With the presence of the KH, NLS and KI domains, hnRNPK can bind to DNA, RNA and proteins with specificity. This allows it to participate in numerous biological processes, including the regulation of gene transcription, alternative mRNA splicing, mRNA polyadenylation, mRNA stability, mRNA translation and cell signal transduction.

hnRNPK attaches to specific DNA locations on genes and participates in the regulation of gene transcription by interacting with DNA proteins. hnRNPKs serve roles in both transcriptional activation and inhibition. hnRNPK can bind to the promoters of numerous genes, including those of the simian vacuolating virus 40, neuronal nicotinic acetylcholine receptor, BRCA1, cellular Src (c-Src), cellular Myc (c-Myc) and eukaryotic translation initiation factor 4E, to increase transcription of the corresponding genes (28). hnRNPK can also bind to the human thymidine kinase gene promoter to inhibit transcription.

Gene expression is regulated by alternative splicing of mRNA. Gene function can be enhanced by altering the splicing of the same DNA segment to produce mRNA, which can subsequently be translated into proteins that exhibit specific biological effects. The most notable cell splicing regulators are hnRNPs, which are found in precursor mRNA and contain splicing enhancement and inhibition elements that selectively bind to cytokines, to open and close splicing sites (22). hnRNPK serves a key role in regulating the variable splicing of Runt-related transcription factor 1 and synaptosome-associated protein 25 kDa mRNA during neuronal differentiation. hnRNPK binds to the enhancer of chicken P-tropomyosin precursor mRNA and promotes exon splicing, specifically when hnRNPK is combined with a splicing inhibitor to suppress the synthesis of the apoptosis-promoting gene Bcl-x short-isoform. Subsequently, ~50% of alternative splicing events in apoptotic genes are affected (29).

Cells tightly regulate mRNA stability through RNA-binding proteins and controlled degradation pathways. The biological functions of expressed proteins and the half-life of mRNA are closely related. mRNA stabilization can be achieved through controlled degradation (30). Currently, four mechanisms of mRNA decay have been recognized (31), including the deadenylation-dependent process, endogenous ribozyme-mediated system, nonsense-mediated pathway and non-stop degradation pathway. Numerous cis-regions in the mRNA sequence can be detected and bound by hnRNPs, which affect mRNA stability primarily through the deadenylation-dependent and nonsense-mediated decay pathways. Proreninogen mRNA is stabilized and renin production is aided by the interaction of hnRNPK with the 3′-untranslated region (UTR) of proreninogen mRNA. To improve viral mRNA stability, the KH domain of hnRNPK interacts with poliovirus RNA-splicing regulatory components (32). Collagen I and III are expressed more efficiently when hnRNPK interacts with the 3′-UTRs of their mRNAs.

hnRNPK is key for controlling cytoplasmic mRNA translation. The final step in the transition from reticulocytes to mature erythrocytes is mediated by reticulocyte 15-lipoxygenase (r15-LOX). Gradual translation of r15-LOX mRNA occurs during cell development. The 3′-UTR of LOX mRNA contains a differentiation control element (DICE), which serves a role in regulating this translation (33). The interaction between hnRNPK and DICE halts translation and hinders the assembly of complete 80S ribosomes. hnRNPK functions as a substrate for c-Src during erythrocyte maturation. To enable the translation of LOX mRNA, active c-Src phosphorylates hnRNPK and disrupts its binding to DICE. hnRNPK can bind to the 5′-UTR of the proto-oncogene Myc in vivo and in vitro, promoting ribosome entry and enhancing c-Myc translation. In addition to the DNA or RNA binding involved in signal transduction, hnRNPK influences the transcription and translation of signaling pathways by interacting with key signaling proteins, such as Vav and c-Src (34). The proto-oncogene Vav is a key regulator of the B cell receptor (BCR) signaling pathway. According to previous studies (2,6), hnRNPK binds to the SH3 domain of the Vav protein and promotes cell transformation through the BCR pathway. c-Src regulates the MAPK/ERK, integrin/focal adhesion kinase and STAT signaling pathways, amongst others, serving a role in biological processes such as cell division and apoptosis (35). Upon hnRNPK binding to the SRC homology 3 domain of c-Src, c-Src is activated, thereby controlling downstream signaling molecules.

