Forkhead box O (FOXO) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways (FOXO/p38 MAPK)

The DAF-16/FOXO and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways are interconnected regulatory networks that govern cellular responses to stress, metabolism, and longevity. DAF-16 is the Caenorhabditis elegans ortholog of the human Forkhead box O (FOXO) family of transcription factors, which includes FOXO1, FOXO3, FOXO4, and FOXO6 [1, 2]. These transcription factors regulate genes involved in antioxidant defense (e.g., SOD2, catalase), DNA repair, and apoptosis [3]. The p38 MAPK pathway is a stress-activated protein kinase cascade that responds to stimuli such as oxidative stress, UV radiation, and inflammatory cytokines [4]. In many contexts, p38 MAPK phosphorylates FOXO proteins, influencing their nuclear localization and transcriptional activity, thereby integrating environmental signals into the cellular survival program [5, 6]. Dysregulation of these pathways is implicated in aging, cancer, neurodegeneration, and chronic inflammatory diseases [7]. While p38 MAPK is a direct therapeutic target for inhibitors like losmapimod, FOXO activity is typically modulated indirectly through upstream kinases such as PI3K, AKT, or p38 itself [8, 9]. [1] UniProt: P10000 (DAF-16). [2] UniProt: O43524 (FOXO3). [3] PubMed: 15107404. [4] UniProt: Q16539 (MAPK14). [5] PubMed: 18256283. [6] PubMed: 22560273. [7] PubMed: 21368824. [8] ClinicalTrials.gov: NCT04068454. [9] PubMed: 30301778.

Other names

DAF-16FOXO transcription factorsp38 MAPKMAPK14Stress-activated protein kinase pathwayPMK-1

Inhibition of p38 MAPK catalytic activity to reduce pro-inflammatory cytokine production; indirect modulation of FOXO transcriptional activity via inhibition of upstream regulatory kinases (PI3K/AKT/p38) to promote stress resistance or apoptosis.