KIF15 (Kinesin-12): molecular biology, physiological functions, and roles in disease

Abstract

Objective

KIF15, a kinesin-12 family motor protein, has emerged as a recurrently upregulated factor in multiple human malignancies and has been implicated in diverse oncogenic processes. This review aims to provide a comprehensive synthesis of the molecular biology of KIF15, its oncogenic and non-oncogenic functions, the regulatory mechanisms governing its expression and activity, and its therapeutic potential across human disease contexts.

Methods

A comprehensive literature review was conducted using PubMed, Web of Science, and Scopus to identify studies addressing KIF15 structure, mitotic and non-mitotic functions, cancer-associated mechanisms, pharmacological targeting, and germline disease associations.

Results

KIF15 is frequently upregulated across multiple solid tumors—including lung, breast, prostate, pancreatic, gastric, colorectal, and hepatocellular cancers—and elevated expression is commonly associated with adverse clinical outcomes. Mechanistically, KIF15 activates mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (MEK-ERK), phosphoinositide 3-kinase–protein kinase B (PI3K-AKT), and epidermal growth factor receptor (EGFR) signaling, androgen receptor (AR) and its splice variant androgen receptor splice variant 7 (AR-V7) to confer enzalutamide resistance, supports glycolytic reprogramming via phosphoglycerate kinase 1 (PGK1) deubiquitination, and maintains cancer stem cells (CSCs) phenotypes through reactive oxygen species (ROS) suppression. KIF15 additionally mediates adaptive resistance to kinesin-5 (Eg5, also known as KIF11), inhibitors via protein regulator of cytokinesis 1 (PRC1)-dependent antiparallel microtubule bundling. Beyond oncology, germline KIF15 variants have been associated with increased genetic susceptibility to idiopathic pulmonary fibrosis. Several KIF15-directed preclinical probes and proof-of-concept inhibitors have been reported, and dual Eg5/KIF15 inhibition has shown synergistic antitumor effects in experimental models.

Conclusions

KIF15 functions as a context-dependent regulator of mitotic adaptation and tumor progression, with reported roles in mitogenic signaling, metabolic reprogramming, and therapeutic resistance across multiple cancer types. Its chemical tractability and non-redundant role in drug-resistant spindle maintenance position it as a compelling candidate for combination anticancer strategies.

Introduction

The kinesin superfamily proteins (KIFs) are adenosine triphosphate (ATP)-dependent molecular motors that move along microtubule tracks to and perform essential functions in intracellular transport, cell division, and cytoskeletal organization (Aizawa et al. 1992). Among these, KIF15—classified as a member of the kinesin-12 family—is notable for its multifaceted biological roles that span both mitotic and post-mitotic contexts. Originally identified as Xklp2 in Xenopus laevis and subsequently termed human kinesin-like protein 2 (HKLP2) in humans, KIF15 was first described as a motor required for centrosome separation and the assembly of bipolar mitotic spindles (Boleti et al. 1996; Tanenbaum et al. 2009).

The kinesin-12 subfamily, to which KIF15 belongs, is defined by a conserved motor domain and a characteristic N-terminal architecture. KIF15 is a tetrameric, plus-end-directed motor protein. It can crosslink antiparallel microtubules and generate sliding forces that contribute to the bipolar organization of the mitotic spindle (Drechsler et al. 2014; Klejnot et al. 2014). KIF15 has been studied in the context of its functional overlap and interplay with kinesin-5 (Eg5, also known as KIF11), the archetypal mitotic kinesin (Tanenbaum et al. 2009; Sturgill et al. 2016). A critical finding was the discovery that KIF15 could sustain spindle bipolarity in the absence of Eg5 activity, thereby conferring resistance to Eg5 inhibitors—a clinically relevant mechanism with direct implications for cancer chemotherapy (Dumas et al. 2016; Sturgill et al. 2016).

Over the past two decades, the biology of KIF15 has expanded well beyond its mitotic functions. In the nervous system, KIF15 has been shown to regulate axonal microtubule organization and neuronal polarity (Buster et al. 2003; Liu et al. 2010; Lin et al. 2012). In reproductive biology, KIF15 has been implicated in spermatogenesis and oocyte meiotic maturation (Wu et al. 2021; Zou et al. 2022). More recently, KIF15 has emerged as a recurrently upregulated factor across multiple cancer types, where its expression correlates with poor prognosis and has been linked to tumor cell proliferation, survival, migration, invasion, stemness, and therapeutic resistance (Li et al. 2020b; Mi et al. 2022; Badraldin et al. 2025). Genetic variation in KIF15 has also been associated with idiopathic pulmonary fibrosis (IPF), a progressive fibrosing interstitial lung disease with limited treatment options (Allen et al. 2020; Zhang et al. 2022a; Hollmén et al. 2023).

Given the rapidly expanding body of research on KIF15, a comprehensive synthesis of current knowledge is both timely and necessary. This review aims to provide an integrated overview of the molecular biology of KIF15, its physiological and pathological functions, the regulatory mechanisms governing its expression and activity, and its potential as a therapeutic target across human diseases. Although a recent focused review has summarized the roles of KIF15 in cancer progression and therapeutic targeting (Badraldin et al. 2025), the present review substantially broadens that scope by encompassing the molecular architecture and biochemical regulation of KIF15, its non-mitotic functions in neural development, reproductive biology, and sensory systems, as well as its emerging implications in non-neoplastic disorders, including IPF, cardiac remodeling, and neuropsychiatric disease. In addition, we critically evaluate the strength of available evidence across different disease contexts and highlight unresolved mechanistic questions to guide future investigation.

Molecular structure and biochemical properties of KIF15

Gene and protein overview

The human KIF15 gene encodes a 1,388-amino acid protein with a molecular weight of approximately 160 kDa (Klejnot et al. 2014). KIF15 is also known by alternative names including HKLP2 (or hKLP2) and KLP2, reflecting its independent identification in different experimental contexts. The protein is a member of the kinesin-12 family, characterized by an N-terminal catalytic motor domain, a central stalk region comprising extended coiled-coil domains, and a C-terminal tail domain (Klejnot et al. 2014). The coiled-coil stalk mediates dimerization and tetramerization, enabling KIF15 to form a homo-tetrameric complex in solution, a structural feature critical to its capacity to crosslink and slide antiparallel microtubules during mitosis (Drechsler et al. 2014; Eskova et al. 2014).

The crystal structure of the KIF15 motor domain was solved by Klejnot et al., providing the structural basis for understanding its biochemical properties (Klejnot et al. 2014). The motor domain adopts the canonical kinesin fold, with switch I/II motifs that coordinate ATP hydrolysis and microtubule binding (Klejnot et al. 2014). Milic et al. subsequently employed single-molecule optical trapping to characterize KIF15 nanomechanics, revealing that KIF15 motility differs significantly from Eg5 (Milic et al. 2018). Complementary work by McHugh et al. established that Kif15 functions as an active mechanical ratchet, using directed conformational changes to preferentially step toward microtubule plus ends (McHugh et al. 2018). These biophysical properties endow KIF15 with the capacity to generate robust antiparallel sliding forces in the spindle midzone and to sustain spindle bipolarity under mechanical stress (Drechsler et al. 2014; Reinemann et al. 2017). The domain organization of KIF15 is summarized in Fig. 1.

Fig. 1.

Domain architecture of KIF15. KIF15 is a 1,388-amino acid (~ 160 kDa) protein organized into three functional regions: a motor domain, a central stalk, and a C-terminal tail. The N-terminal motor domain contains the Switch I/II motifs that coordinate ATP hydrolysis and microtubule binding, and harbors the KBP-binding site through which kinesin-binding protein sterically inhibits microtubule engagement. The motor domain is followed by a short neck linker that couples ATPase activity to directional movement. The central stalk comprises coiled-coil 1 and coiled-coil 2 regions separated by a flexible hinge, enabling homodimerization and tetramerization required for antiparallel microtubule crosslinking. The C-terminal tail mediates interaction with TPX2 for spindle targeting

Regulation by Kinesin-binding protein (KBP) and targeting protein for Xklp2 (TPX2)

The activity and spindle localization of KIF15 are coordinately regulated by two key protein partners, KBP and TPX2, which act through mechanistically distinct but functionally complementary mechanisms to fine-tune KIF15 behavior during mitosis. A key regulatory protein of KIF15 is kinesin-binding protein (KBP), also known as KIFBP or KIAA0556. Notably, KBP controls microtubule dynamics and cargo trafficking by directly inhibiting multiple kinesins including KIF15 (Kevenaar et al. 2016). Cryogenic electron-microscopy structural analyses of the KBP-KIF15 complex demonstrated that KBP interacts with switch I and the α4 helix of the KIF15 motor domain, thereby sterically occluding microtubule binding rather than directly affecting ATPase activity (Atherton et al. 2020; Atherton and Moores 2021). Consistently, KBP has been implicated in the maintenance of mitotic fidelity by fine-tuning the activities of KIF15 and KIF18A, thus preventing excessive motor-dependent force imbalance that could otherwise compromise accurate chromosome segregation (Malaby et al. 2019). Collectively, these studies establish KBP as a critical brake on KIF15 activity, with implications for both normal spindle function and disease states where KBP expression is dysregulated.