Chromatin remodeling factors regulate chromatin structure by altering the position and configuration of nucleosomes during DNA replication and transcription. These changes affect the binding of transcription-related proteins to DNA, thereby controlling gene transcription (36). hnRNPK can directly interact with DNA methyltransferase, EED (a core component of polycomb repressive complex 2) and nuclear scaffold attachment factor B to regulate chromatin remodeling, which, in turn, affects gene expression. The structural framework that remains in the eukaryotic nucleus after removal of the nuclear membrane, soluble proteins and chromatin is known as the nuclear matrix (37). Nuclear matrix proteins constitute the majority of these structures, while DNA, RNA and lipids make up the remainder. The nuclear matrix is important for chromatin remodeling, DNA replication, gene transcription and post-transcriptional regulation. Nuclear matrix proteins, including hnRNPK, are key in maintaining the grid-like structure of the nuclear matrix (38). Changes in the internal structure of the nuclear matrix can affect various biological processes, including chromatin remodeling and gene transcription.

hnRNPK exhibits the ability to interact with numerous ncRNAs and participate in the regulation of various cellular pathways. Long ncRNAs (lncRNAs), small nucleolar RNAs and cyclic RNAs are the three primary categories of ncRNAs (39). lncRNAs, which are >200 nucleotides in length, are key for the biological functions of various types of cancer, including colorectal, hepatocellular, breast and bladder cancer, serving an important role in disease etiology and acting as primary regulators of hnRNPK. Table II illustrates how hnRNPK interacts with cellular processes and contributes to the regulation of protein-coding gene networks. These interactions include: i) lncRNA-hnRNPK interactions, such as lncRNA-p21, Tcl1 upstream neuron-associated lncRNA, lncRNA essential for naïve ESC self-renewal 1, promoter-associated noncoding RNA of ETS1, Ewing sarcoma-associated transcript 1, cancer susceptibility candidate 11, MYC-inducible lncRNA 2 and lncRNA91H, which regulate gene transcription; ii) the regulation of mRNA stability and translation by lncRNA-hnRNPK interactions, including c-Myc-upregulated lncRNA, translation regulatory lncRNA and linc0046660; iii) the promotion of lncRNA nuclear localization, as observed with short interspersed nuclear element-derived nuclear RNA localization; iv) the regulation of genes involved in X-inactive specific transcript activity through lncRNA-hnRNPK interactions; and v) hnRNPK-mediated alternative splicing of lncRNAs such as nuclear paraspeckle assembly transcript 1 (40). Table II (26,27,41–53) summarizes the specific mechanisms underlying these interactions and highlights the diverse roles of hnRNPK in the regulatory networks of protein-coding genes. Notable examples include MYU stabilizing CDK6 expression in the cytoplasm, CTHCC activating YAP1 transcription in the nucleus and CASC11 promoting the Wnt/β-catenin pathway.

hnRNPK controls the expression of numerous oncogenes and tumor suppressor genes in malignancies, as well as the proliferation, apoptosis, migration and invasion of tumor cells. Fig. 2 presents a comprehensive overview of the hnRNPK functional network in malignant tumors, illustrating its multifaceted roles in cancer biology through a number of molecular mechanisms and signaling pathways.

In certain malignancies, hnRNPK has been implicated in the regulation of tumor growth. A previous study suggested that hnRNPK controls the p53/p21/cyclin-D1 axis to suppress tumor cell proliferation, colony formation and tumor progression in gastric cancer cells (11). An association has also been observed between hnRNPK expression and poor prognosis in patients with bladder cancer (54). The primary mechanism of this involves the regulation of cyclin-D1, a key cell cycle protein, by hnRNPK to promote the proliferation and survival of bladder cancer cells. The human telomerase reverse transcriptase and c-Myc genes, which are involved in tumor cell proliferation, are also closely associated with hnRNPK (55).

One of the key hallmarks of cancer is its ability to evade apoptosis. hnRNPK regulates tumor apoptosis through a number of pathways. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel and efficient therapeutic agent that targets tumor cell death (56). The NF-κB pathway, which is implicated in apoptosis, is activated by phosphatidylinositol signaling and can induce apoptosis in non-small-cell carcinomas. Additional research has revealed that TRAIL treatment of H1299 cells promotes hnRNPK accumulation and induced apoptosis. However, ERK1/2 inhibitors and ERK phosphorylation receptor mutations were shown to reduce TRAIL-induced cytoplasmic accumulation of hnRNPK and act as anti-apoptotic agents (57).

