Cancer still represents a considerable health challenge, despite significant improvements in diagnosis and therapy over the past decades (1). Increasing cancer rates and deaths are linked to population growth and aging, variations in risk factor prevalence and distribution, and socioeconomic advancements (2). Consequently, identifying new biomarkers and molecular indicators is essential for predicting patient outcomes and tailoring treatment strategies.

Krüppel-like factor 5 (KLF5) is a member of the KLF family, which is defined by a conserved C-terminal zinc finger domain that confers DNA-binding specificity (3–5), and whose members function as master regulators of fundamental cellular processes including proliferation (6), apoptosis (7), angiogenesis (8), and tumorigenesis (9–11).Existing research confirms that KLFs act as a regulator, playing both driving and inhibitory roles in key steps of progression and metastasis across multiple cancers (11–14).

Consistent with the functions of numerous KLFs, KLF5 exerts a context-dependent influence in oncology. Its well-characterized oncogenic activities are largely attributed to its capacity to transcriptionally activate a network of genes that fuel malignant cell growth (15) and metastatic spread (12). As a potent driver of tumor progression and metastasis, KLF5 accelerates the cell cycle (16), suppresses apoptotic signals (17), and promotes epithelial-mesenchymal transition (18) to enhance invasive potential. It regularly interacts with important oncogenic signaling pathways, including Wnt/β-catenin, to help maintain the properties of cancer stem cells (19). This pro-tumorigenic role of KLF5 is prominently observed in malignancies like lung cancer (18), colorectal cancer (19), liver cancer (16). However, KLF5 exhibits a context-dependent role in certain cancer types, notably in breast cancer (10, 15, 20–22) and prostate cancer (23–25). Studies utilizing multi-omics datasets to systematically investigate the role of KLF5 expression in pan-cancer contexts are still limited.

With the rapid development of omics detection methods such as high-throughput sequencing technology, multi-omics technologies including transcriptomics, genomics, proteomics, and metabolomics have become the core tools for analyzing the molecular profile of tumors (26, 27). Multi-omics technologies can systematically capture key information such as genetic variations, gene expression, protein regulation, and metabolic remodeling of tumor cells at different molecular levels, providing multi-dimensional data support for identifying tumor drivers and identifying potential therapeutic targets (28–30). Based on this, the emerging pan-cancer analysis has broken through the barriers of single-cancer research. By integrating multi-omics data from different cancer types, it conducts common and differential analyses across cancer types (31–33). This not only enables the discovery of shared molecular characteristics and signaling pathways among different tumor types, but also identifies unique molecular markers specific to certain cancer types. Therefore, a comprehensive profiling of KLF5 function in pan-cancer is necessary to address.

We conducted a comprehensive pan-cancer analysis of KLF5, examining its expression, prognostic impact, genomic alterations, post-translational modifications, and functional roles across multi-omics datasets. Validation through in vitro experiments confirmed that KLF5 is upregulated in glioblastoma (GBM) and bladder cancer, and that its knockdown effectively suppresses GBM and bladder cancer growth. These results indicate that KLF5 may be utilized as a diagnostic tool for cancer, a predictor of its progression, and a guide for treatment., with particular promise as a therapeutic target for glioma and bladder cancer. The main design of our study was shown in Figure 1.

Cancer poses a major global public health challenge (1). While existing research has extensively explored molecular mechanisms and pathways in individual cancer types, the emergence of multi-omics databases now enables systematic pan-cancer analyses (38–41). This approach provides a unified framework to investigate specific molecules across malignancies, allowing comprehensive characterization of their transcriptional profiles, expression patterns, post-translational modifications, and pathway activities (42, 43). The fundamental value of pan-cancer analysis lies in its capacity to distinguish universally conserved oncogenic drivers from context-dependent mechanisms, simultaneously revealing both shared therapeutic vulnerabilities and the origins of tissue-specific oncogenic heterogeneity (44).

Within this framework, a focused pan-cancer analysis of KLF5 is warranted. While previous studies have established KLF5’s context-dependent roles—functioning as a potent oncogene in carcinomas such as colorectal (19), yet exhibiting tumor-suppressive properties in specific contexts like breast cancer and prostate cancer (22, 24, 25, 45)—these fragmented findings necessitate a holistic reinterpretation. A pan-cancer analysis is critical to resolve this apparent paradox. It allows for the systematic determination of whether KLF5’s dual nature is dictated by tissue-of-origin, specific mutational backgrounds. By mapping its genomic alteration spectra, expression profiles, and associated clinical outcomes across the cancer spectrum, we can delineate a definitive functionality map for KLF5.