The second major regulator, TPX2, controls KIF15 through a complementary mechanism focused on spatial recruitment rather than direct inhibition. TPX2 was initially identified as a microtubule-associated factor responsible for recruiting Xklp2, the Xenopus homolog of KIF15, to spindle poles in Xenopus egg extracts (Wittmann et al. 2000). In human cells, TPX2 interacts with the C-terminal region of KIF15 to regulate its spindle localization and motor behavior (Vanneste et al. 2009; Mann et al. 2017). Mechanistically, the C terminus of TPX2 directly promotes KIF15 association with spindle microtubules, and this interaction is further modulated by microtubule dynamics (Mann et al. 2017). More recently, KBP has been identified as an additional KIF15-interacting partner that, together with TPX2, contributes to the coordinated regulation of kinetochore-fiber (K-fiber) dynamics and chromosome alignment during mitosis (Brouwers et al. 2017). Taken together, these findings present a coherent picture in which KBP suppresses KIF15 motor activity at the level of the motor domain, while TPX2 spatially licenses KIF15 for productive engagement with spindle microtubules — two complementary layers of regulation that together ensure KIF15 contributes appropriately to spindle assembly and chromosome segregation fidelity.

KIF15 in mitosis and cell division

Bipolar spindle assembly: cooperation with Eg5

A major advance in understanding KIF15 biology came from studies showing that KIF15 and Eg5 cooperate to establish and maintain bipolar spindle assembly (Tanenbaum et al. 2009; Vanneste et al. 2009). Using RNA interference (RNAi)-mediated depletion and chemical inhibition approaches, these studies demonstrated that although Eg5 serves as the primary motor driving centrosome separation, KIF15 can partially compensate for Eg5 loss when Eg5 activity is acutely inhibited (Tanenbaum et al. 2009; Vanneste et al. 2009). Subsequent work further indicated that this compensatory function of KIF15 depends on properly regulated microtubule dynamics, highlighting that its ability to support spindle bipolarity is determined by the balance between microtubule polymerization and depolymerization (Florian and Mayer 2011). More recently, antiparallel microtubule bundling was shown to create a more favorable microtubule architecture for KIF15-driven spindle assembly, suggesting that KIF15 functions most effectively at antiparallel microtubule overlap zones (Salazar and Ohi 2024).

K-Fiber targeting and kinetochore-microtubule dynamics

Beyond its role in establishing spindle bipolarity, KIF15 also contributes to K-fiber organization and kinetochore–microtubule dynamics through a mechanistically distinct mode of microtubule association. KIF15 targets K-fibers via an intrinsic two-step mechanism involving molecular unfolding and two-microtubule binding, which enables its preferential accumulation on bundled microtubules rather than on individual microtubules (Sturgill et al. 2014). This mode of association allows KIF15 to reinforce the mechanical integrity of kinetochore–microtubule attachments, consistent with evidence that K-fiber bundles are mechanically fortified by KIF15 and display reduced cohesion when KIF15-dependent microtubule binding is disrupted (Begley et al. 2021). At a broader level, KIF15 motors suppress microtubule catastrophe (the abrupt switch from microtubule growth to rapid disassembly) and promote the formation of parallel microtubule bundles, thereby contributing to spindle stability and bundle maintenance (Drechsler and McAinsh 2016).

An additional layer of regulation is provided by cell-cycle control prior to mitotic entry. Inhibition of cyclin-dependent kinase 1 (CDK1) during G2 has been shown to enhance the ability of cells to maintain spindle bipolarity in the subsequent mitosis when Eg5 activity is suppressed, an effect that depends on KIF15 (Gayek and Ohi 2016). Mechanistically, G2-phase CDK1 inhibition increases kinetochore–microtubule stability, thereby facilitating KIF15-dependent maintenance of bipolar spindle organization even in the absence of normal Eg5 function (Gayek and Ohi 2016). However, this enhanced spindle robustness is accompanied by reduced mitotic fidelity, as increased kinetochore–microtubule stability is associated with a higher incidence of lagging chromosomes during anaphase (Gayek and Ohi 2016). Together, these findings position KIF15 as a key determinant of K-fiber mechanics and spindle resilience, while also indicating that the efficiency of the KIF15-dependent backup pathway—a secondary, KIF15-driven route for maintaining bipolar spindle integrity when the primary Eg5 motor is inhibited—is shaped by pre-mitotic cell-cycle programming and microtubule stability.

KIF15 in spindle dynamics beyond bipolar spindle assembly

KIF15 further contributes to spindle force regulation through its involvement in poleward microtubule flux. Poleward flux, defined by continuous microtubule polymerization at plus ends coupled to depolymerization at minus ends, is a fundamental property of the mitotic spindle that supports chromosome movement and tension generation. Furthermore, the microtubule-flux in human cells is driven by the coordinated action of four kinesins—CENP-E, KIF4A, Eg5, and KIF15—working together to compensate for microtubule depolymerization and regulate spindle length (Steblyanko et al. 2020). In this context, poleward flux is thought to depend on a dynamic balance between microtubule dynamics and kinesin-driven sliding forces, placing KIF15 within a broader regulatory network that sustains spindle architecture and mechanics (Barisic and Rajendraprasad 2021). Evidence from C. elegans further supports the evolutionary conservation of this function, as KLP-18, the KIF15 ortholog, contributes to kinetochore–microtubule poleward flux during metaphase (Soler et al. 2025).

In addition to its roles in spindle assembly and microtubule force generation, KIF15 is also implicated in centrosome clustering, a process whereby cancer cells harboring supernumerary centrosomes (arising from whole-genome duplication) gather these extra centrosomes into two functional poles (Milunović-Jevtić et al. 2016). This enables the formation of pseudo-bipolar spindles (bipolar-appearing spindles built from more than two centrosomes), which is required for continued cell viability (Milunović-Jevtić et al. 2016). KIF15, together with other kinesins, contributes to the regulation and heterogeneity of centrosome clustering efficiency in this setting, highlighting its importance in adapting spindle mechanics under conditions of centrosome amplification (Lau et al. 2024). Collectively, these findings expand the role of KIF15 from a spindle assembly factor to a broader regulator of spindle dynamics, mechanical resilience, and mitotic force adaptation.

Eg5 inhibitor resistance mechanism

A clinically relevant aspect of KIF15 biology is its role in mediating resistance to Eg5 inhibitors. Eg5 is a motor essential for bipolar spindle assembly in dividing cells. Eg5 inhibitors — including monastrol, ispinesib, and related compounds — were developed as antimitotic anticancer agents on the premise that selective blockade of Eg5 would arrest tumor cell proliferation while sparing post-mitotic normal tissues from the peripheral neuropathy associated with classical tubulin-targeting drugs (Chamariya and Suvarna 2022). Despite promising preclinical activity, these agents showed limited efficacy in clinical trials, partly due to the emergence of drug resistance. A key resistance mechanism is the upregulation of KIF15: chronic exposure to Eg5 inhibitors selects for cells with elevated KIF15 expression, enabling maintenance of spindle bipolarity even in the absence of Eg5 activity (Sturgill et al. 2016). This KIF15-dependent resistance is driven by motor function at the spindle, and accordingly, combined inhibition of Eg5 and KIF15 synergistically disrupts spindle bipolarity and overcomes drug resistance (Sturgill et al. 2016; Solon et al. 2022). In addition, synergistic inhibition of Aurora A and Eg5 has also been reported to suppress KIF15-dependent resistance (Ma et al. 2014). More recently, dual-acting small molecules based on oxindole and quinazolinedione scaffolds have been developed as proof-of-concept compounds for targeting KIF15 and overcoming this resistance mechanism (Dumas et al. 2019).

A further mechanistic layer underlying KIF15-dependent spindle assembly in the setting of Eg5 inhibitor resistance is provided by protein regulator of cytokinesis 1 (PRC1), a microtubule-associated protein that preferentially crosslinks antiparallel microtubules. In Eg5 inhibitor-resistant cells, PRC1 is required for efficient KIF15-driven spindle assembly: PRC1 depletion reduces spindle bipolarity, whereas PRC1 overexpression increases spindle formation efficiency and, when introduced into otherwise drug-naïve cells, promotes resistance to Eg5 inhibition (Salazar and Ohi 2024). These findings support a model in which PRC1-mediated bundling of antiparallel microtubules generates a more favorable microtubule architecture for KIF15, thereby amplifying its ability to drive spindle bipolarity in the absence of normal Eg5 activity. Importantly, this effect is not fully recapitulated by TPX2, indicating that microtubule orientation specificity, rather than bundling alone, is a critical determinant of this resistance mechanism. Taken together, these observations identify the PRC1-KIF15 axis as a key structural adaptation that supports spindle assembly under Eg5 inhibition and highlight antiparallel microtubule bundling as an important determinant of KIF15-dependent drug resistance (Fig. 2).

Fig. 2.

