Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are pivotal components of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a critical role in mediating cellular responses to growth factors and other stimuli (Yao et al., 2003[140]; Zhang et al., 2012[148]). ERKl and ERK2 are serine/threonine kinases with a high degree of similarity. ERK2, being the more studied isoform due to its predominant expression invarious tissues. Both ERKl and ERK2 contain a conserved kinase domain, which is crucial for their enzymatic activity, along with a regulatory domain that controls their activation state (Marampon et al., 2019[85]). The activation of ERK1/2 occurs through a dual phosphorylation mechanism on threonine and tyrosine residues within a specific TEY motif, which is crucial for its kinase activity(Arkell et al., 2008[6]). This phosphorylation is carried out by upstream kinases, MEKl and MEK2, which are activated by the RAS/RAF signaling cascade (Roskoski, 2012[110], 2018[112]).The structure of ERK1/2 enables it to interact with various substrates, including transcription factors, cytoskeletal proteins, and other signaling molecules. This interaction influences numerous cellular processes, such as proliferation, differentiation, and apoptosis. Understanding the structure of ERK1/2 is crucial for developing targeted therapies that aim to modulate its activity in cancers where this pathway is abnormally activated (Hossain, 2024[52]) (Figure 1(Fig. 1)).

Ras proteins, such as KRAS, NRAS, and HRAS, are small GTPases that function as molecular switches in the MAPK signaling pathway. They play a crucial role in transmitting signals from different growth factor receptors to downstream effectors. These include RAF kinases, which then activate the MEK/ERK cascade. Ras is activated when growth factors bind to receptor tyrosine kinases (RTKs), causing the exchange of GDP for GTP and converting it to its active form (Markevich et al., 2004[86]).The active Ras-GTP complex interacts with and activates RAF kinases, specifically A-Raf, B-Raf,and C-Raf, which are responsible for phosphorylating MEK1and MEK2 (Roskoski, 2018[112]). Dysregulation of Ras signaling often due to mutations in KRAS, is implicated in several cancers, including pancreatic, colorectal, and lung cancer (Luo, 2021[80]; Mann et al., 2016[84]). These mutations lead to constitutive activation of Ras, resulting in persistent activation of the MAPK pathway, promoting uncontrolled cell proliferation and survival. Understanding the upstream action of Ras is essential for developing targeted therapies that inhibit its activity or downstream signaling components in Ras-driven malignancies (Therachiyil et al., 2022[130]) (Figure 2(Fig. 2)).

Raf kinases, especially B-Raf, play a crucial role in the MAPK signaling pathway, functioning downstream of Ras proteins (Hatzivassiliou et al., 2010[48]). Raf phosphorylation is essential for its activation and signaling. When activated by Ras-GTP, Raf changes shape and moves to the plasma membrane, where it interacts with proteins associated with the membrane. This interaction promotes Raf's phosphorylation at specific serine and threonine residues, which is vital for its complete activation. The phosphorylation of B-Raf at serine 445 and threonine 573, among others, enhances its kinase activity and promotes the phosphorylation of MEK1 and MEK2. This dual phosphorylation of MEK is necessary for its activation, which then leads to the phosphorylation of ERK1/2 (Dwivedi et al., 2009[29]; Roskoski, 2019[111]). In cancers where B-Raf is mutated, such as the BRAF V600E mutation, the kinase is constitutively active, resulting in continuous signaling through the MAPK pathway, contributing to tumorigenesis (Bharti et al., 2025[8]; Brady et al., 2014[11]). Thus, focusing on the phosphorylation of Raf kinases offers a promising treatment approach to block abnormal MAPK signaling in cancer (Dillon et al., 2021[24]).

