PD98059 / Wayne State University - LARVOL DELTA

Mechanistic Insights into Anti-Melanogenic Effects of Fisetin: PKCα-Induced β-Catenin Degradation, ERK/MITF Inhibition, and Direct Tyrosinase Suppression. (PubMed, Int J Mol Sci) - "The proteasome inhibitor MG132 confirmed that fisetin accelerates β-catenin and MITF degradation. Additionally, inhibition of the PI3K/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin's reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKCα, β-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation."

Journal • Dermatology • Dermatopathology • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • CTNNB1 • MITF • Tyrosinase • TYRP1

FAM83A acts as an amplifier for lipogenic signaling to facilitate the pathogenesis of metabolic dysfunction-associated steatohepatitis. (PubMed, Metabolism) - "FAM83A promotes MASH pathogenesis by interacting with RAF1 to activate ERK signaling, thereby stimulating fatty acid and cholesterol biosynthesis. Targeting this axis may offer therapeutic potential for MASH and metabolic dyslipidemia."

Journal • Dyslipidemia • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • EGFR • FAM83A

WuFu Decoction alleviates osteoarthritis by regulating TGF-β1/Smad and ERK1/2 pathways. (PubMed, Histol Histopathol) - "Furthermore, TGF-β1 inhibitor (Decorin) reversed the improvement effect of WFD on OA, but ERK1/2 inhibitor (PD98059) promoted this improvement effect...This study also identified active ingredients, such as Fumaric acid, Glycyrrhizic acid, Albiflorin, and Isoliquiritigenin. It provides a basis for the clinical application of WFD and for the promotion and development of TCM."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • BMP7 • COL2A1 • IL1B • MMP13 • SMAD2 • SMAD3 • TGFB1 • TGFBR2 • TNFA • TRAP

LGALS3 promotes liver fibrosis by enhancing the expression and phosphorylation of ERK1/2. (PubMed, Eur J Med Res) - "In the LGALS3 overexpression cell model, PD98059 intervention was applied to mimic the therapeutic effect on liver fibrosis.​ LGALS3 overexpression significantly promoted the proliferation and migration of LX-2 cells, along with the expression and phosphorylation of ERK1/2...These findings enhance our understanding of the pathological process of liver fibrosis, suggesting that targeting the LGALS3-ERK1/2 axis may represent a promising target for further investigation in liver fibrosis. It also provides potential targets and innovative directions for the development of anti-liver fibrosis drugs."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • LGALS3 • MAPK1 • MAPK3 • TGFB1

Acupuncture mitigates sciatic neuropathic pain in lumbar disc herniation via inhibiting spinal CXCL12/CXCR4-driven glial activation and neuroinflammation. (PubMed, J Neuroimmunol) - "Pharmacological blockade of CXCR4 with AMD3100 alleviated hypersensitivity and reduced neuronal and glial activation. Acupuncture also inhibited ERK1/2 and NF-κB phosphorylation, and selective inhibition of these pathways with PD98059 or PDTC reproduced its analgesic effects. These findings identify the CXCL12/CXCR4-ERK/NF-κB axis as a critical mediator of LDH-induced neuroinflammation and demonstrate that acupuncture mitigates neuropathic pain by suppressing this signaling pathway and glial activation."

Journal • Back Pain • CNS Disorders • Immunology • Inflammation • Lumbar Back Pain • Musculoskeletal Diseases • Musculoskeletal Pain • Neuralgia • Pain • CXCL12 • CXCR4 • FOS • GFAP • IL1B • IL6 • TNFA

RRBP1 Inhibition Reduces Microglial M1 Polarization and Inflammation-Mediated Neuronal Loss and Oxidative Stress by Regulating ERK Pathway in Alzheimer's Disease. (PubMed, Mol Neurobiol) - "pERK/ERK was lowered after PD98059 treatment, which attenuated the effect of RRBP1 inhibition on microglial M1/M2 phenotypes and inflammatory cytokines in BV-2 and HMC3 cells, and further weakened the effect of microglial RRBP1 inhibition on cell viability, apoptosis rate, ROS, and SOD in HT-22 and SH-SY5Y cells. RRBP1 inhibition represses microglial M1 polarization and inflammation-mediated neuronal loss and oxidative stress by modifying the ERK pathway in AD."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Neuroblastoma • Oncology • Solid Tumor • IL1B • TNFA

