Cervical cancer (CC) is the fourth most frequently diagnosed cancer among women worldwide, accounting for ~266,000 deaths and 528,000 new cases each year (1). CC contributes to 7.5% of all female cancer-related deaths, establishing itself as a notable cause of mortality among women (2). Well-structured screening programs that incorporate affordable treatment techniques, such as cryotherapy, loop electrosurgical excision and thermal ablation, can facilitate the early detection and management of precancerous lesions, thereby reducing the overall disease burden (3).

Nevertheless, in low- and middle-income countries, late-stage CC remains prevalent due to limited access to early diagnostic services and preventive care. Although chemotherapy and radiotherapy continue to serve as the standard treatments for CC, their overall effectiveness remains limited, with a number of patients exhibiting suboptimal responses (4). Notably, targeted therapy and immunotherapy have gained recognition as promising treatment strategies. The approval of PD-1 inhibitors for the management of recurrent or metastatic CC has enhanced host immune responses against human papillomavirus (HPV)-positive malignancies (5). However, despite their potential, several challenges persist, including the immunosuppressive tumor microenvironment, tumor immune evasion, low patient response rates and acquired drug resistance, all of which compromise treatment (6). In the future, treatment paradigms are expected to emphasize personalized medicine by refining targeted therapies to improve cure rates and extend patient survival.

Eukaryotic chromatin is primarily composed of histones and nucleosomes, with nucleosomes consisting of DNA wrapped around histone proteins. The tail regions of histones frequently undergo a range of post-translational modifications (7), collectively referred to as histone modifications. These modifications influence gene transcription through multiple pathways (8) and are essential for several key biological processes. Common histone modifications include acetylation, methylation and ubiquitination, with acetylation and methylation recognized as the predominant types (9). Recently, additional modifications, such as glycosylation, lactylation and palmitoylation, have been identified, further increasing the complexity of histone regulation (10–13). These modifications are vital for regulating gene expression, repairing DNA damage, and controlling the cell cycle, differentiation, apoptosis and tumor progression (14,15).

Histone modifications may act cooperatively or antagonistically, contributing to the formation of a ‘histone code’ that fine-tunes cellular functions (16,17). Disruptions in histone modification patterns are closely associated with various diseases, including cancer, neurodegenerative disorders and immune dysfunction, in which these alterations in gene expression contribute to disease progression (18,19). As a result, epigenetic therapies targeting histone modifications have emerged as a critical area of research in precision medicine.

In CC, histone modifications, an essential component of epigenetic regulation, affect key processes such as persistent HPV infection, dysregulation of the cell cycle, immune evasion and treatment resistance. These pathological features arise from chromatin remodeling and aberrant gene expression (20). Epigenetic therapies aimed at correcting abnormal histone modifications, including histone deacetylase (HDAC) inhibitors, are increasingly being recognized as potential treatments for CC (20). Therefore, a comprehensive analysis of the role of histone modifications in CC and their clinical implications may offer valuable insights into precision treatment strategies.

CC ranks as the fourth most frequently diagnosed cancer among women worldwide, with ~660,000 new cases reported in 2022 (21). The World Health Organization estimates that CC affects 662,000 individuals globally, including 151,000 women in China (22). Despite a substantial reduction in incidence over the past three decades, CC remains a major global public health concern, with considerable regional disparities in both incidence and mortality rates (23,24). In high-income countries, incidence and mortality rates are notably lower than those in developing regions, largely due to widespread HPV vaccination, comprehensive screening programs and greater access to healthcare resources (25–27). Nevertheless, in the later stages of CC, mortality rates in developed nations can be elevated or comparable to those in developing countries, primarily due to the limited availability of effective treatments for advanced disease (28).

CC can be classified into two primary histological types: Cervical squamous cell carcinoma (CSCC), which arises from squamous cells; and cervical adenocarcinoma, which originates from glandular epithelial cells (29). CSCC accounts for >80% of CC cases worldwide and is associated with high incidence and mortality rates (25). This cancer progresses through a series of well-defined precancerous stages, culminating in cellular dysplasia, cervical intraepithelial neoplasia, and ultimately, squamous cell carcinoma (30).

HPV, a member of the Papillomaviridae family, is strongly associated with the development of CC. HPV types associated with CSCC are classified into two groups: Low-risk and high-risk types. Low-risk strains primarily cause genital warts, whereas high-risk strains are implicated in invasive cancer (31). High-risk HPV types 16 and 18 are responsible for ~90% of CC cases. Women infected with high-risk HPV types face a greater likelihood of developing invasive cancer compared with those infected with low-risk types (32).

All HPV types, regardless of risk classification, infect epithelial cells, particularly keratinocytes, leading to cellular immortalization (30). The HPV genome consists of three primary functional regions: The early (E) region, which encodes proteins E1-E7 that are necessary for viral replication; the late (L) region, which produces structural proteins L1 and L2 that are essential for virion assembly; and the long control region, a non-coding segment that contains cis-regulatory elements critical for DNA replication and transcription (33). E1 and E2 are essential for viral DNA replication and act as transcriptional regulators. The viral genome also encodes early genes, such as E5, E6 and E7, which contribute to oncogenic transformation. E5 enhances immune evasion, reduces dependence on growth factors and promotes cellular proliferation (34). E6 interacts with the tumor suppressor protein p53, leading to its degradation (35). E7 binds to retinoblastoma protein, mediating its degradation via the ubiquitin-proteasome system and promoting cell cycle progression (36).