KIF15 in bipolar spindle assembly and Eg5 inhibitor resistance. A Under normal conditions, Eg5/KIF11 (kinesin-5) provides the primary outward force driving centrosome separation, while KIF15 plays a supporting cooperative role, together generating a stable bipolar spindle. B Upon chronic exposure to Eg5 inhibitors (e.g., monastrol, ispinesib), cells upregulate KIF15 expression. PRC1-mediated crosslinking of antiparallel interpolar microtubules creates a favorable substrate for KIF15 motor activity, enabling KIF15 to independently sustain bipolar spindle assembly in the absence of Eg5 function. This PRC1-KIF15 structural axis constitutes a key mechanistic basis for Eg5 inhibitor resistance; combined inhibition of Eg5 and KIF15 synergistically overcomes this resistance mechanism

KIF15 in non-mitotic cellular contexts

Beyond its well-established roles in spindle assembly and mitotic force regulation, KIF15 is increasingly recognized as a multifunctional motor with important roles in post-mitotic tissues. Emerging evidence indicates that KIF15 contributes to neural development, synaptic maintenance, sensory neuron homeostasis, injury-associated responses, and reproductive biology. These non-mitotic functions expand the biological scope of KIF15 and suggest that its ability to regulate microtubule organization and cytoskeletal dynamics is broadly relevant to tissue morphogenesis, physiological maintenance, and disease.

KIF15 in nervous system development and neuronal architecture

Accumulating evidence indicates that KIF15 functions beyond mitosis and contributes to neural development and cytoskeletal organization in differentiated cells. KIF15 is expressed in postmitotic neurons, supporting the idea that its biological roles extend into the developing and mature nervous system (Buster et al. 2003). In this context, KIF15 has been implicated in the regulation of axonal growth, guidance, and branching through its ability to control microtubule polarity and organization within developing axons (Liu et al. 2010). More broadly, KIF15 cooperates with other mitotic motor proteins to shape microtubule architecture in both axons and dendrites, where it counterbalances Eg5-dependent microtubule sliding and thereby fine-tunes neuronal microtubule patterning (Lin et al. 2012).

Evidence from zebrafish further supports an evolutionarily conserved role for Kif15 in neural development. Loss-of-function studies have shown that Kif15 is required for normal axonal growth, as its depletion leads to accelerated axonal outgrowth (Xu et al. 2014). Moreover, genetic disruption of kif15 has been shown to accelerate both axonal outgrowth and regeneration (Dong et al. 2019), highlighting a context-dependent role for Kif15 in controlling neuronal process dynamics. In addition, depletion of Kif15 has been reported to enhance cortical astrocyte migration, suggesting that its functions in the nervous system may extend beyond neurons to include glial cell behavior (Feng et al. 2016). Mechanistic studies further indicate that KIF15 directly interacts with myosin-IIB through their respective tail domains in cortical astrocytes, thereby linking microtubule-based and actomyosin-based cytoskeletal systems (Feng et al. 2016). This interaction has been shown to localize to the lamellar region of astrocytes and to depend on phosphorylation of KIF15 at threonine (Thr) 1142, indicating that post-translational regulation of KIF15 influences glial cell motility (Feng et al. 2016). Disruption of this phosphorylation-dependent KIF15-myosin-IIB interaction promotes astrocyte migration, supporting a model in which KIF15 functions as part of a hetero-oligomeric complex that integrates cytoskeletal forces to restrain or fine-tune cell movement. Notably, this mode of cytoskeletal crosstalk appears to be mechanistically distinct from the actin-related functions described in axonal neurons, highlighting context-specific regulation of KIF15 across different cell types of the nervous system.

The biological relevance of KIF15 in neural tissue organization is further underscored by its role in sensory organ development. In zebrafish, kif15 knockdown causes defects in hair cell organization and impairs auditory function, indicating that KIF15 is required for normal development of the auditory system (Zheng et al. 2022). Together, these findings broaden the functional scope of KIF15 from a mitotic motor to a regulator of neural architecture, cytoskeletal patterning, glial cell motility, and sensory system development.

KIF15 in neural homeostasis and neurological dysfunction

Emerging evidence indicates that KIF15 contributes not only to neural development but also to the maintenance of neural homeostasis and the regulation of neurological dysfunction. In postmitotic neurons, KIF15 has been implicated in synaptic development and structural maintenance, with deficiency leading to altered dendritic morphology, abnormal synaptic protein expression, and behavioral phenotypes associated with mood disorders (Wang et al. 2023; He et al. 2025). Transcriptomic analyses further support this view by showing that loss of KIF15 disrupts the expression of genes involved in synaptogenesis and neuronal connectivity (He et al. 2025). These findings suggest that KIF15 is required for preserving synaptic architecture and neural circuit stability, likely through its effects on microtubule organization in dendrites and axons.

KIF15 has also emerged as a regulator of sensory neuron function and peripheral pain sensitization. In dorsal root ganglion neurons, KIF15 deficiency has been linked to oxaliplatin-induced cold hypersensitivity through altered membrane protein trafficking, including reduced Annexin A2 localization and increased transient receptor potential ankyrin 1 (TRPA1) accumulation at the neuronal membrane (Wu et al. 2025). This observation expands the functional repertoire of KIF15 beyond cytoskeletal organization to include the control of membrane-associated signaling pathways in sensory neurons, with direct implications for chemotherapy-induced peripheral neuropathy.

In addition, KIF15 appears to participate in neural injury-associated responses. In zebrafish models of spinal cord injury, Kif15 has been shown to regulate the migration and phagocytic activity of Coro1a-positive immune cells at the injury site, indicating a role in coordinating innate immune responses during neural repair (Dong et al. 2025). Collectively, these findings position KIF15 as an important regulator of neural homeostasis across multiple levels, spanning synaptic maintenance, sensory signaling, and injury-responsive cellular behavior.

KIF15 in gametogenesis and reproductive biology

KIF15 has also emerged as an important regulator of reproductive biology, with functions in both male and female gametogenesis. In the male reproductive system, KIF15 is expressed in Sertoli cells and is required for normal spermatogenesis through its effects on multiple cytoskeletal networks, including microtubules, actin, vimentin, and septins (Wu et al. 2021). Disruption of KIF15 impairs spermatid transport and release, supporting a role in maintaining the dynamic architecture of the seminiferous epithelium and the functional integrity of the blood-testis barrier (Wu et al. 2021). In addition, KIF15 has been implicated in environmentally induced spermatogenic dysfunction, as its dysregulation is associated with perfluorooctanoic acid (PFOA)-related reproductive toxicity (Luo et al. 2025). These findings indicate that KIF15 contributes to male reproductive homeostasis by coordinating cytoskeletal organization in Sertoli cells and supporting proper germ cell development. In female gametes, KIF15 plays a critical role in meiotic spindle assembly and chromosome alignment. KIF15 has been shown to regulate tubulin acetylation and spindle assembly checkpoint (SAC, a surveillance mechanism that delays chromosome segregation until all kinetochores are correctly attached to spindle microtubules) activity during oocyte meiosis, and its depletion results in spindle disorganization and chromosome misalignment (Zou et al. 2022). Its importance is further highlighted in the context of reproductive aging, where insufficient KIF15 contributes to histone deacetylase 6 (HDAC6)-mediated microtubule instability and deterioration of meiotic spindle quality in aged oocytes (Yin et al. 2024). In addition, KIF15 expression can be modulated by nitric oxide signaling, placing it within a redox-sensitive regulatory network that influences spindle dynamics during oocyte maturation (Xu et al. 2025). Further mechanistic analysis in goat oocytes suggests that KIF15 is embedded within a nitric oxide-dependent signaling pathway that regulates meiotic spindle dynamics. Nitric oxide deficiency disrupts metaphase I (MI) spindle organization, chromosome alignment, and SAC progression, and these defects are accompanied by reduced KIF15 expression (Xu et al. 2025). Mechanistically, activation of the Ras homolog family member A (RhoA)-Rho-associated coiled-coil-containing protein kinase (ROCK) pathway under low-nitric-oxide conditions suppresses KIF15, thereby linking gaseous signaling and small-GTPase signaling to KIF15-dependent control of oocyte spindle integrity (Xu et al. 2025). Collectively, these studies identify KIF15 as a key regulator of cytoskeletal organization and spindle integrity in gametogenesis, with broad relevance to fertility, reproductive aging, and environmentally induced reproductive disorders (Fig. 3).

Fig. 3.