YWHAH‑driven autophagy via MAPK/ERK signaling enhances CRC cell migration and invasion. (PubMed, Int J Mol Med) - "The ERK inhibitor PD98059 reversed autophagy activation by YWHAH knockdown, while the ERK agonist U‑46619 reversed autophagy suppression by YWHAH overexpression. Additionally, the autophagy inhibitor 3‑methyladenine abrogated the inhibitory effects of YWHAH knockdown on migration and invasion, and the autophagy inducer rapamycin reversed the promoting effects of YWHAH overexpression...These findings underscore the role of YWHAH as a critical regulator of CRC progression and suggest it as a potential therapeutic target. Interventions targeting YWHAH or its downstream factors may provide innovative approaches for treating CRC, particularly by modulating autophagy to inhibit tumor growth and metastasis."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ATG7 • YWHAH

The skin hydration and anti-ageing benefits of Ectoine, achieved through enhanced Src-ERK-mediated HAS-2 and JNK-driven AQP-3 expression in human keratinocytes, along with the inhibition of MMP-1-induced collagen-I degradation in human fibroblasts, both with and without UVB irradiation. (PubMed, Int J Cosmet Sci) - "We demonstrated that Ectoine exerts skin hydration effects without or with UVB exposure in human skin keratinocyte (HaCaT) cells and anti-ageing in fibroblast (Hs68) cells. Therefore, Ectoine could serve as a potential natural compound in cosmetic preparations for skin hydration and anti-ageing."

Journal • MAPK1 • MMP1

Inhibition of astrocytic AT1R ameliorates sleep deprivation induced Aβ deposition and glymphatic dysfunction via the MAPK/Cx43 pathway. (PubMed, Sleep Med) - "Furthermore, using MAPK inhibitor PD98059 both in vivo and in vitro, we demonstrated astrocytic AT1R regulated AQP4 hyperplasia distribution via MAPK/Cx43 pathway in astrocytes. Collectively, our findings reveal a direct contribution of astrocytic AT1R in SD by modulating GS clearance mediated by the perivascular AQP4 localization, highlighting its potential as a novel preventive or therapeutic target for cognitive disorders associated with SD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders

Rotenone-mediated mitochondrial ROS generation inhibits melanogenesis in B16F10 cells by inducing the ERK activation-MITF degradation pathway. (PubMed, Biochem Biophys Res Commun) - "Treatment with N-acetylcystein (NAC), a ROS scavenger, or PD98059, an ERK inhibitor, suppressed the decrease in MITF protein induced by rotenone, thereby eliminating the hypopigmentation effect of rotenone. These findings provide novel insights into the whitening activity mechanism of rotenone and suggest that mitochondrial damage may affect melanogenesis."

Journal • Ophthalmology • MITF

HOXB7 drives bladder cancer progression via H-Ras/ERK signaling: a potential therapeutic target and prognostic biomarker. (PubMed, Front Oncol) - "Western blotting and rescue assays with ERK pathway modulators (Ro67-7476 and PD98059) were performed to assess the involvement of the H-Ras/Raf-1/MEK/ERK signaling cascade...These findings highlight HOXB7 as a potential prognostic biomarker and therapeutic target in BC. Furthermore, our results lay the foundation for future investigations into the broader molecular and immunological networks modulated by HOXB7 in BC."

Biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • HOXB7

Gold nanoparticles reduce ischemic brain injury in rats by activating autophagy and inhibiting apoptosis. (PubMed, Brain Res) - "Furthermore, Au-NPs treatmentalleviated tMCAO induced apoptosis in rats and increased autophagy. In addition, Au-NPs treatment activated the ERK and ERK inhibitor PD98059 reversed the neuroprotective effects of Au-NPs on ischemic stroke injury."