If cellular DNA is not repaired promptly after exposure to ionizing radiation, chemotherapeutic agents or other external stimuli, it can lead to chromosomal remodeling, gene loss and genome instability, thereby promoting cancer development (47). Aberrant hnRNPK expression in tumor cells has been shown to impair DNA repair capacity. When the expression of hnRNPK was downregulated in irradiated bronchial epithelial cells, DNA strand repair was notably impeded. Proteomics analysis has shown that hnRNPK binds to chromatin in response to DNA damage in HeLa cells (58).

Tumor metastasis occurs through direct extension, hematogenous and lymphatic spread and implantation of tumor cells. The early diffusion stage involves the adhesion plaque complex precursor, in which hnRNPK is expressed. Disruption of hnRNPK synthesis increases tumor cell metastasis, indicating that hnRNPK serves a rate-limiting role in tumor growth (59). The relationship between hnRNPK and metastasis has been established in colon, prostate and gallbladder cancer types. Notably, tumor size typically does not exceed 2–3 mm without blood supply and the angiogenic agents that facilitate this include vascular endothelial growth factor (VEGF) and fibroblast growth factor. Therefore, hnRNP proteins have been shown to regulate angiogenic factors and under hypoxic conditions, hnRNPL preferentially binds to the 3′-UTR of VEGF mRNA (60). Inhibition of hnRNPK expression suppresses glioma growth and invasion, suggesting that hnRNPK promotes tumor angiogenesis and facilitates malignant progression.

hnRNPK is further associated with tumor metastasis. Through the Ras-Raf-MAPK pathway, hnRNPK promotes the expression of metastasis-related genes, such as MMP3 and MMP10, prostaglandin G/H synthase 2 and thymosin. Ras and cholecystokinin expression further promotes tumor spread. DAB2-interacting protein stimulates hnRNPK nuclear accumulation, enhances MMP2 transcription and drives colorectal cancer invasion and metastasis through the MAPK/ERK pathway (61). hnRNPK also promotes tumor spread in nasopharyngeal cancer by upregulating MMP12 expression. Strozynski et al (62) found that hnRNPK was markedly expressed in irradiated cells using two-dimensional electrophoresis and mass spectrometry.

Targeted inhibition of hnRNPK expression can reduce the metastatic potential of head and neck squamous cell carcinoma cells. In small-cell renal carcinoma, cytoplasmic aggregation of hnRNPK promotes tumor cell invasion into surrounding tissues. hnRNPK deletion results in transcriptional inactivation of p53 target genes and defective cell cycle arrest. DNA damage-induced hnRNPK undergoes small ubiquitin-related modifier (SUMO)-ylation, which regulates p53 transcriptional activation (63). Additionally, methylation of arginine residues at positions 296 and 299 inhibits the phosphorylation of serine at position 302 by the pro-apoptotic protein kinase C, thereby reducing apoptosis induced by DNA damage. This suggests that hnRNPK serves a key role in anti-apoptotic mechanisms in tumor cells. Chen et al (25) demonstrated that hnRNPK exhibits anti-apoptotic activity by regulating downstream genes. Specifically, hnRNPK binds to the promoter of anti-apoptotic FLICE inhibitory protein and activates its expression. The lncRNA CASC11 interacts with hnRNPK to activate the WNT/β-catenin pathway, ultimately contributing to colorectal cancer development (43).

hnRNPK has been shown to be associated with drug resistance in tumor cells. After radiotherapy, hnRNPK increased in a dose-dependent manner and accumulated in the cytoplasm of melanoma cells with neuroblastoma RAS viral oncogene homolog mutations, causing the cells to become radiotherapy-tolerant (64). Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors can downregulate hnRNPK expression, which, when combined with radiation, markedly increases apoptosis and promotes radiosensitivity (65). Targeted inhibition of hnRNPK expression was found to be consistent with the pro-apoptotic effects of MEK inhibitors. A similar conclusion was reached in colorectal cancer (CRC) cells. Kirsten rat sarcoma virus-mutant CRC cells exhibited rapid upregulation of hnRNPK following radiation therapy, which increased their tolerance to irradiation. MEK inhibitor therapy downregulates hnRNPK, improving sensitivity to radiation (66). hnRNPK is highly expressed in resistant cell lines and the bone marrow of patients with drug-resistant acute myeloid leukemia (AML). Drug-resistant cells lose their tolerance to doxorubicin through targeted suppression of hnRNPK expression. In addition, hnRNPK may contribute to doxorubicin resistance by regulating autophagy.

