mitogen-activated protein kinase (MAPK) pathway

Overview

The mitogen-activated protein kinase (MAPK) pathway is a conserved intracellular signaling network that transduces extracellular cues into coordinated cellular responses, including proliferation, differentiation, survival, stress adaptation, inflammation, and apoptosis. In mammalian cells, MAPK signaling is commonly organized through kinase cascades that culminate in activation of ERK, JNK, and p38 modules, with the ERK arm often linked to growth factor and oncogenic signaling such as KRAS, RAF, and EGFR-MET-driven programs.

Because of its central role in cell fate control, the MAPK pathway is a major biomedical target in cancer, inflammatory disease, and tissue injury. Dysregulated MAPK signaling is frequently associated with tumor growth, resistance to targeted therapy, and inflammatory amplification. In recent studies, MAPK activity has been examined alongside PI3K/Akt signaling, NF-κB signaling, and cGAS-STING/NF-κB signaling pathways, reflecting the pathway’s integration with broader stress-response and survival networks.

Focus of Latest Publications

Recent publications used the MAPK pathway as a mechanistic readout, therapeutic target, or resistance axis across diverse disease models.

In KRAS-driven cancer, MAPK signaling remained a central focus. A study on anaplastic thyroid cancer reported that acquired resistance to type I RAF inhibitors and MEK inhibitors was associated with reactivation of the mitogen-activated protein kinase pathway, together with immunosuppressive macrophage proliferation. This supports the idea that MAPK pathway rebound is a key mechanism of resistance in MAPK-targeted therapy. In another KRAS-mutant non-small cell lung cancer study, anti-PCDH7 monoclonal antibodies suppressed downstream MAPK pathway activation and inhibited tumor growth in multiple mutant KRAS-driven models, indicating that PCDH7 contributes to MAPK-dependent oncogenic signaling. Similarly, discovery work on SOS1 inhibitors in KRAS-driven colorectal cancer found that the compounds induced G1 arrest and suppressed both MAPK and PI3K signaling pathways, reinforcing the importance of dual pathway inhibition in KRAS-dependent tumors. A separate pancreatic cancer study showed that SHP2 inhibition with SDUY104 suppressed MAPK signaling while triggering compensatory PI3K-AKT activation, highlighting pathway cross-talk and the need to anticipate adaptive bypass signaling. In another cancer-focused analysis, apigenin from Scutellaria barbata was identified as an Akt1 inhibitor, with network analysis showing enrichment in PI3K-Akt, MAPK, and TNF signaling pathways, suggesting broader pathway-level effects rather than a single-node mechanism.

Several studies examined MAPK signaling in inflammatory and degenerative disease contexts. Genistein from Thai fermented soybean was reported to attenuate osteoarthritis pathogenesis through dual inhibition of NF-κB and MAPK signaling, with computational analysis predicting effective inhibition and favorable gastrointestinal absorption. In acute pancreatitis, METTL1-dependent regulation of MSC mRNA stability promoted macrophage M1 polarization and pancreatic acinar cell injury through phosphorylation of NF-κB, JNK, and MAPK proteins, linking MAPK activation to inflammatory injury. In a neuroinflammation model using BV-2 cells and mice, Phy-Blica-O reduced NF-κB signaling but showed no significant effect on MAPK signaling, suggesting that its neuroprotective action was MAPK-independent. Environmental toxicology studies also implicated MAPK-related programs: plasticizer exposure was associated with subtype-resolved enrichment patterns consistent with VEGF/MAPK signaling in dilated cardiomyopathy and TNF/IL-17 and AGE-RAGE axes in ischemic cardiomyopathy, while bisphenol A exposure was linked to inflammatory responses, extracellular matrix remodeling, angiogenesis, and PI3K-Akt and MAPK signaling in diabetic foot ulcers.

The pathway was also studied in the context of tumor immunogenicity and combination therapy. A nanoparticle-based strategy combined belzutifan and trametinib, using self-sealed porous silicon nanoparticles to sustain drug release for more than 10 days in aqueous physiological medium. This degradation-governed release was designed to prolong intracellular exposure and support synchronized HIF-2α and MEK inhibition, illustrating how MAPK pathway blockade can be integrated with hypoxia-targeted therapy to reprogram tumor immunogenicity. In another study, high-affinity anti-PCDH7 monoclonal antibodies were developed in humanized and murinized formats, including Hu-mAb7-IgG1 and Ms-mAb7, and glycoengineering was used to optimize antibody properties. These antibodies inhibited downstream MAPK pathway activation in KRAS-mutant models, supporting a receptor-proximal strategy to suppress MAPK signaling.