Once activated, ERK1/2 translocate to the nucleus, where they phosphorylate a variety of substrates, including transcription factors such as c-Fos, c-Jun, and Elk-1. This phosphorylation regulates gene expression, which is essential for cell cycle progression, differentiation, and survival. ERK1/2 also influence cytoplasmic processes, including the modulation of cytoskeletal dynamics and the enhancement of cell migration and invasion (Acconcia et al., 2006[2]). The effects of ERK1/2 signaling depend on the context and can vary according to the cellular environment and the specific stimuli. In cancer, aberrant activation of the ERK1/2 pathway often results in enhanced cell proliferation and resistance to apoptosis (Zhang et al., 2020[149]; Zhou et al., 2011[152]), contributing to tumor growth and metastasis. Additionally, feedback mechanisms allow ERK1/2 to phosphorylate upstream components like Raf and Ras. This creates a complex regulatory network that can result in both positive and negative feedback loops. This intricate signaling network underscores the importance of ERK1/2 in maintaining cellular homeostasis and its potential as a therapeutic target in cancer treatment (Liu et al., 2023[75]) (Figure 2(Fig. 2)).

The Ras/Raf/MAPK pathway is a key signaling cascade that controls various cellular processes, such as growth, differentiation, and survival (Leicht et al., 2007[64]; Guo et al., 2020[42]). The core mechanism consists of the step-by-step activation of Ras, Raf, MEK, and ERK. When stimulated by growth factors, Ras is activated and binds to Raf. This binding causes Raf to become phosphorylated and activated. Activated Raf then phosphorylates MEK, which in turn activates ERK through dual phosphorylation (Muslin, 2005[95]; Dwivedi et al., 2009[29]). This cascade is carefully controlled by feedback mechanisms and scaffolding proteins, which ensure both specificity and timing in signaling. When this pathway is dysregulated, often due to mutations in Ras or Raf, it can result in oncogenic transformation and is associated with various cancers.. The pathway's role in mediating responses to external stimuli and its involvement in cell fate decisions make it a critical target for therapeutic interventions. Inhibitors targeting different components of this pathway are being developed and tested in clinical settings, highlighting the pathway's significance in cancer therapy (Chen et al., 2024[17]) (Figure 3(Fig. 3)).

ERK1/2 activation mainly occurs through the phosphorylation by MEK1 and MEK2, which are activated by Raf kinases (Su et al., 2010[126]). When growth factor receptors send signals, Ras activates Raf, which then phosphorylates MEK and subsequently ERK (McCubrey et al., 2007[93]; Sebolt-Leopold, 2004[116]). This activation is tightly controlled by negative feedback mechanisms that prevent excessive signaling. For example, activated ERK can phosphorylate and inhibit upstream components like Raf and MEK. This creates a feedback loop that limits both the duration and intensity of the signal. Various phosphatases, including dual specificity phosphatases (DUSPs) (Arnoldussen and Saatcioglu, 2009[7]; Li et al., 2021[67]), can dephosphorylate ERK, reverting it to an inactive state. This negative feedback regulation is crucial for maintaining cellular homeostasis and preventing uncontrolled cell proliferation. In cancers where these feedback mechanisms are disrupted (Haney et al., 2016[47]; Hsu et al., 2016[54]), such as through mutations in Ras or Raf, the result is often persistent ERK activation, contributing to tumorigenesis and resistance to therapies. Understanding these regulatory mechanisms is essential for developing effective strategies to target the MAPK pathway in cancer treatment (Hong et al., 2023[51]).

The ERK1/2 pathway is primarily activated by growth factors and cytokines that attach to receptor tyrosine kinases (RTKs).This triggers a series of phosphorylation events that activate ERK1/2. This activation is essential for converting external signals into responses that encourage cell growth. For example, in cancers like breast and colorectal cancer, irregularities in the ERK1/2 signaling pathway are associated with increased cell growth and survival. Research indicates that mutations in upstream components of the pathway, such as KRAS and BRAF, cause the continuous activation of ERK1/2, leading to unchecked cell proliferation (Dillon et al., 2021[24]).

Additionally, the interaction between ERK1/2 and other signaling pathways, including the PI3K/AKT pathway, amplifies proliferative signals. For example, the activation of ERK1/2can promote the expression of cyclins and other cell cycle regulators, facilitating the transition from the Gl phase to the S phase of the cell cycle. This mechanism is particularly evident in hepatocellular carcinoma (HCC), where the synergistic interaction between ERK1/2 and Pl3K signaling enhances cell proliferation and survival in response to growth factors (Kim et al., 2019[62]). Furthermore, the activation of ERK1/2is linked to the upregulation of genes involved in metabolic pathways that facilitate rapid cell division. This underscores the significance of this signaling cascade in tumor biology.