Organ-level functional map of KIF15 in non-neoplastic biology. KIF15 regulates axonal microtubule polarity, astrocyte migration, sensory neuron TRPA1 trafficking, and synaptic maintenance in the nervous system. In reproduction, KIF15 supports spermatid transport and oocyte meiotic spindle integrity; age-related KIF15 decline impairs spindle quality via HDAC6, and a RhoA-ROCK-KIF15 axis links nitric oxide to spindle dynamics. In the cardiovascular system, FoxO6-KIF15-TGF-β1 drives cardiac fibrosis and KIF15 promotes vascular smooth muscle migration in atherosclerosis. Genetically, KIF15 is a causative IPF gene; the p.Gly243Ser variant associates with earlier disease onset

Molecular mechanisms of KIF15 in cancer progression

KIF15 as an upstream regulator of oncogenic signaling networks

Accumulating evidence indicates that KIF15 has been implicated in the regulation of multiple oncogenic signaling pathways in cancer. Among these, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) axis appears to be one of the most recurrent downstream effectors of KIF15. KIF15 has been shown to promote MEK1/2 activation and ERK phosphorylation in pancreatic ductal adenocarcinoma (PDCA) (Wang et al. 2017), and similar pathway engagement has subsequently been reported in bladder cancer (BC) (Zhao et al. 2019), non-small cell lung cancer (NSCLC) (Luo et al. 2022), and hepatocellular carcinoma (HCC) (Zhang et al. 2022b), supporting the view that MEK-ERK signaling represents a broadly relevant effector pathway downstream of KIF15. In colorectal cancer (CRC), this signaling module is further integrated into treatment response, as B7-H3 (also known as CD276)-driven KIF15 activity sustains ERK1/2 phosphorylation under irradiation, thereby linking immune checkpoint signaling to MAPK-dependent radio-resistance (Ma et al. 2020).

In addition to MAPK activation, KIF15 also engages the PI3K-AKT pathway in several tumor contexts. KIF15 depletion suppresses AKT phosphorylation and promotes apoptosis in prostate cancer (PCa), indicating that KIF15 functions upstream of survival signaling through PI3K-AKT (Bi et al. 2023). Similar pathway activation has also been described in chordoma (Yang et al. 2024) and ovarian cancer (Sun et al. 2021), suggesting that PI3K-AKT signaling constitutes another recurrent downstream node of KIF15-mediated tumor promotion. Together, these findings support a model in which KIF15 engages multiple proliferative and survival pathways in a cancer-type-specific manner, potentially linking cytoskeletal or mitotic programs to broader signaling outputs.

A more context-specific mechanism has been described in castration-resistant prostate cancer (CRPC), where KIF15 promotes sustained EGFR pathway activation. Rather than acting through canonical ligand-dependent receptor stimulation, KIF15 has been shown to stabilize EGFR protein by inhibiting its lysosomal degradation, thereby maintaining EGFR-RAS-ERK signaling and supporting castration-resistant growth (Gao et al. 2021b). This observation broadens the functional scope of KIF15 beyond spindle regulation and suggests that it can also modulate receptor tyrosine kinase stability at the post-translational level (Fig. 4).

Fig. 4.

KIF15 as a multifunctional signaling hub in cancer progression. KIF15 drives tumor progression through multiple downstream oncogenic pathways. KIF15 stabilizes EGFR by blocking its lysosomal degradation, sustaining RAS-MEK-ERK and PI3K-AKT signaling to promote proliferation and survival. In CRPC, KIF15 recruits USP14 to stabilize AR and AR-V7, maintaining AR signaling under enzalutamide treatment; AR in turn transcriptionally activates KIF15, forming a positive feedback loop. In pancreatic cancer, KIF15 scaffolds USP10-mediated stabilization of PGK1, enhancing aerobic glycolysis. KIF15 also suppresses intracellular ROS, protecting CSCs-like populations from oxidative apoptosis and promoting self-renewal. Upstream, KIF15 expression is regulated by METTL3/VIRMA-mediated m6A modification, ZNF367 and REST/P300 transcriptional activation, and the ANCCA/MLL1 chromatin remodeling axis

KIF15 in metabolic adaptation, apoptosis resistance, and invasive progression

Beyond classical mitogenic signaling, KIF15 also contributes to cancer progression by regulating metabolic adaptation and stress resistance. One prominent example is its role in glycolytic reprogramming in PDCA, where KIF15 facilitates ubiquitin-specific protease 10 (USP10)-mediated deubiquitination and stabilization of phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme (Quan et al. 2023). Loss of KIF15 promotes PGK1 ubiquitination and degradation, reduces glycolytic flux, and impairs tumor growth, thereby directly linking KIF15 to metabolic reprogramming and cancer cell survival (Quan et al. 2023).

KIF15 additionally exerts anti-apoptotic effects through modulation of reactive oxygen species (ROS) homeostasis. In gastric cancer (GC), KIF15 suppresses ROS-mediated apoptosis by enhancing antioxidant defense programs (Tao et al. 2020). A similar protective function has been described in HCC, where KIF15 overexpression reduces intracellular ROS levels and thereby shields cancer stem cells (CSCs, a subpopulation of tumor cells with self-renewal capacity and therapy resistance)-like populations from oxidative stress-induced cell death (Li et al. 2020a). These observations suggest that KIF15 supports tumor cell fitness not only by driving proliferation but also by buffering oxidative stress and apoptosis, although the precise mechanisms underlying its regulation of redox homeostasis remain to be fully defined.

Another important aspect of KIF15 biology is its contribution to tumor cell motility and invasiveness. KIF15 has been linked to epithelial-mesenchymal transition (EMT, a process by which epithelial cancer cells lose cell–cell adhesion and acquire invasive, migratory properties)-associated phenotypes in several cancer types, with reported effects on E-cadherin, vimentin, and EMT-related transcription factors such as Snail and Slug (Bi et al. 2023; Cai et al. 2023). In PDCA, KIF15 post-translational regulation through phosphorylation and acetylation further promotes focal adhesion disassembly, facilitating migration and invasion (He et al. 2022). In addition, KIF15 has been implicated in cargo-specific endocytic trafficking during interphase. A quantitative RNAi screen identified KIF15 as a regulator of α2 integrin trafficking, and mechanistic analyses showed that KIF15 promotes the plasma membrane localization of the clathrin adaptor disabled homolog 2 (Dab2), thereby facilitating clathrin-mediated internalization and redistribution of α2 integrin (Eskova et al. 2014). This observation further supports a role for KIF15 in adhesion remodeling and cell motility beyond its canonical functions in spindle dynamics. Collectively, these findings indicate that KIF15 promotes invasive behavior through coordinated effects on signaling, cytoskeletal dynamics, and adhesion remodeling.

KIF15 in therapy resistance and CSC maintenance

Among the clinically most relevant molecular functions of KIF15 is its role in therapeutic resistance. In PCa, KIF15 has been shown to physically interact with androgen receptor (AR) signaling components and stabilize both AR and androgen receptor splice variant 7 (AR-V7, lacking the ligand-binding domain and constitutively active) by protecting them from ubiquitin-proteasome-mediated degradation (Gao et al., 2021a). As a consequence, AR target gene expression and tumor cell survival can be maintained even under enzalutamide treatment, thereby establishing KIF15 as a key mediator of antiandrogen resistance (Gao et al., 2021a). Importantly, genetic or pharmacological inhibition of KIF15 restores sensitivity in enzalutamide-resistant CRPC models, highlighting the translational significance of this mechanism (Gao et al., 2021a).

KIF15 has also been associated with CSC biology, although the nature of this relationship varies across tumor types and requires careful interpretation. In HCC, KIF15 supports self-renewal, sphere-forming ability, and apoptosis resistance through regulation of ROS balance, indicating that in this context KIF15 actively promotes stemness (Li et al. 2020a). In gastric and endometrial cancers, KIF15 has similarly been identified within gene networks associated with CSC-related programs (Huang et al. 2020; Liu et al. 2021). However, in triple-negative breast cancer (TNBC), the relationship is more nuanced: while KIF15 expression is incorporated in stemness-associated prognostic models, functional studies have shown that KIF15 knockdown in TNBC cells paradoxically increases the expression of pluripotency markers including Nanog homeobox (NANOG), SRY-related HMG-box 2 (SOX2), and octamer-binding transcription factor 4 (OCT4), suggesting that KIF15 may suppress rather than promote stemness in a subpopulation of TNBC cells (Guo et al. 2024b). This divergence across tumor types may reflect differences in the baseline redox state, epigenetic landscape, and degree of epithelial-mesenchymal plasticity between cancer lineages.

Taken together, these studies indicate that KIF15 may contribute to cancer progression through a diverse but interconnected set of mechanisms, including engagement of MEK-ERK and PI3K-AKT signaling, stabilization of EGFR and AR/AR-V7, modulation of ROS homeostasis, metabolic reprogramming, invasive behavior, and CSC-associated traits. These findings position KIF15 not merely as a mitotic kinesin aberrantly expressed in cancer, but as a multifunctional cancer-associated regulator linked to proliferative signaling, stress adaptation, and therapeutic escape.

KIF15 in cancer: pan-cancer dysregulation, prognostic relevance, and oncogenic mechanisms

Pan-cancer expression and prognostic significance

KIF15 is frequently upregulated across a broad spectrum of human malignancies, and elevated expression is consistently associated with unfavorable clinical outcomes (Li et al. 2020b; Mi et al. 2022; Badraldin et al. 2025). Pan-cancer profiling has shown that KIF15 mRNA is upregulated in the majority of tumor types relative to normal tissues, with particularly prominent expression in lung adenocarcinoma (LUAD), breast cancer, HCC, and PCa (Mi et al. 2022). Consistent with this widespread dysregulation, high KIF15 expression has been repeatedly associated with reduced overall survival, recurrence-free survival, and other adverse prognostic indicators across multiple cancer types, supporting its potential value as a prognostic biomarker (Qiao et al. 2018; Li et al. 2020b; Mi et al. 2022). To provide a comprehensive overview of its expression patterns, associated mechanisms, and clinical relevance across different tumor types, we summarize the current evidence in Table 1.

