p38 MAPK

The p38 mitogen-activated protein kinase (p38 MAPK) family is a multifunctional serine/threonine kinase system that regulates cellular adaptation to stress, inflammation, and proliferation^[1][2]. Mechanistically, p38 MAPK modulates apoptosis, cell cycle, differentiation, and gene expression in response to exogenous and endogenous stimuli^[3][1]. Four isoforms—p38α, p38β, p38γ, and p38δ—exhibit distinct tissue distributions and biological functions, with p38α being ubiquitously expressed and primarily responsible for inflammatory mediator production^[2][4]. Activation of p38 MAPK in endothelial cells induces cytoskeletal remodeling, angiogenesis, and DNA damage responses, highlighting its central role in cardiovascular homeostasis and cancer progression^[2]. In disease models, p38 MAPK contributes to neurodegeneration, such as spinal muscular atrophy and Alzheimer’s disease, where pharmacological inhibition improves neuronal survival and cognitive function^[5][6][7]. Compared with p38β, which promotes SARS-CoV-2 replication and suppresses type-I interferon responses, p38α mainly regulates stress and inflammatory signaling^[4]. Selective inhibitors, including SB203580, MW150, and VX-702, have been applied in experimental systems to delineate isoform-specific roles and evaluate therapeutic potential in inflammatory, neurodegenerative, and viral disease models^{[8][5][9][10]}. Agonists or modulators, such as RO27-3225, influence upstream or parallel pathways to p38 MAPK, providing experimental tools to study neuroinflammation and signal compensation^[11].