The ERK1/2 pathway plays a crucial role in the cell cycle, especially during the change from the G1 phase to the S phase. When ERKl/2 is activated, it phosphorylates several downstream targets, including transcription factors that control the expression of cyclins and cyclin-dependent kinases (CDKs). For instance, the activation of ERK1/2promotes the expression of cyclin Dl, which is critical for the progression of the cell cycle (Huang et al., 2023[55]). In breast cancer, dysregulated ERK1/2 signaling is associated with changes in cell cycle dynamics, which contribute to the aggressive behavior of tumors.

Additionally, ERK1/2 plays a role in both cell cycle regulation and the response to DNA damage. Research shows that ERK1/2 can alter the activity of checkpoint proteins that manage the cell cycle when faced with genotoxic stress. For instance, inhibiting ERK1/2 signaling increases cancer cells' sensitivity to DNA-damaging agents. This indicates that targeting this pathway may enhance the effectiveness of current chemotherapy treatments (Huang et al., 2023[55]). The potential of ERK1/2 as a therapeutic target in cancer treatment is underscored by its dual role in promoting cell cycle progression and participating in DNA damage response mechanisms.

The regulation of ERK1/2 signaling is influenced by autocrine and paracrine mechanisms that enable communication between tumor cells and their microenvironment. By secreting growth factors and cytokines, tumor cells activate ERK1/2 signaling not only in themselves but also in neighboring cells. For example, in breast cancer, tumor cells produce factors like IL-6 and CXCL1 that activate ERK1/2 signaling pathways, promoting tumor proliferation and survival (Khojasteh et al., 2021[60]).

Moreover, the interaction between tumor cells and stromal cells, including cancer-associated fibroblasts (CAFs), plays a crucial role in modulating ERK1/2 activity. CAFs secrete various factors that enhance the proliferative signals tumor cells receive. This process promotes tumor growth.. For example, studies have shown that CAF-derived factors can activate ERK1/2 signaling in neighboring tumor cells, leading to increased proliferation and migration (Song et al., 2024[123]). This paracrine signaling not only supports tumor growth but also helps create a tumor-promoting microenvironment.

In conclusion, the ERK1/2 signaling pathway is a key regulator of tumor proliferation. It influences various aspects of cell cycle progression and is modulated by both autocrine and paracrine mechanisms. Understanding these regulatory networks is crucial for developing targeted therapies. These therapies aim to effectively disrupt the dysregulated signaling pathways present in cancer cells. More research is needed to understand the intricate connections between ERK1/2 signaling and other pathways, and to explore how the tumor microenvironment affects these connections.

The ERKl/2 pathway is crucial for tissue remodeling and cell migration, both of which are essential for tumor invasion and metastasis. ERKl/2 is a key part of the MAPK signaling pathway. This pathway is activated by different growth factors and cytokines. Upon activation, ERK1/2 translocates to the nucleus where it regulates the expression of genes involved in cell proliferation, survival, and migration (Qin et al., 2023[107]). Remodeling of the extracellular matrix (ECM) is essential for tumor cells to migrate and invade surrounding tissues. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are crucial in this context as they degrade ECM components, facilitating the movement of cancer cells (Huang et al., 2023[55]). In tumors, MMP expression is often increased, while their activity is tightly controlled by tissue inhibitors of metalloproteinases (TIMPs).The balance between MMPs and TIMPs is critical; an increase in MMP activity relative to TIMP levels leads to enhanced tissue remodeling, which promotes tumor invasion (Yu et al., 2024[143]). Additionally,ERK1/2 signaling regulates MMP expression, linking this pathway's activation to the tumor's invasive potential (Dudka et al., 2022[28]) (Figure 4(Fig. 4)).