Journal • Preclinical • Cardiovascular • CNS Disorders • Ischemic stroke • Reperfusion Injury • Vascular Neurology

Benzophenone-3 drives osteoarthritis pathogenesis by regulating chondrocyte senescence. (PubMed, Chem Biol Interact) - "Strikingly, the ERK-specific inhibitor PD98059 effectively blocked BP-3-induced ERK activation, Elk-1 phosphorylation, chondrocyte senescence, and ECM degradation. Collectively, these findings establish a novel mechanism for BP-3 as an environmental osteoarthritic hazard, in which it triggers chondrocyte senescence and promotes OA pathogenesis through the specific activation of the ERK pathway."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • CDKN1A • COL2A1

C-C chemokine receptor type 5 activation stimulates adipocyte differentiation through ERK-dependent pathway. (PubMed, Int J Med Sci) - "Moreover, pretreatment with the CCR5 inhibitor maraviroc and the ERK inhibitor PD98059 significantly reduced RANTES-induced adipocyte differentiation. In vivo, WT mice on a high-fat diet showed higher plasma RANTES levels and increased adipose CCR5 expression, as well as obesity, whereas these changes were absent in CCR5-/- mice. The results suggest that CCR5 activation by RANTES enhances adipocyte differentiation via an ERK-dependent pathway, and that CCR5 plays a critical role in the development of obesity."

Journal • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • CCR5 • PPARG

Histamine regulates the activity and the expression of the Na+/H+ exchanger (NHE)3 in human epithelial HK-2 cells. (PubMed, Inflamm Res) - "Histamine shows early (within 60 min) and late (48 h) effects on NHE3 expression. The histamine H1 and H4 receptors are shown to contribute to these effects differentially. The findings of this study extends the evidence for a direct contribution of histamine on the renal reabsorptive machinery."

Journal

Gut Microbiota-Bile Acid-Brain Axis and TGR5-ERK1/2 Signaling Mediate ADT-Induced Cognitive Impairment. (PubMed, CNS Neurosci Ther) - "Our findings suggest that gut microbiota-mediated bile acid dysregulation, particularly reduced TDCA, contributes to ADT-induced cognitive dysfunction via impaired TGR5-ERK1/2 signaling. Targeting this pathway may represent a novel therapeutic strategy to mitigate cognitive impairment in prostate cancer patients undergoing ADT."

Journal • Alzheimer's Disease • Cognitive Disorders • Gastrointestinal Disorder • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Exploring the In Vitro Anti-Inflammatory Effect of Citrus Fruit Hesperidin Supplementation. (PubMed, Food Sci Nutr) - "Likewise, in the assay of IL-8, IL-1β and TNF-α production assay, the mean production rate of cytokines was 0.6 ± 0.21 ng/mL, 0.47 ± 0.012 ng/mL, and 0.3633 ± 0.045 ng/mL according to the exposure rate of hesperidin as 0.01 mg/mL, 0.1 mg/mL, and 20 μM of the positive control drug PD98059...The inhibitory effect of hesperidin was more significant in IL-8 as compared to IL-1β and TNF-α. Conclusively, hesperidin did prove to be a significant antioxidant and anti-inflammatory agent."

Journal • Preclinical • CXCL8 • IL1B • TNFA

p62/SQSTM1 signaling nexus and orchestration of ERK and mTOR pathways are crucial for Bacoside A- induced autophagy-mediated apoptosis in chronic myelogenous leukemia. (PubMed, Arch Pharm Res) - "Inhibition of ERK1/2 using PD98059 reversed mTOR dephosphorylation and autophagy induction, whereas mTOR overexpression restored ERK1/2 phosphorylation to basal levels. Collectively, these findings delineate BCA as a novel autophagy-inducing agent in CML, exerting cytotoxic effects via ERK1/2-mTOR signaling and p62/SQSTM1-mediated autophagy-apoptosis crosstalk."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • BECN1 • CASP8 • EIF4EBP1 • SQSTM1

Aquaporin 2 is differentially expressed in granulosa cells of various stages of human follicles and is regulated by luteinizing hormone. (PubMed, Front Cell Dev Biol) - "H89 (a PKA inhibitor) or PD98059 (an ERK1/2 signaling inhibitor) was applied in the presence of LH to evaluate crosstalk between the Gn/cAMP and MAPK cascades...This study provides the first evidence for the mechanisms by which AQP2 influences follicular growth and FF formation, highlighting LH-driven, ERK1/2-dependent regulation of AQP2. These findings offer new insights into the ovarian microenvironment and identify potential therapeutic targets for follicle growth disorders."