During the later phases of infection, viral late genes become active within the suprabasal layers, initiating circular genome replication and the synthesis of structural proteins. As the virus ascends to the outer layers of the skin or mucosal surfaces, mature viral particles are assembled and subsequently released. Additionally, HPV alters gene expression and activates several signaling pathways, such as those mediated by growth factor receptors, Notch, RAS and PI3K/Akt/mTOR, all of which promote host cell survival and proliferation. These molecular alterations collectively contribute to cervical carcinogenesis (37–39) (Fig. 1).

Given the pivotal role of HPV in the pathogenesis of CC, prevention strategies targeting the virus have proven highly effective. Specifically, vaccination against high-risk HPV types has led to a notable reduction in CC incidence, particularly in developed countries (40). In addition, surgery, radiotherapy and chemotherapy are the standard treatments for locally advanced cervical cancer and have notably reduced the mortality rate of patients with CC; however, their effectiveness in treating more advanced or recurrent disease remains limited (41–43).

Advancements in immunotherapy and targeted therapy have demonstrated considerable promise in cancer treatment. Inhibitors of PD-1/PD-L1, such as nivolumab and pembrolizumab, function by disrupting immune checkpoint pathways, thereby enhancing the ability of the immune system to detect and eliminate cancer cells (44). Additionally, the use of CTLA-4 inhibitors, such as ipilimumab, has been explored as an immune checkpoint-based therapy for CC (45). Emerging evidence has indicated that these therapies exhibit substantial efficacy, particularly when combined with chemotherapy or radiotherapy, in patients with advanced or recurrent disease (46,47).

Although these therapies hold considerable promise, several challenges persist. Immunotherapy can induce immune-related adverse events, such as autoimmune disorders and severe inflammation, and its efficacy is often reduced in tumors exhibiting strong immune tolerance (48–50). Similarly, although targeted therapies are designed to act on specific molecular targets, their effectiveness is limited by tumor heterogeneity and the development of drug resistance, thereby reducing their long-term efficacy (48–50). Moreover, the success of both therapeutic approaches is influenced by individual patient factors and the complexity of the tumor microenvironment (48–50). As a result, future therapeutic strategies should emphasize personalized medicine and the continued development of targeted therapies, with the aim of improving cure rates and extending patient survival.

Histone modifications serve a critical role in regulating biological processes by altering chromatin structure, thereby influencing the expression of specific genes. Although most research has focused on well-characterized modifications, such as acetylation, methylation and phosphorylation, histones also undergo a variety of other modifications (51). These include citrullination, ubiquitination, ADP-ribosylation and O-GlcNAcylation, as well as less-studied modifications such as propionylation, butyrylation, crotonylation, lactylation and palmitoylation (51). These diverse modifications affect chromatin structure and gene expression, contributing to critical processes such as the cell cycle, DNA repair, differentiation and immune regulation. They also serve a role in the pathogenesis of diseases, including cancer (including CC), neurodegenerative disorders (such as Alzheimer's disease) and metabolic conditions (including diabetes mellitus) (52–54).

The regulation of histone modifications is mediated by ‘writers’ and ‘erasers’, enzymes that add or remove modifications, thereby ensuring appropriate gene expression (55). For example, histone acetyltransferases (HATs) introduce acetyl groups, leading to chromatin relaxation and enhanced transcription, whereas HDACs remove acetyl groups, resulting in chromatin condensation and transcriptional repression (56). Similarly, histone methylation is catalyzed by histone methyltransferases (HMTs), whereas histone demethylases are responsible for removing methyl groups. The coordinated activity of these enzymes modulates chromatin architecture and is essential for the regulation of gene expression (57). Notably, certain ‘writers’ and ‘erasers’ are capable of regulating multiple types of histone modifications. For example, G9a, a HMT, primarily catalyzes the methylation of lysine 9 on histone H3 (H3K9), but also modulates histone acetylation, thereby influencing gene silencing and chromatin structure (58). Likewise, p300/CBP, a HAT, facilitates histone acetylation and transcriptional activation (59), and has also been shown to catalyze histone lactylation, a modification particularly relevant under conditions of altered cellular metabolism, such as hypoxia or inflammation (60). Similarly, HDACs primarily remove acetyl groups, leading to chromatin condensation and transcriptional repression; however, certain HDAC family members, such as sirtuin (SIRT)1, serve pivotal roles not only in histone deacetylation but also in regulating non-histone proteins, such as p53, thereby modulating apoptosis and DNA repair (61,62). In addition, lysine-specific demethylase (KDM)1, an ‘eraser’, can remove methyl groups from lysine 4 on histone H3 (H3K4) to suppress gene expression and from H3K9 to promote gene activation (54,63). The cross-regulation by these multifunctional enzymes indicates that histone modification is not a linear process but rather a highly dynamic and interactive network that enables precise control of gene expression, allowing cells to adapt to environmental changes and maintain gene expression homeostasis. A comprehensive summary of the major histone modifications, including ‘writer’ and ‘eraser’ proteins, their family classifications, target sites and functional roles, is presented in Table I.