Table 1.

Pan-cancer overview of KIF15 expression, mechanisms, and clinical significance

Cancer type	Expression	Primary downstream mechanism	Key functional effects	Clinical relevance	Refs
Lung adenocarcinoma (LUAD/NSCLC)	UP	Raf/MEK-ERK activation	Promotes proliferation, inhibits apoptosis, enhances migration/invasion	High KIF15 expression → poor OS; independent prognostic factor	(Luo et al. 2022)
Breast cancer (TNBC/ ER+)	UP	ANCCA/MLL1-driven H3K4me3 transcriptional activation; VIRMA/m6A epitranscriptomic upregulation; ZNF367-mediated promoter activation	Promotes proliferation, migration, invasion; maintains tamoxifen resistance	High KIF15 expression correlates with poor relapse-free survival and endocrine therapy resistance	(Zou et al. 2014; Sheng et al. 2019)
CRPC	UP	Cdc42-dependent EGFR stabilization → MAPK/PI3K-AKT; USP14-mediated AR/AR-V7 deubiquitination and stabilization	Promotes proliferation; confers enzalutamide resistance	High KIF15 expression associates with enzalutamide treatment failure; particularly elevated in NEPC	(Gao et al., 2021a; Gao et al. 2021b)
PDAC	UP	MEK-ERK activation; USP10-mediated PGK1 deubiquitination (glycolytic reprogramming); phosphorylation/acetylation-dependent FAK regulation	Promotes proliferation, glycolytic reprogramming, migration, and metastasis	High KIF15 expression → poor prognosis	(Wang et al. 2017; He et al. 2022; Quan et al. 2023)
GC	UP	Suppression of ROS-mediated apoptosis via JNK/c-Jun axis	Promotes tumor growth, proliferation; inhibits apoptosis	High KIF15 expression correlates with larger tumor size and poor patient prognosis	(Tao et al. 2020)
CRC	UP	NRAS ubiquitination regulation; B7-H3 → KIF15 → ERK1/2 (radio-resistance axis)	Promotes proliferation, migration; confers radiotherapy resistance	B7-H3/KIF15 co-expression predicts poor radiotherapy response	(Ma et al. 2020; Shi et al. 2023)
HCC	UP	PSMD12 → KIF15 → MEK-ERK; KIF15 → ROS suppression → CSCs maintenance	Promotes malignant progression; sustains CSCs self-renewal and apoptosis resistance	High KIF15 expression → poor OS; KIF15 expression in tumor-associated monocytes holds independent prognostic value	(Chen et al. 2017; Zhang et al. 2022b)
GBM	UP	REST/P300 co-transactivation of KIF15 promoter	Promotes proliferation, metastasis, cell cycle progression	High KIF15 expression → poor patient OS; co-elevation of REST and P300 further worsens prognosis	(Zeng et al. 2020; Yu et al. 2024)
NPC	UP	METTL3-mediated m6A modification → KIF15 upregulation → STAT3 activation → ATG7-dependent autophagy suppression	Promotes proliferation, migration, invasion; confers radiotherapy resistance	High KIF15 expression → poor radiotherapy efficacy	(Li et al. 2025)
BC	UP	MEK-ERK activation; upstream regulation by GSG2/Haspin	Promotes tumor cell proliferation and growth	High KIF15 expression → poor prognosis	(Zhao et al. 2019; Chen et al. 2020)
Osteosarcoma	UP	Pro-proliferative/anti-apoptotic programs (mechanism not fully defined)	KIF15 knockdown inhibits proliferation, migration; induces G2 arrest and partial apoptosis	High expression correlates with advanced pathological stage	(Wu et al. 2019)
MPNST	UP	Synthetic lethality with combined KIF15 and KIF11 inhibition	KIF15 inhibition reduces cell viability	KIF15 identified as a potential therapeutic vulnerability	(Terribas et al. 2020)

Tumor-type-specific clinical evidence and lineage-specific regulatory mechanisms

The molecular mechanisms through which KIF15 drives cancer progression — including activation of MEK-ERK and PI3K-AKT signaling, metabolic reprogramming, redox regulation, and therapeutic resistance — are described in detail in Sect.  5. The present section focuses on the tumor-type-specific clinical and biological evidence supporting KIF15 as a cancer-relevant factor, with particular attention to prognostic associations, tumor-lineage-specific upstream regulatory programs, and nuances that cannot be generalized across cancer types. The cancers discussed below are grouped by organ system; pan-cancer similarities and key lineage-specific differences are highlighted throughout.

Thoracic malignancies

In LUAD, KIF15 overexpression independently predicts poor prognosis and is consistently associated with adverse clinicopathological features (Qiao et al. 2018). Beyond its role in MEK-ERK-driven tumorigenesis, KIF15 has been incorporated into mitotic spindle-related and senescence-associated gene signatures that characterize immune microenvironment features in LUAD, suggesting that its prognostic value extends beyond direct proliferative effects to broader tumor biology (Shen et al. 2023; Zhao et al. 2026). These findings collectively support KIF15 as a biologically and clinically relevant factor in lung cancer, with potential utility as both a prognostic biomarker and a therapeutic target.

Breast cancer

Breast cancer represents one of the most extensively studied contexts for KIF15 dysregulation, and several features distinguish it from other tumor types. KIF15 is overexpressed across breast cancer subtypes, with particularly strong evidence in aggressive TNBC (Sheng et al. 2019; Gao et al. 2020; Guo et al. 2024b). A notable lineage-specific regulatory mechanism is the estrogen–ANCCA-MLL1 chromatin axis in estrogen receptor (ER)-positive disease: ER induces coordinated transcriptional activation of KIF15 through ANCCA-dependent recruitment of E2F and MLL1 to kinesin gene promoters, depositing activating H3K4me3 marks (Zou et al. 2014). KIF15 expression correlates with ANCCA overexpression and poor relapse-free survival in ER-positive tumors, and KIF15 depletion suppresses growth of both tamoxifen-sensitive and tamoxifen-resistant cells — directly implicating KIF15 in endocrine therapy resistance in this subtype (Zou et al. 2014). In TNBC, KIF15 expression is additionally enhanced through Vir-like m6A methyltransferase associated (VIRMA)-mediated m6A epitranscriptomic regulation (Chen et al. 2023). Beyond tumor cell-intrinsic effects, KIF15 has been linked to an immunosuppressive tumor microenvironment (TME) in breast cancer, suggesting that its cancer relevance extends to immune evasion (Zhang et al. 2026). One important caveat specific to TNBC is the context-dependent relationship between KIF15 and stemness: unlike in HCC and gastric cancer where KIF15 promotes CSCs programs, KIF15 knockdown in a subset of TNBC cells paradoxically increases pluripotency marker expression (Guo et al. 2024b), likely reflecting lineage-specific differences in redox state and epigenetic landscape.

Urological and gynecological malignancies

PCa represents the tumor type with perhaps the strongest evidence for KIF15 as a clinically actionable target. In CRPC, KIF15 drives enzalutamide resistance through AR/AR-V7 stabilization, and independent functional-genomic evidence from the Cancer Dependency Map confirms KIF15 as a high-priority dependency in PCa cell lines with direct correlation to poor clinical outcomes (Feng et al. 2025). KIF15 expression is particularly elevated in neuroendocrine prostate cancer (NEPC), an aggressive AR-independent subtype, and is reduced by abiraterone treatment, suggesting regulation by AR pathway activity (Feng et al. 2025). Proof-of-concept studies targeting KIF15-dependent programs have demonstrated anti-CRPC activity, further supporting translational interest (Han et al. 2025). In BC, KIF15 promotes tumor growth through MEK-ERK activation and is additionally regulated by GSG2/Haspin kinase, representing a lineage-specific upstream regulatory input not observed in other tumor types (Zhao et al. 2019; Chen et al. 2020). In ovarian cancer, KIF15 knockdown promotes apoptosis through activation of multiple cell death pathways, and high expression correlates with poor prognosis (Sun et al. 2021).

Gastrointestinal and hepatobiliary malignancies

Gastrointestinal and hepatobiliary cancers collectively provide some of the broadest mechanistic evidence for KIF15 in cancer, spanning metabolic reprogramming, redox regulation, immune checkpoint-linked radio-resistance, and survival signaling. From a clinical and lineage-specific perspective, several additional features are noteworthy.