Besides regulating matrix metalloproteinases (MMPs), ERK1/2 signaling also affects cytoskeletal dynamics, which are crucial for cell motility. During cell migration, the actin cytoskeleton is significantly remodeled. ERK1/2 activation is linked to changes in actin filament organization, allowing cancer cells to become more migratory (Zhan et al., 2023[147]). The interaction between ERK1/2 and other signaling pathways, such as the Rho family of GTPases, further highlights its role in regulating the migratory capabilities of tumor cells (Huang et al., 2023[55]). The ERK1/2 pathway orchestrates a complex network of signals that facilitate tissue remodeling and cell migration, contributing to the invasive characteristics of tumors.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play a crucial role in the degradation of the extracellular matrix (ECM), a process essential for tumor invasion and metastasis. The elevated levels of various MMPs, particularly MMP-2 and MMP-9, in malignant tumors often indicate a poor prognosis (Huang et al., 2023[55]). The regulation of MMP expression is complex and involves several signaling pathways, one of which is the ERKl/2 pathway. Activation of the ERKl/2 pathway increases MMP expression, which enhances the invasive potential of cancer cells (Huang et al., 2023[55]).

In cancer, MMPs break down ECM components, enabling tumor cells to migrate through the stroma and invade surrounding tissues. For instance, MMP-9 is linked to the invasion of breast and colorectal cancers, with its expression correlating to tumor progression and metastasis (Huang et al., 2023[55]). The activity of MMPs is tightly regulated by their tissue inhibitors (TIMPs), and an imbalance between MMPs and TIMPs can lead to increased tumor aggressiveness. Studies have shown that overexpressed MMPs, especially in the presence of inflammatory cytokines, can create a pro-tumorigenic microenvironment. This environment further promotes invasion and metastasis (Huang et al., 2023[55]).

Additionally, MMP expression is affected by factors such as hypoxia, which is prevalent in solid tumors. Hypoxia can trigger MMP expression through the HIF-1α pathway, which increases tumor invasiveness (Huang et al., 2023[55]). This emphasizes the complex role of MMPs in cancer biology, as they not only aid in ECM remodeling but also help create a supportive microenvironment for tumor progression.

The interaction of various signaling pathways is crucial in cancer biology, especially regarding tumor invasion and metastasis. The ERKl/2 pathway interacts with other pathways, including Pl3K/Akt and Wnt, rather than functioning alone. This interaction modifies how cells respond to external stimuli (Huang et al., 2023[55]).This cross-talk significantly influences tumor cell invasion by integrating signals from multiple sources.

The PI3K/Akt pathway promotes cell survival and growth. Its activation enhances ERK1/2signaling effects on MMP expression and activity. This interaction can result in a more aggressive tumor phenotype, marked by increased migration and invasion. Furthermore, the Wnt signaling pathway, which regulates cell fate and proliferation, also interacts with ERK1/2 signaling, complicating the regulatory networks that influence tumor behavior (Huang et al., 2023[55]).

Additionally, the interaction between these pathways can contribute to therapeutic resistance. For example, tumors with abnormal activation of both the ERK and Pl3K/Akt pathways may not respond well to therapies that target only one of these pathways (Huang et al., 2023[55]). It is vital to understand these interactions to create effective therapies, as targeting multiple pathways might be needed to overcome resistance and improve clinical outcomes in cancer treatment.

In summary, the ERKl/2 pathway is crucial for tumor invasion. It influences tissue remodeling, regulates MMP expression, and interacts with other signaling pathways. The complexity of these interactions highlights the necessity for a thorough understanding of the molecular mechanisms behind cancer progression. This knowledge could lead to the creation of innovative therapeutic approaches.

