From mechanism to therapeutics: targeting the mitogen-activated protein kinase 1 (MAPK1)/extracellular signal-regulated kinase 2 (ERK2) pathway in renal fibrosis

Renal fibrosis represents a crucial pathological event in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), with currently limited therapeutic options. 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 comprehensively elucidate the regulatory network of the MAPK1/ERK2 pathway, summarize recent advances in targeted therapies against renal fibrosis, and provide directions for developing novel anti-fibrotic drugs. Special attention is given to bioactive compounds, including both chemically synthesized drugs and natural products. Through cextensive literature searches of databases including PubMed and Web of Science, this review discusses how the MAPK1/ERK2 pathway responds to upstream signals to promote myofibroblast activation, inflammation, and aberrant extracellular matrix (ECM) deposition via downstream effectors. The review highlights that these compounds demonstrate notable antifibrotic efficacy in preclinical models, primarily by directly or indirectly inhibiting MAPK1/ERK2 phosphorylation. Furthermore, we emphasize that these chemically defined compounds represent promising molecular probes and therapeutic candidates. In conclusion, targeting the MAPK1/ERK2 pathway remains strategically important. Given the current absence of approved anti-fibrotic drugs, in-depth exploration of specific molecular targets within this pathway holds considerable translational potential and may fill a critical gap in this field. This narrative review synthesizes current knowledge on the MAPK1/ERK2 pathway in renal fibrosis, highlighting its regulatory mechanisms and therapeutic promise.