In pancreatic ductal adenocarcinoma (PDAC), KIF15 contributes through at least three mechanistically distinct programs — MEK-ERK proliferative signaling, USP10-PGK1 glycolytic reprogramming, and phosphorylation/acetylation-regulated focal adhesion dynamics — making it one of the most functionally versatile KIF15-expressing tumors documented to date (Wang et al. 2017; He et al. 2022; Quan et al. 2023). In GC, high KIF15 expression correlates with poor prognosis, and co-targeting KIF11 and KIF15 has shown synergistic antitumor effects in GC models, providing preclinical rationale for kinesin pathway co-inhibition as a therapeutic strategy (Ding et al. 2020; Tao et al. 2020; Sun et al. 2023). In CRC, a distinctive feature is the connection between KIF15 and immune checkpoint signaling: B7-H3 drives KIF15 activity to sustain ERK1/2 phosphorylation under irradiation, linking an immune checkpoint molecule to MAPK-dependent radio-resistance through KIF15 (Ma et al. 2020; Shi et al. 2023).

In HCC, KIF15 is consistently overexpressed across multiple bioinformatic datasets, and a notable lineage-specific feature is its expression in tumor-associated monocytes — the only tumor type in which KIF15 expression in non-malignant stromal cells has been proposed as a prognostic indicator — suggesting that KIF15’s cancer relevance in HCC may extend into the TME (Kitagawa et al. 2020). In gallbladder cancer (GBC), a biliary malignancy associated with poor prognosis and limited therapeutic options, KIF15 is significantly overexpressed in tumor tissues relative to adjacent non-malignant tissues, with expression levels correlating with tumor malignancy grade (Wang et al. 2021a). Functional studies demonstrate that KIF15 knockdown suppresses GBC cell proliferation and migration while promoting apoptosis, and KIF15 silencing significantly impairs xenograft tumor growth in vivo (Wang et al. 2021a). Mechanistically, KIF15 deficiency leads to decreased activity of TNF, PI3K-AKT, and MAPK signaling pathways, along with p21-mediated CDK6 suppression; the anti-tumor effects of KIF15 knockdown can be rescued by AKT activator treatment, confirming PI3K-AKT as the dominant effector axis (Wang et al. 2021a). These findings add GBC to the list of biliary malignancies in which KIF15 represents a potential therapeutic vulnerability.

Central nervous system, head and neck, and additional malignancies

In GBM, KIF15 promotes tumor cell proliferation and is inversely associated with patient survival. A lineage-specific regulatory feature is the involvement of context-specific RE1-silencing transcription factor (REST)/histone acetyltransferase P300-dependent promoter activation programs that sustain aberrant KIF15 expression in glioma cells, a mechanism not described in other tumor types (Wang et al. 2020; Yu et al. 2024). In nasopharyngeal carcinoma (NPC), KIF15 overexpression contributes to proliferation, migration, invasion, and therapy resistance, with N(6)-adenosine-methyltransferase catalytic subunit METTL3 (METTL3)-driven m6A methylation of KIF15 mRNA providing a lineage-specific epitranscriptomic mechanism that couples KIF15 expression to radio-resistance through signal transducer and activator of transcription 3 (STAT3)-mediated autophagy suppression (Cai et al. 2023; Li et al. 2025). Beyond these representative types, KIF15 dysregulation has been reported across a broad range of additional malignancies including melanoma (Yu et al. 2019), osteosarcoma (Wu et al. 2019), Burkitt lymphoma (Wang et al. 2021b), leiomyosarcoma (Ge et al. 2021), chordoma (Yang et al. 2024), and malignant peripheral nerve sheath tumors (MPNST), in which combined KIF15 and KIF11 inhibition shows enhanced efficacy (Terribas et al., 2020). Collectively, these findings establish KIF15 as a recurrently upregulated and clinically relevant cancer-associated factor across diverse tumor lineages.

KIF15 at the tumor-immune interface

Emerging evidence suggests that the cancer relevance of KIF15 is not restricted to tumor cell-intrinsic functions. Host Kif15 deficiency has been shown to suppress the growth of transplanted tumors, even when the implanted tumor cells themselves retain KIF15 expression, indicating that KIF15 in the host compartment can influence antitumor responses (Zhang et al. 2023b). In this setting, Kif15 loss is associated with increased CD8⁺ T-lymphocyte abundance and broader immune activation, and pharmacologic inhibition of Kif15 has also been reported to enhance macrophage phagocytosis of tumor cells in vitro (Zhang et al. 2023b). Together with evidence linking KIF15 to an immunosuppressive TME in breast cancer, these findings suggest that KIF15 may function at the tumor-immune interface and that its inhibition could potentially provide dual benefits by suppressing tumor cell proliferation while enhancing antitumor immunity (Zhang et al. 2023b, 2026).

Regulation of KIF15 expression, activity, and proteostasis

Post-translational regulation of KIF15 activity

Post-translational regulation of KIF15 remains relatively less well characterized than its transcriptional or cancer-associated functional roles, but available evidence indicates that phosphorylation and acetylation can modulate its activity in a context-dependent manner. In PDCA, dynamic phosphorylation and acetylation of KIF15 cooperate to regulate focal adhesion turnover, integrin β1/focal adhesion kinase (FAK) signaling, and metastatic behavior, supporting the view that post-translational modification of KIF15 can influence its subcellular interactions and pro-migratory functions (He et al. 2022). In parallel, studies in mouse oocytes indicate that KIF15 contributes to spindle integrity and chromosome alignment by maintaining acetylated tubulin levels and recruiting HDAC6-, N-acetyltransferase 10 (NAT10)-, and sirtuin 2 (SIRT2)-associated regulatory machinery, thereby linking KIF15 to microtubule acetylation-dependent control of meiotic progression (Zou et al. 2022). Together, these findings suggest that KIF15 activity is modulated not only at the level of expression but also through post-translational mechanisms that affect cytoskeletal organization and microtubule-associated functions.

Epitranscriptomic, transcriptional, and epigenetic control of KIF15 expression

KIF15 expression is subject to multilayered upstream regulation at the epitranscriptomic, transcriptional, and epigenetic levels. m6A-dependent regulation has emerged as a recurring mechanism in cancer, with METTL3-mediated methylation enhancing KIF15 expression in NPC and promoting STAT3-dependent tumor progression and radio-resistance (Li et al. 2025). Similarly, the m6A writer component VIRMA has been shown to increase m6A-dependent KIF15 expression in TNBC, thereby supporting malignant progression (Chen et al. 2023). At the transcriptional level, KIF15 can be activated by tumor-context-specific regulatory programs, including REST/ P300-dependent transactivation in GBM and zinc finger protein 367 (ZNF367)-mediated promoter activation in breast cancer (Zeng et al. 2020; Yu et al. 2024). DNA methylation may represent an additional regulatory layer, although current evidence is more preliminary: integrative analyses in HCC have suggested that promoter hypomethylation may contribute to KIF15 upregulation, while multi-omics work in atrial fibrillation has implicated KIF15-associated methylation-expression networks outside the cancer setting (Liu et al. 2020; Matsushita et al. 2020). Overall, these observations support the concept that KIF15 dysregulation in disease reflects not only altered mitotic demand but also active control by RNA modification, transcription factor networks, and locus-specific epigenetic states.

KIF15-associated proteostasis networks in cancer

In addition to being regulated at the expression and post-translational levels, KIF15 also participates in protein stability networks that reinforce malignant phenotypes. In PDCA, KIF15 promotes USP10-mediated deubiquitination and stabilization of PGK1, thereby sustaining glycolytic reprogramming and tumor growth (Quan et al. 2023). In leiomyosarcoma, KIF15 enhances ubiquitin-specific protease 15 (USP15)-dependent deubiquitination of DEK proto-oncogene (DEK) and prevents its degradation, linking KIF15 to proteostasis control of an oncogenic chromatin-associated factor (Ge et al. 2021). In PCa, KIF15 stabilizes AR and AR-V7 by facilitating ubiquitin-specific protease 14 (USP14)-associated protection from proteasomal degradation, thereby contributing to enzalutamide resistance (Gao et al. 2021a). These studies collectively indicate that KIF15 should not be viewed solely as a microtubule motor; rather, it also functions as a scaffold or facilitator within proteostasis-regulatory complexes that influence the stability of key cancer-driving proteins.

KIF15 in non-neoplastic diseases

Genetic association of KIF15 with fibrotic lung disease

Among non-neoplastic conditions, the strongest current evidence for disease relevance of KIF15 comes from IPF. Genome-wide association (GWAS) studies identified the KIF15 locus as a susceptibility signal for IPF (Allen et al. 2020). Subsequent genetic analyses further demonstrated that both rare deleterious variants and common variants in KIF15 contribute to disease risk, supporting its role as an IPF susceptibility gene (Zhang et al., 2022a). Additional cohort-based studies have linked specific KIF15 missense variants to earlier disease onset, particularly in defined population cohorts (Hollmén et al. 2023). Collectively, these findings position KIF15 as one of the clearest examples of a kinesin family member with direct relevance to non-neoplastic human disease susceptibility, and they suggest that KIF15 genetic screening may have value in risk stratification for IPF.