hnRNPK may serve as a prognostic and chemosensitivity marker in nasopharyngeal carcinoma, as it regulates thymidine phosphorylase expression. Cells with high thymidine phosphorylase levels are sensitive to doxifloruridine treatment (67). Interferon-stimulated gene 15 (ISG15) regulates hnRNPK expression in lung cancer cells. ISG15 downregulation induces cell cycle arrest, allowing extended repair of cisplatin-damaged DNA, stabilization of p53 and increased hnRNPK expression. This process can enhance cisplatin resistance. In lung adenocarcinoma cells, hnRNPK blocks the phosphorylation of glycogen synthase kinase-3 at Ser9 to stabilize cellular FLICE inhibitory protein and increase TRAIL resistance. Zhang et al found that hnRNPK increases AML resistance to adriamycin through modulation. These findings suggest that hnRNPK regulates tumor cell sensitivity to chemotherapy and may serve as a marker for chemosensitivity (68).

In Traditional Chinese Medicine, certain therapeutic compounds can target hnRNPK to exert antitumor effects. Further research using bioinformatics and biochemical methods revealed that the ethanol extract of Indian ginseng serves a role in inhibiting tumor metastasis and angiogenesis by downregulating metastasis-related proteins, including hnRNPK, VEGF and MMPs (69). The ethanol extract of Indian ginseng selectively inhibits tumor cell activity and suppresses metastasis, invasion and angiogenesis. Gambogic acid in Garcinia nujiangensis extract can lower hnRNPK levels by promoting the ubiquitin-proteasome-dependent degradation of hnRNPK, leading to cell cycle arrest and antitumor effects. The protein hnRNPK, associated with human telomerase reverse transcriptase, is a potential biomarker for liver cancer prognosis and may also serve as a therapeutic target for liver cancer (70). The primary antigen target is located at the N-terminus of hnRNPK and contains a glutamic acid-rich domain. Therefore, hnRNPK may be used as a biomarker for the detection of hepatocellular carcinoma associated with hepatitis B virus (HBV). hnRNPK is a biomarker of chemoresistance in gastric cancer (GC). Additionally, upregulation of hnRNPB1 has been identified as a useful biomarker for the early diagnosis of lung cancer and human squamous cell carcinomas. While these preclinical findings are promising, it is important to note that hnRNPK-targeted therapeutic development remains in early stages. Unlike established targets such as HER2 or EGFR, to the best of our knowledge, no hnRNPK-specific inhibitors have yet entered clinical trials. The primary challenge lies in the multifunctional nature and context-dependent role of the protein, which complicates the development of selective therapeutic strategies. Current research focuses primarily on understanding the mechanistic roles of hnRNPK across different cancer types to identify optimal intervention points.

CML, specifically the late acute phase, has a poor prognosis. With this, research into hnRNPK and its family members during the acute phase of CML is relatively common. Other chromosomal and molecular abnormalities are also present in patients with CML, in addition to the aberrant BCR/ABL fusion gene (73). Together with other defective genes, the BCR/ABL gene can influence transcription, protein function and mRNA translation, and improperly abnormally activate downstream signaling pathways, thereby contributing to disease progression. The ability of hnRNPK, hnRNPE1 and hnRNPE2 to limit the proliferation of BCR/ABL-positive cells is inhibited by the upregulation of CML-blast crisis expression (74). The leukemogenic activity of BCR/ABL, which can increase c-Myc gene expression, enhance CML cell proliferation, block apoptosis and potentially promote rapid transformation, relies heavily on hnRNPK-mediated regulation of mRNA translation. The homologous region of the hnRNPK is the structural motif shared by hnRNPK and hnRNPE1/E2. The structural basis of the hnRNPK-mRNA interaction is described as follows. MAPK/ERK1/2 can enhance hnRNPK transcription and mRNA stability in bone marrow cells and lymphocytes expressing the BCR/ABL fusion gene through a BCR/ABL-dependent mechanism (75). Leukemia can be induced by hnRNPK, which inhibits cytokine-dependent colony formation in BCR/ABL-positive cells. hnRNPK binds to MYC mRNA through the internal ribosome entry site (IRES) and upregulates MYC expression at both the transcriptional and translational levels, ultimately promoting cell proliferation and inhibiting apoptosis in hepatocellular carcinoma cells. These effects may be linked to the dysregulation of the oncogene, MYC (76). To identify hnRNPK expression at the protein and transcriptional levels in the bone marrow cells of patients with CML in the chronic and acute phases, Zhu et al (77) used western blotting and reverse transcription-quantitative PCR techniques, finding that hnRNPK expression varied before and after the acute phase of CML, indicating that mRNA translation regulation may underlie changes in hnRNPK protein levels.