VEGF plays a crucial role in angiogenesis, and its expression is regulated by several signaling pathways, including the ERK1/2 pathway (Liu et al., 2016[71]; Ding et al., 2022[25]). Activation of ERKl/2 by upstream signals like growth factors increases VEGF expression, which promotes the proliferation and migration of endothelial cells. Research indicates that phosphorylating ERK1/2 boosts VEGF expression indifferent cell types, such as endothelial and tumor cells (Shu et al., 2002[118]; Yamada et al., 2015[139]). For example, in hypoxic conditions, which are common in tumors, the ERKl/2 pathway mediates the upregulation of VEGF. This pathway is activated by hypoxia-inducible factor (HlF) (Sutton et al., 2007[128]; Li et al., 2008[68]). This mechanism underscores the role of ERK1/2 in how hypoxic stress affects angiogenesis, helping tumors adapt to low oxygen by promoting new blood vessel formation.

The relationship between VEGF and ERKl/2 is reciprocal: VEGF activates the ERK1/2 pathway, and in turn, ERK1/2 enhances VEGF signaling through several feedback mechanisms. For instance, studies show that when ERKl/2 is activated, it increases the expression of VEGF receptors, which boosts the angiogenic response (Andrikopoulos et al., 2017[5]; Aiken and Birot, 2016[3]). This feedback loop is essential for balancing angiogenesis and vascular stability, particularly in tumor microenvironments where abnormal angiogenesis frequently happens (Gianni-Barrera et al., 2020[38]; Luo et al., 2023[79]).

The mechanisms of angiogenesis are complex and involve many signaling pathways and cellular interactions. The extracellular signal-regulated kinase 1/2 pathway plays a central role in these processes. It integrates signals from various growth factors and cytokines to regulate the behavior of endothelial cells. When activated, this pathway promotes key processes important for angiogenesis, such as endothelial cell proliferation, migration, and tube formation.

A crucial aspect of angiogenesis is the remodeling of the extracellular matrix (ECM), essential for forming new blood vessels (Sottile, 2004[125]; Bogaczewicz et al., 2006[9]). The ERKl/2 signaling pathway regulates the expression of matrix metalloproteinases (MMPs) that degrade ECM components, allowing endothelial cells to migrate and form new capillary structures. This pathway also regulates cell adhesion molecules, which are crucial for maintaining the stability of endothelial cell junctions during angiogenesis.

Additionally, ERK1/2 plays a role in angiogenesis that extends beyond endothelial cells. It also affects pericytes and smooth muscle cells, which are crucial for stabilizing newly formed blood vessels (Halaidych et al., 2019[45]; Abraham et al., 2008[1]). ERK1/2 regulates the interaction between endothelial cells and these supporting cells, ensuring that the newly formed vessels are functional and stable.

In cancer and other diseases, improper regulation of the ERKl/2 pathway can result in excessive blood vessel formation, which promotes tumor growth and spread. Consequently, researchers are exploring strategies to target this pathway to inhibit angiogenesis in tumors (Qin et al., 2023[108]). Various inhibitors of the MAPK pathway are being tested in clinical trials to reduce tumor blood vessel formation and improve patient outcomes (Podar et al., 2004[103]).

The potential of targeting the ERK1/2pathway for anti-angiogenic therapy is highly promising, particularly due to the crucial role of angiogenesis in tumor progression. Anti-angiogenic strategies today mainly concentrate on blocking VEGF signaling using monoclonal antibodies and small-molecule tyrosine kinase inhibitors (Sia et al., 2014[119]). However, these therapies often face challenges such as drug resistance and limited efficacy.

Combining anti-angiogenic agents with therapies that target the ERK1/2 pathway may improve treatment outcomes. This approach could overcome resistance mechanisms and help normalize tumor blood vessels. For example, studies show that using ERK inhibitors together with VEGF-targeted therapies can more effectively suppress tumor growth and metastasis (Lang et al., 2008[63]; Dai et al., 2009[22]). This combination approach aims to inhibit the formation of new blood vessels and enhance the delivery and effectiveness of concurrent chemotherapy.

Furthermore, discovering biomarkers related to the ERKl/2 pathway activation can assist inidentifying patients who are likely to benefit from anti-angiogenic therapies. Personalized treatment strategies that take into account the tumors' molecular profiles can improve clinical outcomes and reduce toxicity.