Despite the genetic evidence implicating KIF15 in IPF susceptibility, the biological mechanism by which KIF15 variants promote lung fibrosis remains to be established. KIF15 is a mitotic kinesin whose canonical functions are restricted to dividing cells; its connection to the pathobiology of IPF — which is driven by alveolar epithelial cell injury, aberrant fibroblast-to-myofibroblast differentiation, and dysregulated transforming growth factor beta (TGF-β) signaling — is not mechanistically self-evident. Several possibilities merit investigation. Loss-of-function KIF15 variants identified in IPF patients may impair cell division fidelity in the rapidly renewing alveolar epithelium, leading to replicative stress, senescence, or chromosomal instability in type II pneumocytes — pathological hallmarks of IPF that are increasingly recognized as central to disease initiation. Alternatively, KIF15 has non-mitotic roles in microtubule organization in post-mitotic cells, and its dysfunction could theoretically impair mucociliary transport or ciliary function in airway epithelial cells, disrupting the mechanical barrier that protects against fibrogenic stimuli. A third possibility is that the IPF-associated KIF15 variants act through haploinsufficiency—a state in which one damaged gene copy reduces protein output below the threshold required for normal tissue repair—affecting the proliferative response of progenitor cells following alveolar injury (Matharu et al. 2019). Systematic functional studies in relevant cell types — including primary human type II alveolar epithelial cells and lung fibroblasts derived from carriers of the identified KIF15 variants — are urgently needed to define the pathophysiological mechanism.

KIF15 in cardiovascular and vascular remodeling

Emerging evidence also implicates KIF15 in cardiovascular and vascular remodeling. In the heart, KIF15 has been identified as a downstream effector of forkhead box protein O6 (FoxO6) in pressure overload-induced pathological remodeling, where activation of the FoxO6-KIF15-TGF-β1 axis contributes to hypertrophy, fibrosis, and cardiac dysfunction (Zhang et al., 2023a). In the vasculature, KIF15 has been linked to environmentally induced vascular injury, as polystyrene nanoplastics were shown to accelerate atherosclerosis in part by inducing KIF15-dependent vascular smooth muscle cell migration (Zhong et al. 2024). This finding places KIF15 within the mechanistic framework of environmentally driven cardiovascular disease (Zhong et al. 2024). By contrast, the evidence connecting KIF15 to smoking-related endothelial dysfunction and broader atherosclerosis-associated gene networks is currently more exploratory and derives primarily from bioinformatic analyses rather than direct mechanistic validation (Guo et al. 2024a). Taken together, these studies suggest that KIF15 may contribute to non-neoplastic tissue remodeling beyond the lung, although the strength of evidence varies substantially across disease contexts.

KIF15 as a therapeutic target

Pharmacological targeting of KIF15: chemical tractability and direct inhibition

Interest in therapeutic targeting of KIF15 has been driven by its reported roles in tumor progression and, in particular, its ability to support resistance to Eg5 inhibition. Early efforts to identify direct KIF15-targeting compounds included computational and repurposing-based approaches, which nominated dihydropyrazole- and dihydropyrrole-related scaffolds, as well as benserazide, as candidate molecules capable of perturbing KIF15-associated functions and inducing mitotic defects in cultured cancer cells (Sebastian 2017; Sebastian and Rathinasamy 2020). However, these studies are more appropriately regarded as proof-of-concept or tool-compound efforts rather than evidence of clinically optimized KIF15 inhibitors (Sebastian 2017; Sebastian and Rathinasamy 2020). More direct chemical evidence for KIF15 tractability came from the identification of oxindole- and quinazolinedione-based chemical probes that inhibit KIF15 through distinct allosteric mechanisms (Dumas et al. 2019). These compounds provided an important framework for mechanistic interrogation of KIF15 and supported the view that the motor is chemically tractable using structurally diverse small molecules (Dumas et al. 2019). Biophysical studies further characterized the nanomechanical basis of KIF15 inhibition and showed that KIF15 motility can be potently suppressed by small-molecule inhibitors, thereby providing a mechanistic basis for future inhibitor optimization (Milic et al. 2018). More recently, selective chemical inhibition of KIF15 was strengthened by the identification of additional small molecules, including Munesib-1 and Fift-IN, which inhibit KIF15 in vitro and in cells and reduce the ability of cells to acquire resistance to Eg5 inhibitors (Solon et al. 2022).

Acknowledging the clinical precedent set by Eg5/KIF11 inhibitors is critical before discussing the therapeutic potential of KIF15. Despite robust preclinical rationale, multiple Eg5 inhibitors (including ispinesib, SB743921, and filanesib/ARRY-520) demonstrated only modest single-agent efficacy in solid tumor trials. This limited activity largely stemmed from resistance mechanisms inherent to solid tumors, including a reduced mitotic index in slow-cycling cells, adaptation of the SAC, and compensatory spindle rescue pathways — a bypass mechanism directly mediated by KIF15 itself (Garcia-Saez and Skoufias 2021). The sole exception, filanesib, has shown activity in multiple myeloma, likely due to the inherently high proliferative index of this hematologic malignancy. These clinical observations carry direct implications for KIF15 inhibitor development: the same tumor biology factors that limited Eg5 inhibitors—namely mitotic specificity, SAC bypass, and inter-tumor heterogeneity in proliferative index—are likely to pose parallel challenges for KIF15-targeted agents unless rational combination strategies are employed from the outset. Taken together, these findings support the chemical tractability of KIF15 but also highlight that its clinical translation, while feasible, will depend on overcoming the biological hurdles established by its kinesin predecessor (Table 2).

Table 2.

Summary of KIF15-targeting compounds and combination strategies

Compound	Chemical class / origin	Mechanism of action	Key experimental evidence	Development stage	Refs
GW108X	Oxindole (identified from kinase inhibitor library)	Allosteric inhibition of KIF15 ATPase activity; mechanistically distinct from Kif15-IN-1	Inhibits KIF15 motor activity in vitro; mechanistically complementary to Eg5 inhibitors	Lead compound / tool compound	(Dumas et al. 2019)
Quinazolinedione probe	Quinazolinedione scaffold	Allosteric KIF15 inhibition at a site distinct from GW108X	Dual-probe validation of KIF15 chemical tractability in vitro	Tool compound	(Dumas et al. 2019)
Kif15-IN-1	Commercially available small molecule (structure undisclosed)	Inhibition of KIF15 ATPase motor activity	Suppresses KIF15 motility in vitro; enhanced antitumor effect when combined with Eg5 inhibitors in cells	Tool compound	(Milic et al. 2018)
Munesib-1	Identified by high-throughput screen	Inhibits KIF15 motor activity; interferes with microtubule binding	Inhibits KIF15 in vitro and in cells; reduces acquisition of Eg5 inhibitor resistance	Tool compound	(Solon et al. 2022)
Fift-IN	Identified by high-throughput screen	Inhibits KIF15 motor activity via a mechanism distinct from Munesib-1	Validated in vitro and in cells; mechanistically complementary to Munesib-1	Tool compound	(Solon et al. 2022)
Benserazide	Approved drug (Parkinson’s disease); repurposing	Disrupts KIF15-KBP protein-protein interaction	Prolongs metaphase by 47 ± 10 min in HeLa cells; IC₅₀ ≈ 101 µM; 12% mitotic arrest rate; no direct tubulin binding	Proof-of-concept / drug repurposing	(Sebastian and Rathinasamy 2020)
Dihydropyrazole / dihydropyrrole derivatives	Computationally designed; virtual screening hits	Docking-based targeting of KIF15 motor domain	Pharmacophore modeling and QSAR; no cell-based validation reported	In silico stage	(Sebastian 2017)
ATR-I	Natural product (extract of Atractylodes macrocephala)	Targets KIF15 → promotes ubiquitin-proteasome-mediated AR/AR-V7 degradation	Inhibits CRPC growth and reverses enzalutamide resistance in vitro and in vivo	Phytochemical validation stage	(Han et al. 2025)
Eg5 inhibitor + KIF15 inhibitor (combination)	Combination strategy	Synergistic disruption of spindle bipolarity	Synergistic anti-proliferative effect; reduces emergence of Eg5 inhibitor resistance in cancer cells	Preclinical combination strategy	(Solon et al. 2022)
Aurora A inhibitor + KIF11 inhibitor (combination)	Combination strategy (indirect suppression of KIF15-mediated resistance)	Aurora A pathway blockade synergizes with KIF11 inhibition to override KIF15 compensation	Overcomes KIF15-dependent SB743921 resistance; synergy confirmed by isobologram analysis	Preclinical combination strategy	(Ma et al. 2014)

KIF15-targeted combination strategies and therapeutic sensitization

A major therapeutic rationale for targeting KIF15 is to overcome adaptive resistance to Eg5 inhibitors. Cells exposed to Eg5 inhibitors can maintain spindle bipolarity through KIF15-dependent mechanisms, and this adaptive response has provided the conceptual basis for dual targeting of Eg5 and KIF15 (Sturgill et al. 2016; Solon et al. 2022). Consistent with this model, combined inhibition of KIF15 and Eg5 has been shown to synergistically disrupt spindle bipolarity, impair cancer cell proliferation, and reduce the emergence or maintenance of Eg5 inhibitor resistance (Sturgill et al. 2016; Milic et al. 2018; Solon et al. 2022).

