (Table 2). Currently, research on the role of PIP5K1α and the development of its inhibitors are predominantly focused within the realm of cancer, such as prostate cancer. However, existing inhibitors such as ISA-2011B, exhibit significant off-target effects and strongly inhibited the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) isoform [163]. ISA-2011B inhibits the expression and activity of PIP5K1α, thereby inhibiting AKT phosphorylation at Ser473, affecting the downstream phosphoinositide 3-kinase (PI3K)/AKT/androgen receptor (AR) pathway. It inhibits the expression of the key cell cycle regulators, arrests cells in the G2/M phase, and preventing proliferation [164].

Table 2.

PIP5K1α inhibitors in different biological processes

Inhibitors	Formula	IC50 (µM)	Cells	Associated processes	References
ISA-2011B	C22H18ClN3O4	–	T cell, PC3, PNT1A, LNCaP, 22Rv1	PI3K/AKT/AR, and cell cycle pathways, induce apoptosis	[164]
GSK2291363	C24H32N8O	–	–	narrow‐spectrum indazole‐pyrimidine compound	[163]
Pyranobenzoquinone scaffold compound 13	C28H34N2O5	1.55	LNCaP, DU145, PC3	substrate competitive inhibitor	[170, 171]
4 aminopyridine derivatives compounds 8, 20 and 25	Compound 8 C25H27N4O3 Compound 20 C25H27N4O3 Compound 25 C27H29N4O4	0.095 0.058 0.011	NIH3T3, U2OS, BT474, Caco-2	modulate PIP2, PIP5K1α activity, AKT phosphorylation, PLCγ pathway	[172]
1,2,3-Triazole-totarol -1,8-naphthalimide (3r)	C29H36N4O3	0.46	LNCaP, PC3, DU145	block the interaction of ATP with PIP5K1α	[173]
PKA	–	–	NIH 3T3	PKA-dependent phosphorylation PIP5K1α phosphorylation and activity suppressed at Ser214	[22]

T cell primary T cells, PNT1A human prostatic cell line, LNCaP lymph node metastasized prostate cancer cells, PC3 bone metastasized prostate cancer cells, DU145 cerebral metastasis of epithelial prostate cancer cells, 22Rv1 human prostate carcinoma epithelial cell line, NIH3T3 NIH Swiss mouse fibroblast 3T3, U2OS human osteosarcoma cell line, BT474 human breast cancer cell line, Caco-2 human colon adenocarcinoma cell line, PKA Protein kinase A

Therefore, the targeting specificity of PIP5K1α inhibitors should be carefully considered for developing future therapeutic approaches, although such strategies remain to be successfully translated into clinical practice [165]. Therefore, a critical priority for upcoming studies should be to rigorously evaluate the safety and tolerability of PIP5K1α inhibitors in patients. To date, only a few studies have performed screening of inhibitors from natural product libraries. For instance, totarol is isolated from the leaves of Retrophyllum rospigliosii (Pilger) C. N. Page and 1,2,3-triazole-totarol conjugates is synthesized through a copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition. Therefore, thoroughly exploring and fully leveraging this indispensable resource for drug development and design is an attractive and promising approach [166]. Current inhibitors have demonstrated promising efficacy in both in vitro and in animal models [167], highlighting the significance of these preclinical studies and underscoring their considerable potential for future clinical translation.

Discussions and prospects

Although direct investigation of PIP5K1α in asthma remains limited, its pivotal roles in regulating airway immune homeostasis, airway hyper-responsiveness, and airway remodeling, provide novel insights into the pathogenesis of this disease. While most currently available inhibitors are primarily designed to target specific molecules, thereby minimizing off-target effects, single-pathway inhibitors may exhibit limited efficacy in addressing the multifaceted pathogenesis of asthma. Airway smooth muscles are increasingly considered as an important feature of asthma control [87, 123]. Therefore, targeting PIP5K1α in conjunction with strategies targeting airway or lung-resident immunocytes, may offer a more comprehensive therapeutic approach and potentially yield superior clinical outcomes. However, the underlying mechanisms of PIP5K1α regulation in asthma remain unclarified, representing an exciting area of basic, translational, and clinical asthma research.