In conclusion, understanding the complex relationship between ERK1/2 signaling and angiogenesis is essential for tumor biology and opens avenues for further exploration. Ongoing research into the molecular mechanisms of this relationship will lead to new therapeutic strategies that effectively target angiogenesis in cancer and other diseases with abnormal vascular growth. As our understanding of these pathways deepens, the opportunities for developing more effective anti-angiogenic therapies will continue to grow.

DNA methylation, a crucial epigenetic modification, involves the addition of methyl groups to specific positions on DNA molecules, typically occurring at the 5th carbon position of cytosine (C) residues. The DNA methyltransferase (DNMTs) family plays a central role in this process, primarily including DNMT1, DNMT3A, and DNMT3B. DNMT1 is primarily responsible for maintaining existing DNA methylation patterns, while DNMT3A and DNMT3B are involved in establishing new methylation patterns. Studies have shown that the expression and activity of these enzymes significantly influence the development and progression of various cancers, particularly playing a critical role in the silencing of tumor suppressor genes (Sinclair, 2021[120]). Studies have revealed that the hypermethylation of tumor suppressor genes such as APC, TP53, and SMAD4 in colorectal cancer is closely associated with enhanced tumor aggressiveness and metastatic potential (Nishiki et al., 2025[97]).The ERK pathway induces hypermethylation of tumor suppressor genes (such as tumor suppressor genes and differentiation-related genes) by regulating the activity of DNA methyltransferases (DNMTs). In thyroid cancer, the synergistic interaction between the ERK and PI3K/Akt pathways leads to the epigenetic silencing of genes like PTEN, promoting tumor cell survival and invasion (Gómez Sáez, 2011[41]; Brzezianska and Pastuszak-Lewandoska, 2011[14]). In B-cell lymphoma, DNA hypermethylation in the promoter region of Spry2 (a negative regulator of ERK signaling) results in its transcriptional silencing, thereby relieving inhibition of the MAPK-ERK pathway and enhancing cell proliferation and survival (Frank et al., 2009[32]). This mechanism has been confirmed in both mouse models and human lymphoma, and demethylating drugs (e.g., 5-aza-2'-deoxycytidine) can restore Spry2 expression and suppress ERK activity (Frank et al., 2009[32]). Studies have demonstrated that promoter hypermethylation of RASSF1A is significantly elevated in multiple tumor types, leading to its transcriptional downregulation. This epigenetic silencing further activates the ERK signaling pathway, thereby promoting tumor cell proliferation and metastasis (Mai et al., 2023[83]; Xiong et al., 2025[137]).

Histone post-translational modifications represent a pivotal component of epigenetics, regulating gene expression by modulating chromatin structure and transcriptional activity. These modifications include phosphorylation, acetylation, methylation, and ubiquitination. Notably, the acetylation and methylation states of histones are widely recognized as critical regulators of the ERK signaling pathway. During TGF-β-induced epithelial-mesenchymal transition (EMT), rapid ERK activation within 5 minutes is associated with a marked upregulation of histone H3K27 trimethylation (H3K27me3). The methyltransferase Ezh2, responsible for H3K27me3 deposition, synergizes with ERK signaling to promote chromatin condensation and transcriptional activation of EMT-associated genes such as Snail and Twist, thereby enhancing tumor metastatic potential (Lu et al., 2019[76]).