Histone modifications are fundamental to the initiation and progression of cancer, primarily through their effects on chromatin structure and gene expression. Consequently, these modifications influence the transcription of genes involved in tumorigenesis. Aberrant histone modifications, including acetylation, methylation, phosphorylation and ubiquitination, can lead to the silencing of tumor suppressor genes or the activation of oncogenes, thereby facilitating tumor progression. For example, trimethylation of lysine 27 on histone H3 (H3K27me3), a repressive histone mark mediated by EZH2, is frequently observed in breast cancer and hepatocellular carcinoma (HCC), leading to the silencing of key tumor suppressor genes (64,65). For example, EZH2 promotes the stemness of HCC by inducing the transcriptional repression of the tumor suppressor gene TOP2A through H3K27me3-mediated silencing (65). Similarly, elevated levels of histone H3 lysine 9 acetylation (H3K9ac) and H3 lysine 27 acetylation have been associated with oncogene activation, contributing to the progression of colorectal and lung cancer (66). Moreover, histone modifications influence DNA damage repair pathways; for example, phosphorylation of H2AX is activated in response to DNA damage, and affect the tumor microenvironment, such as HDAC-driven immune suppression (67). They are also associated with resistance mechanisms; for example, KDM5A-mediated demethylation enhances chemotherapy resistance (68). As a result, epigenetic therapies targeting histone modifications, including inhibitors of HDACs and HMTs/KDMs, hold notable promise for precision cancer treatment, particularly when used in combination with immunotherapy and molecular targeted therapies.

Histone modifications serve a critical role in regulating the initiation, progression and therapeutic response of CC. Modifications such as acetylation, methylation, phosphorylation and ubiquitination are central to modulating gene expression, altering chromatin architecture and influencing cellular signaling networks, all of which contribute to cancer development. Aberrant histone modifications can lead to the suppression of tumor suppressor genes or the activation of oncogenes, thereby promoting cellular processes, such as proliferation, invasion and immune evasion. Furthermore, histone modifications are closely associated with the development of resistance to therapies, including chemotherapy, radiotherapy and targeted treatments. This section examines the role of histone modifications in the pathophysiology of CC.

Numerous preclinical studies have explored the potential of targeting histone-modifying enzymes as a therapeutic approach for CC. Histone modifications, such as acetylation and methylation, serve essential roles in regulating cancer cell proliferation, metastasis and resistance to therapy. For example, small-molecule inhibitors (such as p-coumaric acid, ferulic acid, sinapinic acid and resveratrol) that target HDACs or HMTs have demonstrated efficacy in reducing the proliferation and migration of CC cells, thereby inhibiting tumor progression (109–112).

In addition, some clinical studies have begun investigating the utility of histone modifications as prognostic biomarkers (97,103). By examining specific histone modification patterns in CC tissues, clinicians can obtain early insights into disease progression, recurrence risk and treatment response. Changes in histone modifications may be associated with tumor invasiveness, metastatic potential and resistance to standard therapies, offering valuable guidance for personalized treatment planning.

Although the clinical application of histone modification-targeted therapies in CC is still in its infancy, such agents, especially in the context of hematologic malignancies, have already advanced to large-scale clinical trials and have demonstrated encouraging results (Table II). Ongoing research suggests that these strategies may evolve into effective therapeutic options for CC. In the future, precise modulation of histone modification pathways could lead to advancements in early detection, prognostic evaluation and the development of individualized treatment strategies.

Histone modifications serve a crucial role in regulating the proliferation, migration, invasion and drug resistance of CC cells by altering chromatin structure and modulating gene expression. Although research into therapies targeting histone modifications in CC is still in its early stages, preclinical studies have suggested that enzymes such as HDACs and HMTs may effectively inhibit tumor growth and metastasis.

Moreover, histone modifications hold promise as biomarkers for early diagnosis, prognostic assessment and monitoring therapeutic responses. Distinct histone modification patterns may help predict tumor invasiveness and response to treatment. While drugs targeting histone modifications have not yet undergone widespread clinical testing in CC, emerging research indicates that these therapies may represent a novel option for personalized treatment strategies.

However, in low- and middle-income countries, the high cost and limited accessibility of histone modification-targeting therapies present substantial barriers to their use. Challenges such as inadequate healthcare infrastructure, unstable drug supply chains and restricted insurance coverage prevent a number of patients from receiving timely and effective treatments (113–115). Therefore, reducing drug costs, enhancing access to therapies and strengthening public health policy support are critical steps toward expanding the availability of these promising treatments, particularly for CC, which has a disproportionately high incidence in resource-limited settings.

In conclusion, histone modifications are integral to the pathogenesis of CC and offer substantial clinical potential. Future research should focus on elucidating the molecular mechanisms underlying these modifications and advancing clinically applicable therapies for early detection, individualized treatment and prognostic prediction.