MAPK/ERK/JNK signaling pathways

Overview

The MAPK/ERK/JNK signaling pathways are interconnected mitogen-activated protein kinase cascades that transmit extracellular and intracellular signals to regulate gene expression, cell proliferation, differentiation, survival, stress responses, inflammation, and apoptosis. In biomedical research, these pathways are often discussed together because they share upstream activators and downstream transcriptional outputs, while also exerting distinct and sometimes opposing effects depending on cell type and stimulus.

Within this signaling network, ERK is classically associated with growth-factor-driven proliferation and survival, whereas JNK is more often linked to cellular stress responses, inflammatory signaling, and apoptosis. Dysregulation of MAPK/ERK/JNK signaling is implicated in cancer, immune-mediated disease, fibrosis, neuroinflammation, and tissue injury. Because of this broad biological relevance, the pathways are frequent targets in pharmacology and translational research, including studies of colorectal cancer, retinoblastoma, breast cancer, acute myeloid leukemia, cardiac hypertrophy, autoimmune hepatitis, spinal cord injury, and inflammatory disorders.

Focus of Latest Publications

Recent publications have examined MAPK/ERK/JNK signaling pathways in a range of inflammatory, neurological, and cancer-related contexts, often as mechanistic readouts of therapeutic intervention. In a psychotic-like mouse model, ketamine was shown to induce histone H3 Ser10 phosphorylation in hippocampal neurons and mouse hippocampus, with the effect primarily driven by JNK activation. Pharmacological inhibition of JNK with SP600125 reversed this epigenetic mark and attenuated ketamine-induced hyperlocomotion and cognitive deficits, while multi-omics profiling of the hippocampus revealed coordinated transcriptional and chromatin accessibility changes, including MAPK-pathway-associated genes.

Several studies focused on anti-inflammatory effects mediated through MAPK-related signaling. Turmeric volatile oil alleviated ovalbumin-induced allergic rhinitis in mice and reduced inflammation in lipopolysaccharide- and interferon-γ-treated human mast cells, with proteomic analysis implicating MAPK and nuclear factor kappa B signaling. In this setting, JNK and Relb were identified as key mediators, and Relb knockdown enhanced the anti-inflammatory effect. Similarly, in Helicobacter pylori-infected gastric epithelial cells, the LOX-1 inhibitor BI-0115 reduced LOX-1-associated inflammatory cascades by inhibiting phosphorylated p38-MAPK, ERK1/2, JNK, and NF-κB, alongside increasing E-cadherin and ZO-1 expression.

The pathway was also linked to cardiovascular remodeling and cancer signaling. In transverse aortic constriction-induced cardiac hypertrophy, propylene glycol alginate sodium sulfate formulated in trimethyl chitosan-coated multivesicular liposomes delayed disease progression, and cell-level experiments indicated that PSS inhibited myocardial cell hypertrophy and fibrosis through MAPK and TGF-β/Smad signaling pathways. In RAS-driven cancers, pyridone derivatives were developed as pan-MEK/RAF nondegrading molecular glues; the lead compound D56 blocked MEK and ERK phosphorylation, induced MEK1-BRAF and MEK1-CRAF complex formation, and suppressed tumor growth in xenograft models.

A further publication described Tianwangbuxiandan decoction as alleviating constipation and associated emotional disorders via regulation of the brain-gut axis, explicitly involving MAPK/ERK/JNK signaling pathways, although the abstract provides limited mechanistic detail. Collectively, these studies position MAPK/ERK/JNK signaling as a recurring node in stress responses, inflammatory regulation, tissue remodeling, and oncogenic signaling, with therapeutic modulation reported through small-molecule inhibitors, natural products, and traditional formulations.

Key Publications

NEWJun Ketamine enhances histone H3 (Ser10) phosphorylation via JNK signaling and multi-omics profiling of the hippocampus in a psychotic-like mouse model. (Behavioral and brain functions : BBF, 2026, PMID 42351237): "...an effect primarily driven by JNK activation."
NEWJun Multi-omics combined analysis of turmeric volatile oil alleviating allergic rhinitis through the JNK/MAPK-Relb/NF-κB pathway. (NPJ science of food, 2026, PMID 42310315): "Proteomic analysis using four-dimensional data-independent acquisition indicated that the mitogen-activated protein kinase (MAPK) and transcription factor nuclear factor-κB (NF-κB) signaling pathways are involved in TVO's anti-inflammatory mechanism."
May Harnessing plant-derived bioactive compounds as LOX-1 inhibitors in Helicobacter pylori-driven gastric inflammation. (Toxicology and applied pharmacology, 2026, PMID 42128233): "Since LOX-1 is linked to inflammatory signalling pathways, we investigated the phosphorylation of p38-MAPK, ERK1/2, JNK, and NF-κB."
Jun PSS and its trimethyl chitosan coating multivesicular liposomes ameliorate transverse aortic constriction-induced cardiac hypertrophy. (International journal of biological macromolecules, 2026, PMID 42106034): "Additionally, the cell-level studies identified that PSS could inhibit myocardial cell hypertrophy and prevent fibrosis through MAPK and TGF-β/Smad signaling pathways."
May Identification and Optimization of Pyridone Derivatives as Pan-MEK/RAF Nondegrading Molecular Glues for the Treatment of RAS-Driven Cancers. (Journal of medicinal chemistry, 2026, PMID 42098597): "D56 could effectively block MEK and ERK phosphorylation with IC50 values of 0.379 and 0.015 nM, respectively."
May Melissa officinalis L. protects against reflux esophagitis by attenuating NF-κB- and MAPK-mediated inflammation in rats. (Journal of ethnopharmacology, 2026, PMID 41775309): "...attenuating NF-κB- and MAPK-mediated inflammation in rats."
May Tianwangbuxiandan decoction alleviates constipation and associated emotional disorders via regulating the brain-gut axis: Involving MAPK/ERK/JNK signaling pathways. (Journal of ethnopharmacology, 2026, PMID 41654070): "Tianwangbuxiandan decoction alleviates constipation and associated emotional disorders via regulating the brain-gut axis: Involving MAPK/ERK/JNK signaling pathways."