Additional work connected MAPK signaling to broader systems biology and disease subtype analysis. In heart failure, integrative toxicogenomic analyses suggested that plasticizer clusters were associated with pathogenic axes including inflammatory remodeling, metabolic stress, and extracellular matrix processes, with VEGF/MAPK enrichment in dilated cardiomyopathy. In glycosylation perturbation studies, phosphorylation signaling was rewired away from canonical RTK/MAPK/mTOR-Rho growth pathways toward calcium/PLC-linked signaling and cell cycle programs, indicating that MAPK pathway organization can be reshaped by altered protein glycosylation. Across these studies, MAPK signaling emerged not only as a canonical growth-control pathway but also as a node of resistance, inflammatory amplification, and pathway cross-talk with PI3K/Akt signaling pathway, NF-κB, TNF, and VEGF-related networks.

Key Publications

• Jul Degradation-controlled synchronization of HIF-2α and MEK inhibition using self-sealed porous silicon nanoparticles to reprogram tumor immunogenicity. (Acta biomaterialia, 2026, PMID 42217661): "In contrast, degradation-governed release from PSiNPs sustained the availability of belzutifan and trametinib in aqueous physiological medium for >10 days supporting prolonged intracellular drug exposure when combined with the established cellular internalization of this carrier system."
• Jun Plasticizer-responsive molecular axes in heart failure: a subtype-aware toxicogenomic framework relevant to environmental health. (Environment international, 2026, PMID 42235321): "Integrative analyses suggested associations between plasticizer clusters and HF-relevant pathogenic axes, including inflammatory remodeling, metabolic stress, and extracellular matrix processes, with subtype-resolved enrichment patterns consistent with VEGF/MAPK and hormonal signaling in dilated cardiomyopathy (DCM) and TNF/IL-17 and the diabetes-associated AGE-RAGE axis in ischemic cardiomyopathy (ICM)."
• Jul Characterizing the Effects of Protein Glycosylation Perturbation on Phosphorylation Signaling. (Analytical chemistry, 2026, PMID 42294758): "...differentiated phosphorylation responses compared to wild-type cells but also comprehensively rewired away from canonical RTK/MAPK/mTOR-Rho growth pathways toward calcium/PLC-linked signaling and cell cycle programs."
• Jun Neuroprotective mechanisms of Thai traditional brain tonic Phy-Blica-O against LPS-induced neuroinflammation: Inhibition of NF-κB in microglia and mice. (PloS one, 2026, PMID 42361074): "Mechanistic analysis revealed that PBO exerts its protective effects primarily through inhibition of the NF-κB signaling pathway, reducing p-IκBα levels by 23% (p=0.018) and p-p65 levels by 34% (p=0.039) at 250 μg/mL in vitro, with no significant effect on MAPK signaling."
• Jun In silico screening and molecular analyses identify apigenin from Scutellaria barbata as a potent AKT1 inhibitor in breast cancer. (PloS one, 2026, PMID 42348584): "Network analysis identified AKT1, IL6 and TNF as central hub targets, significantly enriched in the PI3K-Akt, MAPK, and TNF signaling pathways."
• Jun SHP2 Inhibition Reveals Compensatory PI3K-AKT Activation in KRAS-Driven Pancreatic Cancer: Discovery of SDUY104 and Rational Approaches for Combination Therapy. (Journal of medicinal chemistry, 2026, PMID 42261691): "Mechanistic studies revealed that SDUY104 suppressed MAPK signaling while triggering compensatory PI3K-AKT activation."
• Jun Genistein from Thai Fermented Soybean (Thua-nao) Attenuates Osteoarthritis Pathogenesis via Dual Inhibition of NF-κB and MAPK Signaling: Evidence from Ex Vivo, Computational, and In Vitro Models. (Journal of agricultural and food chemistry, 2026, PMID 42290531): "Computational analysis predicted genistein to inhibit NF-κB and MAPK signaling effectively, with high gastrointestinal absorption."
• Jun Discovery of Highly Potent and Selective SOS1 Inhibitors for the Treatment of KRAS-Driven Colorectal Cancer. (Journal of medicinal chemistry, 2026, PMID 42247371): "Moreover, both compounds showed submicromolar 3D-antiproliferative activity across a panel of CRC cells, induced G1 phase arrest, and suppressed MAPK and PI3K signaling pathways."
• Jun Methyltransferase METTL1 regulates MSC mRNA stability via m7G modification in acute pancreatitis. (Cell death & disease, 2026, PMID 42331782): "Functional experiments demonstrated that MSC upregulation activates TNF signaling through phosphorylation of NF-κB, JNK, and MAPK proteins, thereby promoting macrophage M1 polarization and pancreatic acinar cell injury."
• Jun Understanding and overcoming innate and acquired MAPK inhibition resistance in anaplastic thyroid cancer. (Cell reports. Medicine, 2026, PMID 42143022): "Here, multi-region whole-genome, high-coverage whole-exome, and single-nuclei RNA sequencing of tumors from ATC patients undergoing type I RAFi and MEKi therapy reveals that reactivation of the mitogen-activated protein kinase (MAPK) pathway, along with immunosuppressive macrophage proliferation, may underlie the development of acquired resistance."