Although hnRNPK expression was not observed during the aberrant proliferation of healthy alveolar and bronchiolar epithelial cells, it was slightly upregulated in cells with bronchial epithelial dysplasia (78). The localization of hnRNPK was also shown to gradually shift from the nucleus to the cytoplasm in the study by Huang et al (79) on lung cancer cell lines, suggesting that this shift is associated with the biological state of tumor cells. According to Li et al (55), hnRNPK was expressed in both the cytoplasm and nucleus of lung cancer tissues and control lung tissues. These findings suggest that the hnRNPK positivity rate in lung cancer tissues is higher than that in non-cancerous lung tissues. A total of three histological subtypes of lung cancer stained positive for hnRNPK and the positivity rates for small cell and non-small cell lung cancers did not differ significantly. Although hnRNPK was notably expressed in lung cancer tissues, there was no clear association between hnRNPK expression and the tissue type. In addition, this study found that invasive and metastatic lung cancer tissues showed notable levels of hnRNPK expression, which may indicate a connection between hnRNPK and tumor aggressiveness. However, the precise role of hnRNPK in lung cancer initiation, progression and metastasis remains elusive.

In accordance with findings by Huang et al (8), hnRNPK is a useful prognostic marker in patients with GC. Han et al (80) discovered that hnRNPK is a GC-related antigen, with tissue microarray analysis revealing that hnRNPK expression was elevated in GC tissue. Patients with high hnRNPK expression exhibited a poor prognosis, suggesting that hnRNPK may be associated with GC occurrence, progression and prognosis. Poor prognosis in GC is linked to low hnRNPK transcription levels, particularly in patients with early-stage disease without metastasis. Through the p53/p21/cyclin D1 pathway, hnRNPK upregulation decreases tumor cell proliferation and colony formation in vitro and tumor growth in vivo (81). hnRNPK interacts with tumor-associated genes, including p53 and p21. High hnRNPK expression has been observed in GC tissue. Infection with the L-form of Helicobacter pylori may promote the expression of hnRNPK. The expression of hnRNPK and Helicobacter pylori L-form infection may work together to increase the risk of GC. The degree of differentiation, lymphatic metastasis and clinical stage of GC are associated with hnRNPK expression (82). Research has demonstrated that hnRNPK is primarily expressed in the nucleus of human GC SGC-7901 cells, with a minor quantity expressed in the cytoplasm of in vitro cultured gastric mucosal cell lines and GC SGC-7901 cells (53). The expression of hnRNPK was found to be higher in human GC SGC-7901 cells than in gastric mucosal gastric epithelial-1 cells, both in the cytoplasm and nucleus. hnRNPK was also marginally expressed in the nucleus of gastric mucosal GES-1 cells, but not in the cytoplasm of these cells. Knockdown of hnRNPK reduced the proliferation, migration and invasion of human GC SGC-7901 cells. The cytoplasmic localization and elevated expression of hnRNPK in SGC-7901/DDP cells indicated that hnRNPK was associated with drug resistance in human GC SGC-7901 cells.