In parallel, synergistic inhibition of Aurora A and KIF11 has also been shown to overcome KIF15-dependent drug resistance, supporting the broader concept that KIF15-mediated therapeutic escape can be suppressed through rational combination strategies targeting parallel spindle assembly pathways (Ma et al. 2014). Notably, not all compounds that modulate this resistance landscape act by directly inhibiting KIF15 itself (Al-Obaidi et al. 2016). For example, MAC1 restores spindle bipolarity in monastrol-treated cells by promoting the formation of additional microtubule nucleation centers and thereby enabling Kif15-dependent spindle assembly, highlighting the plasticity of the spindle system that must be considered when designing combination therapies (Al-Obaidi et al. 2016).

Beyond Eg5 resistance, KIF15-targeted strategies may also sensitize tumors to other treatment modalities. In GC, combined inhibition of KIF11 and KIF15 produces synergistic antitumor effects in vitro and in vivo (Sun et al. 2023). In NPC, KIF15 inhibition enhances radiosensitivity by restoring autophagy-associated cell death through the STAT3-ATG7 axis (Li et al. 2025). In CRPC, suppression of KIF15 resensitizes tumor cells to enzalutamide by destabilizing AR and AR-V7 signaling (Gao et al., 2021a). In CRC, KIF15 contributes to B7-H3-mediated radio-resistance through ERK1/2 activation, suggesting that KIF15 inhibition may also improve the efficacy of radiotherapy in this setting (Ma et al. 2020). Collectively, these studies indicate that the therapeutic value of KIF15 may extend beyond direct cytotoxicity and instead lie in its use as a sensitizing target across multiple anticancer treatment contexts.

Natural compounds and emerging translational opportunities

Natural products may provide an additional entry point for therapeutic exploitation of KIF15 (Han et al. 2025). Atractylenolide I has been reported to suppress CRPC growth and overcome enzalutamide resistance by targeting KIF15, thereby promoting ubiquitin-proteasomal degradation of AR and AR-V7 (Han et al. 2025). This study provides proof-of-concept support for the idea that naturally derived compounds can modulate KIF15-dependent oncogenic programs and may serve as starting points for future optimization (Han et al. 2025). At present, however, the translational development of KIF15-targeted therapeutics remains at a preclinical stage, and the field still relies predominantly on chemical probes, mechanistic inhibitors, and rational combination strategies rather than clinically validated KIF15-directed drugs.

Genetic variants and germline associations

Although current interest in KIF15 has focused largely on its therapeutic tractability in cancer, pharmacologic targeting represents only one dimension of its clinical relevance. Increasing genetic evidence indicates that germline variation in KIF15 is associated with susceptibility to fibrotic and developmental disorders, thereby extending its significance beyond acquired oncogenic dysregulation.

As discussed in Sect.  8.1, the genetic evidence linking KIF15 variants to IPF currently represents one of the strongest examples of a kinesin family member with direct relevance to non-neoplastic inherited disease susceptibility. The identification of both rare loss-of-function alleles and a common GWAS susceptibility signal at the KIF15 locus, together with the association of the p.Gly243Ser missense variant with early-onset IPF, supports the potential relevance of KIF15 to genetic risk stratification in fibrotic lung disease (Table 3).

Table 3.

KIF15 germline variants and disease associations

Variant class	Specific variant / locus	Associated disease	Effect direction	Cohort / source	Key finding	Refs
Common variant (GWAS signal)	KIF15 locus (see Allen et al. for rs identifiers)	IPF	Increased disease risk	Multi-center GWAS meta-analysis	KIF15 locus reaches genome-wide significance as an IPF susceptibility signal	(Allen et al. 2020)
Rare deleterious variant (heterozygous LOF)	Multiple heterozygous loss-of-function variants	IPF	Causative (designated as causal IPF gene)	Whole-exome sequencing + meta-analysis	Convergent evidence from rare and common variants establishes KIF15 as a causal IPF gene	(Zhang et al. 2022a)
Missense variant	p.Gly243Ser (c.727G > A)	IPF (early-onset)	Earlier disease onset	Finnish prospective IPF cohort	Carriers exhibit significantly earlier disease onset compared to non-carriers	(Hollmén et al. 2023)
Loss-of-function mutation (homozygous / biallelic)	Biallelic LOF mutation	Braddock-Carey syndrome genocopy	Causative	Single consanguineous Saudi Arabian family	Congenital thrombocytopenia + Pierre-Robin sequence; KIF15 is the first kinesin family member linked to congenital thrombocytopenia	(Sleiman et al. 2017)

Beyond pulmonary fibrosis, loss-of-function mutations in KIF15 have also been reported in a Braddock-Carey syndrome genocopy, a rare multisystem developmental disorder characterized by thrombocytopenia, neurodevelopmental abnormalities, and dysmorphic features (Sleiman et al. 2017). This phenotype underscores the broader developmental importance of KIF15 and suggests that disruption of its function can affect multiple organ systems beyond the lung (Sleiman et al. 2017). By contrast, evidence linking germline KIF15 variants to inherited cancer susceptibility remains limited, and current oncologic studies have focused predominantly on somatic overexpression and the prognostic or functional significance of KIF15 in tumors rather than on clearly established heritable cancer-predisposition alleles (Li et al. 2020b; Mi et al. 2022; Badraldin et al. 2025).

Conclusions and future perspectives

KIF15 has emerged as a multifunctional kinesin whose biological significance extends beyond its initially defined role in mitotic spindle assembly. As a kinesin-12 family motor, KIF15 contributes to spindle bipolarity, generates forces within spindle microtubule arrays, and can compensate for Eg5 under defined conditions, thereby providing a mechanistic basis for adaptive resistance to spindle-targeting therapies. This functional plasticity highlights KIF15 as a clinically relevant mediator of antimitotic drug resistance and a promising candidate for therapeutic intervention.

In cancer biology, KIF15 is broadly overexpressed across multiple human malignancies and exerts oncogenic effects through diverse signaling pathways, including MEK-ERK, PI3K-AKT, EGFR, and STAT3, in a tumor- and context-dependent manner. In addition, KIF15 has been implicated in the maintenance of CSC-associated traits, the promotion of invasive and EMT-like phenotypes, metabolic reprogramming, and resistance to chemotherapy, radiotherapy, and targeted therapy. Taken together, these properties position KIF15 as an attractive oncologic target with potential relevance across multiple treatment contexts.

Beyond cancer, KIF15 participates in a broad range of physiological and pathological processes, including neuronal microtubule organization, synaptic and sensory system function, spermatogenesis, oocyte meiosis, and tissue remodeling. Its dysregulation has been linked to neuropsychiatric phenotypes, pain sensitization, cardiac pathological remodeling, vascular disease, and IPF. Notably, the identification of KIF15 as an IPF susceptibility gene has expanded its significance beyond oncology and suggests new opportunities for genetic risk stratification in non-neoplastic disease.

Despite these advances, several important questions remain unresolved. First, structural information is still incomplete, as available studies have provided insight into the KIF15 motor domain, TPX2-dependent regulation, and KBP-kinesin motor interactions, but a full-length KIF15 structure captured in functionally relevant assemblies, particularly in complex with microtubules and major regulatory partners, remains lacking. Second, the mechanisms by which KIF15 engages intracellular signaling networks, including MEK-ERK and PI3K-AKT, independently of or in parallel with its canonical motor activity remain insufficiently defined. Third, the regulation of KIF15 expression across developmental, physiological, and disease contexts, including its transcriptional, epitranscriptomic, and epigenetic control, requires more systematic investigation. Fourth, although multiple KIF15-directed compounds and chemical probes have now been described, the development of selective, potent, and pharmacokinetically favorable inhibitors suitable for in vivo and clinical investigation remains an unmet need.

Future work should also more fully define the non-cell-autonomous roles of KIF15 within the TME (Kitagawa et al. 2020; Zhang et al. 2026). The observation that KIF15 expression in tumor-associated monocytes is prognostically informative in HCC, together with evidence implicating KIF15 in immunosuppressive tumor phenotypes in breast cancer, suggests that its biological functions may extend beyond tumor cell-intrinsic proliferation and survival programs (Kitagawa et al. 2020; Zhang et al. 2026). These findings raise the possibility that KIF15-directed strategies could be explored not only in combination with spindle-targeting agents, radiotherapy, or endocrine therapy, but also in the context of immune-modulating approaches. In summary, KIF15 is a multifunctional molecular motor positioned at the intersection of cell division, development, cancer biology, and non-neoplastic disease. Continued clarification of its mechanistic functions, together with progress in pharmacologic targeting and genetic characterization, is likely to further define the clinical relevance of KIF15 in both oncology and inherited or fibrotic disorders.

Author contributions

Sumeng Xiang, Yuxuan Li, Haihui Zhuang and Ying Lu wrote and edited the article. Ying Lu revised the article.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no conflict of interest.