The ERK signaling pathway dynamically influences gene expression through diverse histone modifications, playing a central role in tumorigenesis. Key mechanisms include: Activating MSK1/2 kinases to induce phosphorylation of histone H3 at serine 10/28 (H3S10ph/S28ph), which facilitates chromatin relaxation and proto-oncogene transcription (McCoy et al., 2020[92]; Zhang et al., 2019[150]; Park et al., 2021[101]); Enhancing p300/CBP-mediated acetylation of histone H3 at lysine 9/27 (H3K9ac/K27ac) to drive pro-tumorigenic gene expression (Fang et al., 2022[30]; Li et al., 2018[70]; Gupta et al., 2020[43]); Phosphorylating SMYD3 to elevate H3K4 trimethylation (H3K4me3), counteracting DNA methylation-mediated silencing of tumor suppressor genes (Hamamoto et al., 2021[46]; Wang et al., 2019[134]); Suppressing EZH2 activity to reduce H3K27me3 levels, thereby alleviating repression of differentiation-associated genes (Kim et al., 2020[61]; Suva et al., 2021[129]); Upregulating RNF20/40 via ELK1 to promote H2B ubiquitination at lysine 120 (H2BK120ub), sustaining DNA repair capacity (Nakamura et al..2022[96]; Chen et al., 2023[16]). These modifications cooperatively regulate cell proliferation, invasion, and chemoresistance through a "histone code" mechanism. Targeting the ERK-epigenetic crosstalk-via strategies such as combined MSK and HDAC inhibitors-has emerged as a promising therapeutic approach in oncology (Zhang et al., 2019[150]; Wang et al., 2019[134]).

The interplay between ERK signaling and epigenetic non-coding RNAs (ncRNAs) constitutes a sophisticated regulatory axis that amplifies oncogenic programs through bidirectional crosstalk. ERK activation dynamically modulates the expression of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) via phosphorylation of transcription factors (e.g., c-Myc, AP-1) or chromatin-modifying enzymes.The bidirectional regulatory interplay between the ERK signaling pathway and non-coding RNAs (ncRNAs) plays a pivotal role in cellular differentiation, cancer progression, drug response, and disease pathogenesis.

ERK-Mediated Regulation of ncRNAs: In hepatocellular carcinoma (HCC), hyperactivation of the BRAF/MEK/ERK pathway drives tumor proliferation and drug resistance by modulating lncRNAs. For instance, hypoxia-induced upregulation of the lncRNA H19 enhances P-glycoprotein expression via ERK signaling, thereby promoting chemotherapeutic drug efflux and resistance (Li et al., 2015[69]; Sokolov et al., 2024[122]; Gnoni et al., 2019[39]).

ncRNA-Mediated Feedback Control of ERK Signaling: FOXM1, a downstream effector of ERK, is post-transcriptionally regulated by miRNAs and lncRNAs. Certain lncRNAs (e.g., FOXM1-AS) function as miRNA sponges to relieve FOXM1 suppression, amplifying ERK activity and accelerating cell cycle progression and metastasis in HCC (Gao et al., 2025[34]). In parathyroid tumors, promoter methylation-induced silencing of the RASSF1A gene elevates ERK phosphorylation (pERK/ERK) to drive tumorigenesis, a process potentially linked to dysregulated expression of the lncRNA ANRASSF1A (Verdelli et al., 2025[131]).

Therapeutic Implications: Resistance to ERK-targeted therapies (e.g., sorafenib in HCC) is closely associated with lncRNA-mediated epigenetic escape mechanisms. Combinatorial strategies-such as co-inhibiting ERK and oncogenic lncRNAs (e.g., H19 or ANRASSF1A)-show promise in overcoming drug resistance (Sokolov et al., 2024[122]; Verdelli et al., 2025[131]). Emerging evidence highlights natural compounds as dual-target modulators that disrupt m6A modification enzymes (e.g., METTL3, FTO), destabilizing ERK-associated ncRNAs to exert anticancer effects. These findings underscore the potential for developing epigenetic-signaling dual inhibitors (Song et al., 2022[124]; Garcia-Lezana et al., 2021[36]).

The search for effective ERK1/2 inhibitors has intensified, especially in cancers with abnormal MAPK signaling. Recent studies have focused on creating small molecule inhibitors that specifically target the ERK1/2 pathway. For example, Ulixertinib, an established ERK2 inhibitor, has been modified to identify new structures with similar binding properties, showing promising pharmacodynamic and pharmacokinetic profiles in preclinical studies (Pathania et al., 2022[102]). Additionally, new RAF dimer inhibitors like lifirafenib have demonstrated synergistic effects when used with MEK inhibitors. This combination enhances antitumor activity specifically in KRAS-mutant tumors (Yuan et al., 2020[144]). These advancements underscore the therapeutic potential of targeting the ERK1/2 pathway, particularly in cancers with specific genetic alterations.