Journal • Endocrine Disorders

Chondroitin sulfate protects against synaptic impairment caused by fluorosis through the Erk1/2-MMP-9 signaling pathway. (PubMed, Sci Rep) - "Importantly, treatment of SH-SY5Y cells with PD98059 or CS attenuated fluoride-induced effects, indicating a regulatory role of CS in the Erk1/2/MMP-9 signaling pathway. However, MMP-2 was not implicated in this process. These data demonstrate the neuroprotective effects of CS and highlight its potential for protecting against fluoride-induced neurotoxicity and synaptic impairment."

Journal • Cognitive Disorders • MMP2 • MMP9 • SYP

The role of microparticles in oxidative stress and inflammation in patients with vascular intimal hyperplasia. (PubMed, J Int Med Res) - "Microparticles derived from patients with mild intimal hyperplasia stimulated the proliferation and migration of human coronary artery smooth muscle cells (partially blocked by PD98059); increased the phosphorylation of ERK and P38, but not JNK; and enhanced the production of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule 1 (blocked by SB20358). All these effects were more pronounced in patients with serious intimal hyperplasia.ConclusionsThe effects of microparticles in patients with intimal hyperplasia may reveal a therapeutic target for intimal hyperplasia."

Journal • Inflammation • MAPK8 • VCAM1

Inhibition of Growth and Survival of Head and Neck Cancer Cells by Silibinin Involves the Down-Regulation of Erk1/2, AKT and STAT3 Signaling. (PubMed, Mol Carcinog) - "Silibinin augmented PD98059 and LY294002-induced cell death and inhibition of pSTAT3. Further, oral silibinin inhibited Cal33 tumor xenograft growth. Hence, silibinin could have promising therapeutic efficacy for HNSCC."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BAX • BCL2 • CASP3 • CCND1 • CDK2 • CDK4 • CDKN1A • CHEK1 • CHEK2 • EGFR • H2AX • RAD51 • TP53

FTO-mediated MMP1 m6A modification promotes osteogenic differentiation of bone marrow mesenchymal stem cells via the ERK pathway in congenital scoliosis. (PubMed, Sci Rep) - "A specific ERG inhibitor called PD98059 prevents MMP1-mediated promotion. Additionally, our research revealed that FTO affects how BMSCs can differentiate in CS patients by regulating MMP1 levels. FTO-mediated MMP1 m6A modification underlies MMP1's promotion of osteogenic differentiation via the ERK pathway, implying that it could be a viable treatment target for CS."

Journal • Genetic Disorders • Obesity • FTO • MMP1

Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells. (PubMed, Antioxidants (Basel)) - "Pretreatment with antimycin A, apocynin, allopurinol, and PD98059, and the overexpression of p-Akt significantly recovered cell viability and reduced apoptosis, confirming the involvement of these pathways. This study is the first to demonstrate piperine induces apoptosis in CRC cells through a multifaceted oxidative stress mechanism and by critically modulating PI3K/Akt and ERK signaling pathways."

Journal • Colorectal Cancer • Oncology • Solid Tumor

PACAP/PAC1R activation promotes group 2 innate lymphoid cells-dependent allergic rhinitis via ERK pathway. (PubMed, Arch Biochem Biophys) - "These effects were effectively reversed by ERK inhibitor PD98059. Importantly, both PAC1R knockdown and ERK inhibition significantly decreased p-ERK expression and ILC2s proliferation, while ameliorating AR pathological features. Our findings revealed that PACAP/PAC1R activation promoted ILC2s proliferation and allergic inflammation through ERK pathway, which provides novel insights into the regulation of ILC2s and potential therapeutic targets in allergic rhinitis."

Journal • Allergic Rhinitis • Contact Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • ADCYAP1 • IL13 • IL5 • MAPK1