From mechanism to therapeutics: targeting the MAPK1/ERK2 pathway in renal fibrosis
Abstract
Renal fibrosis represents a pivotal pathological event in the progression of chronic kidney disease to end-stage renal disease, with limited therapeutic options currently available. As a key regulator of cell proliferation and differentiation, the mitogen-activated protein kinase 1 (MAPK1)/extracellular signal-regulated kinase 2 (ERK2) signaling pathway plays a central role in the development of renal fibrosis. This review aims to systematically elucidate the regulatory network of the MAPK1/ERK2 pathway, integrate recent advances in targeted anti-renal fibrosis therapies, and provide directions for developing novel anti-renal fibrosis drugs. The focus centers on identified bioactive compounds, encompassing both chemically synthesized drugs and natural bioactive compounds. Through systematic literature searches in databases such as PubMed and Web of Science, this review elucidates how the pathway responds to upstream signals and promotes myofibroblast activation, inflammatory responses, and abnormal extracellular matrix deposition via downstream effector molecules. The review highlights that these specific compounds and drugs demonstrate significant antifibrotic efficacy in preclinical models, primarily achieved through direct or indirect inhibition of MAPK1/ERK2 phosphorylation. We highlight that these chemically defined monomeric compounds and drugs represent ideal molecular probes and therapeutic leads. In conclusion, targeting the MAPK1/ERK2 pathway remains strategically important. Given the current absence of approved anti-fibrotic drugs, in-depth exploration of precise molecular targets within this pathway holds significant clinical translational potential and may fill a critical gap in this field.