We observed notably high expression of KLF5 in normal tissues such as the gastrointestinal epithelium, urothelium, lung and skin. Similarly, studies of cell line databases consistently showed increased KLF5 expression in gastrointestinal, bladder, lung, and head and neck cancers. However, analysis of tumor and matched normal tissues from TCGA database demonstrated that while elevated KLF5 expression was observed in gastrointestinal tumors, its expression was conversely lower in several other cancers, including breast cancer, prostate cancer, and kidney cancer. This pattern may suggest a context-dependent role for KLF5 expression in tumorigenesis. A comprehensive cancer survival analysis demonstrated a strong correlation between KLF5 expression and patient prognosis, underscoring its role as a prognostic biomarker. Analysis of KLF5 copy number variation revealed two major patterns: heterozygous amplification, primarily in gastrointestinal, lung adenocarcinoma, and bladder cancers, and heterozygous deletion with a broader distribution across multiple cancer types. It indicates that determining whether KLF5 acts as an oncogene requiring amplification or a context-dependent tumor suppressor susceptible to loss is essential for understanding its pathobiology in a given tumor (46). In addition, we analyzed the pan-cancer profile of PTMs of KLF5 and identified significant DNA hypomethylation across multiple cancer types. However, previous studies indicates the hypermethylation of KLF5 may promote caner (47, 48). Further characterization of specific methylation sites will help elucidate the regulatory role and functional impact of KLF5 methylation in pan-cancer contexts (49, 50).

GBM, remains the most aggressive primary brain tumor with a dismal prognosis. a major bottleneck in glioma treatment lies in the lack of specific targeted therapeutic targets: existing targeted drugs rarely achieve durable efficacy due to the blood-brain barrier, tumor heterogeneity, and rapid development of drug resistance (51). Similarly, bladder cancer, particularly muscle-invasive bladder cancer, faces significant clinical challenges. Although immune checkpoint inhibitors have improved outcomes for some patients, most cases still require radical cystectomy, which severely impairs quality of life (52). Against this backdrop, identifying novel molecular targets and prognostic biomarkers for glioma and bladder cancer is critical to breaking through current treatment bottlenecks. We further selected various cell lines of GBM and bladder cancer for functional cellular assays, and the results indicated that KLF5 could serve as a potential biomarker for glioma and bladder cancer.

Currently, the research and development of KLF5 inhibitors presents diversified characteristics in terms of structural types and mechanisms of action. Among small-molecule inhibitors that directly target KLF5, ML264 and its optimized derivative SR18662 are the representative compounds that first came into research view (53, 54). In addition, Pterosin B derived from natural products can not only inhibit KLF5 expression, but also improve cognitive impairment and alleviate myocardial hypertrophy simultaneously, demonstrating multi-target therapeutic potential (55, 56). At the preclinical research and translational application level, KLF5 inhibitors have shown broad tumor type adaptability and potential for combination therapy. Despite the phased breakthroughs achieved in the research and development of KLF5 inhibitors, many challenges remain: some compounds have problems such as insufficient in vivo activity and poor targeting; the physiological functions of KLF5 in normal tissues may also lead to off-target toxicity of inhibitors; and the lineage plasticity of tumor cells may trigger acquired resistance to KLF5 inhibitors. Therefore, in-depth analysis of the tissue-specific regulatory mechanism of KLF5, development of highly selective inhibitors, and exploration of multi-target combination strategies will become the core directions to promote the transition of KLF5-targeted therapy from basic research to clinical application.

The study has particular limitations that should be noted. First, most of the enrolled datasets were derived publicly, additional in-house samples and cohorts are necessary to be replenished to validate our findings. Second, although we assessed that KLF5 was vital in GBM and bladder cancer progression, the lack of in vivo validation using animal models limits the translation of our in vitro findings to clinical settings, and in-depth mechanisms based on this phenomenon should be conducted and the interaction between KLF5 and tumor microenvironment are crucial to be explored. Third, the potential application of KLF5 inhibitors into clinical practice need to be verified, either alone or in combination with existing therapies. These efforts will further consolidate the role of KLF5 as a prognostic biomarker and therapeutic target, facilitating its translation into clinical practice.

Collectively, we provide thorough exploration of KLF5 across various cancers. systematically characterizing its expression patterns, genomic alterations, and clinical relevance across diverse human cancers. We experimentally validated its potent oncogenic functions in GBM and bladder cancer cell lines. Our work confirms that KLF5 plays distinct, context-dependent roles in different tumor types, yet its targeted inhibition emerges as a consistently viable therapeutic strategy. Importantly, these findings position KLF5 as a promising molecular biomarker with the potential to guide more precise and effective treatment decisions in clinical oncology.