To demonstrate that hnRNPK is primarily expressed in the nucleus, Meng et al (33) examined hnRNPK expression in hepatocellular carcinoma and adjacent tissues. Findings revealed that hnRNPK protein expression was higher in 70% of hepatocellular carcinoma tissues than in the corresponding adjacent tissues (83), suggesting that it promotes liver cancer cell development. By separating the cytoplasm and nucleus of hepatoma cells at various densities, changes were observed in hnRNPK expression during cell proliferation. These findings indicate that hnRNPK expression in the nucleus increases with higher cell density, suggesting that elevated nuclear hnRNPK expression may promote cell proliferation (84). In addition, while only 50% of HBV-negative liver cancer tissues showed higher hnRNPK expression than their adjacent tissues, 80% of HBV-positive liver cancer tissues did, indicating an association between hnRNPK expression and HBV infection. Further research is needed to determine whether hnRNPK has a synergistic effect with HBV in promoting liver cancer development and whether HBV upregulates hnRNPK expression in liver cancer tissues. Harris et al (85) demonstrated that hnRNPK can interact with the 3′-UTR of the hepatitis C virus and participate in viral replication. The IRES, located at the 3′ end, is a key regulatory element in viral gene translation. IRES and hnRNPK work together to notably enhance the mRNA translation efficiency, thereby increasing viral expression and replication, thus accelerating disease progression.

With regard to OSCC, researchers used isotope-labeled relative and absolute quantitative techniques combined with liquid chromatography-mass spectrometry and found that hnRNPK protein expression increased with higher tumor-lymph node-metastasis tumor staging levels and was associated with poor prognoses. Therefore, hnRNPK has the potential to be a useful marker for the early detection and prognostic monitoring of OSCC (86). N6-methyladenosine (m6A) levels in OSCC tissues were notably higher than those in adjacent non-tumor tissues and eight m6A-modified genes, including hnRNPC, exhibited differential expression patterns. HnRNPC alone may serve as a standalone biomarker and therapeutic target in OSCC. Compared with healthy oral mucosal tissues, OSCC tissues exhibit markedly elevated levels of hnRNPL, which is primarily concentrated in discrete nuclear regions, forming a punctate structure (87). The expression of hnRNPL was higher in mesenchymal tissues than in epithelial tissues. A novel target of hnRNPL, Ser/Arg-rich splicing factor 3, may be regulated by hnRNPL at both the transcriptional and post-transcriptional alternative splicing levels.

In accordance with results from a study by Mukhopadhyay et al (88), while the androgen receptor (AR) can control the production of androgen-responsive genes and the proliferation of prostate cancer cells, hnRNPK can reduce AR expression by inhibiting the translation of AR mRNA. Analysis of hnRNPK expression in 188 patients with bladder cancer (89) revealed that bladder cancer tissues had markedly higher levels of hnRNPK expression and that hnRNPK expression levels were associated with prognosis. Additionally, research has demonstrated that hnRNPK inhibits tumor growth in vivo by enhancing proliferation, inhibiting apoptosis and contributing to treatment resistance in bladder cancer cells (90). This mechanism involves hnRNPK-mediated transcriptional regulation of cyclin D1, excision repair cross-complementing group four, amongst other components that influence bladder cancer activity.

After examining modifications in hnRNPK protein functionality in patients with advanced prostate cancer, researchers have found that reducing cholesterol levels inhibited the release of hnRNPK protein and hnRNPK-containing exosomes from prostate cancer cells (91). Prostate cancer cells release exosomes to facilitate the spread of the disease to other organs. hnRNPK helps regulate the quantity of exosomes produced by prostate cancer cells, thereby preventing the spread of malignancy to other parts of the body (92). Exosomes act as regulators prior to metastasis, conditioning the microenvironment of distant tissues to facilitate tumor cell colonization. According to Iwabuchi et al (93), decreasing cellular cholesterol levels may prevent hnRNPK from exiting tumor cells and transmitting oncogenic signals.

Despite extensive mechanistic studies, the clinical translation of hnRNPK research faces several limitations. The majority of current evidence derives from retrospective analyses of tumor samples and correlative studies. For instance, while multiple studies have demonstrated associations between hnRNPK expression and prognosis across numerous cancer types (30,35), these findings have not yet been incorporated into clinical practice guidelines. The lack of standardized detection methods and validated cut-off values for hnRNPK expression limits its immediate clinical utility. Furthermore, the dual nature of hnRNPK as both oncogene and tumor suppressor in different contexts presents unique challenges for therapeutic targeting, requiring more sophisticated patient stratification processes than currently available.