Several PIP5K1α functions are related to its kinase activity, which recruits and generates PIP2. However, its role as a protein indirectly modulating cellular and disease processes remains unclear. Nonetheless, it is foreseeable that PIP5K1α inhibitors have broad prospects for application in the future. In the screening process of inhibitors, the application of virtual screening can enhance the efficiency and accuracy of the drug design process [168]. Moreover, the integration of machine learning will enable effective exploration of large compound libraries [169].

In summary, PIP5K1α appears to play a role in several key processes underlying asthma pathogenesis: airway immune homeostasis, airway hyper-responsiveness, and airway remodeling. Specifically, PIP5K1α regulates T cell/ILCs-mediated immune response, TLR4/MyD88/NF-κB signaling pathway, Let-7 miRNA biogenesis, and its regulatory modifications, thereby influencing airway immune homeostasis. It also modulates calcium release regulation of airway smooth muscle contractility, and epithelial barrier dysfunction, contributing to airway hyper-responsiveness. Furthermore, PIP5K1α regulates cell migration, proliferation, epithelial remodeling, and cytoskeleton modulation, driving airway remodeling. Therefore, PIP5K1α is implicated in the development and progression of asthma related biological processes, suggesting its potential therapeutic target. Targeting PIP5K1α may offer a novel strategy for managing this chronic respiratory disease, such as asthma. Further investigation into the precise mechanisms by which PIP5K1α exerts these effects is warranted, particularly focusing on the therapeutic mechanisms and applications of PIP5K1α inhibitors in asthma. Future research should devise strategies to target airway and lung-resident immunocytes to achieve optimized drug delivery and clinical outcomes.

Abbreviations

PIP5Ks

Type I phosphatidylinositol 4-phosphate 5-kinases

PIP5K1α

Phosphatidylinositol 4-phosphate 5-kinases type I alpha

PIP2

Phosphatidylinositol-4,5-bisphosphate

PI4P

Phosphatidylinositol-4-phosphate

GINA

Global Initiative for Asthma

ASMC

Airway smooth muscle cell

OVA-LPS

Ovalbumin-lipopolysaccharide

CRA

Cockroach allergen

HDM

House dust mite

TDI

Toluene diisocyanate

AKT

Protein kinase B

PKC

Protein kinase C

Orai

Calcium release-activated calcium modulator

STIM

Stromal interaction molecules

TMEM16A

Transmembrane protein 16A

P53

Tumor protein 53

MyD88

Myeloid differentiation primary response protein 88

TCRs

T cell receptors

Th17

T helper 17 cells

IL-17A

Interleukin-17A

IBS

Irritable bowel syndrome

ILCs

Innate lymphoid cells

IFN-γ

Interferon gamma

ICAM-1

Intercellular adhesion molecule 1

RORγt

Retinoic acid-related orphan receptor gamma t

Nck

Non-catalytic region of tyrosine kinase

XPO5

Nuclear export protein exportin 5

NEDD4

Developmentally down-regulated gene 4

NF-κB

Nuclear factor kappa-B

IP3

Inositol 1,4,5-triphosphate

DAG

Diacylglycerol

PLC

Phospholipase C

SOCE

Store-operated Ca²⁺ entry

LRP6

Low-density lipoprotein receptor-related protein 6

EGFR

Epidermal growth factor receptor

TLR

Toll-like receptor

ICS

Inhaled corticosteroids

LTRA

Leukotriene receptor antagonist

AR

Androgen receptor

PIK3CA

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

Author contributions

WSJ, YFW, and YLM offered direction and guidance for the manuscript. WSJ drafted the manuscript and illustrated the figures for the manuscript. YFW and YLM contributed to the revision of the manuscript. All the authors approved the final manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82274646) and "Academic leaders" supported by Shanghai Municipal Health Commission (2022XD016).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.