Ongoing trials are evaluating the clinical efficacy of these inhibitors, focusing on their safety profiles and effectiveness in different types of cancer. For instance, researchers are exploring the combination of ERK inhibitors with standard chemotherapy or immunotherapy. This approach aims to overcome resistance mechanisms and improve patient outcomes. Identifying patients most likely to benefit from these targeted therapies is crucial and requires integrating biomarker-based approaches into clinical trial designs.

Combination therapies have emerged as a promising strategy to enhance the therapeutic efficacy of ERK1/2 inhibitors. The rationale for this approach is based on the complex interactions of signaling pathways involved in tumor progression and resistance, which necessitates the exploration of combination therapies. For example, research shows that combining ERK inhibitors with drugs that target the Pl3K/AKT/mTOR pathway can improve antitumor effects in preclinical models of hepatocellular carcinoma (HCC) (Kim et al., 2019[62]).This combination not only inhibits tumor cell growth but also promotes apoptosis, emphasizing the potential for synergistic interactions between various treatment approaches..

The combination of ERK inhibitors with immune checkpoint inhibitors is currently being investigated to exploit the immunogenic potential of tumors. These combinations may improve overall response rates in patients with advanced malignancies by modifying the tumor microenvironment and boosting T-cell responses. Clinical trials are currently evaluating the safety and efficacy of these combinations. Preliminary results show promising outcomes in certain patient populations (Bratu et al., 2021[12]).

Novel delivery systems, such as nanoparticles, are an important aspect of exploring combination therapies, as they can enhance the bioavailability and targeting of ERK inhibitors. For example, antibody-modified nanoparticles can deliver ERK inhibitors directly to tumor cells, reducing off-target effects and enhancing therapeutic outcomes (Shen et al., 2020[117]). This innovative method highlights the importance of ongoing research to optimize combination therapies and delivery mechanisms for maximizing the clinical benefits of targeting the ERK1/2 pathway.

The use of biomarkers in ERK1/2-targeted therapies is vital for identifying patients who are most likely to benefit from these treatments. By providing insights into the molecular mechanisms that drive tumorigenesis, biomarkers facilitate the stratification of patients according to their likelihood of responding to therapy. For example, KRAS mutations are common in several types of cancer and are linked to the activation of the MAPK pathway, making them potential biomarkers for selecting patients for ERK1/2-targeted therapies (Hong et al., 2023[51]).

Moreover, downstream effectors of theERK1/2 pathway, like phosphorylated ERK, may act as predictive biomarkers for treatment response. Studies indicate that tumors with high phosphorylated ERK levels tend to be sensitive to ERK inhibitors. In contrast, tumors with low phosphorylated ERK expression may exhibit resistance (Huang et al., 2023[55]). Therefore, it is crucial to develop robust biomarker assays that can reliably assess the activation status of the ERK1/2 pathway in tumor samples.

Liquid biopsies are emerging as non-invasive methods that analyze circulating tumor DNA(ctDNA) and circulating tumor cells (CTCs) to monitor treatment responses and detect resistance mechanisms in real-time. By integrating these technologies with biomarker analysis, we can gain a comprehensive understanding of tumor dynamics and enhance personalized treatment strategies (Moon et al., 2025[94]).

In summary, the rapidly evolving research on ERK1/2 shows great promise, highlighted by advancements in novel inhibitors, combination therapies, and biomarkers that could significantly enhance cancer treatment outcomes. By focusing on these areas, researchers aim to improve treatment outcomes for patients with malignancies linked to aberrant MAPK signaling. Ongoing research is crucial to fully harness the therapeutic potential of targeting the ERK1/2pathway and to develop effective, biomarker-driven strategies for cancer treatment.

All authors provided permission for publication.

No authors have any conflicts of interest or competing interests to declare.

This research was funded by the Natural Science Foundation of Zhejiang Province(LGD21H160003).

The authors confirm that artificial intelligence tools were not used in the preparation or analysis of this manuscript. The authors used DeepSeek to check for grammar and style.