EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma

• GSK126, a specific EZH2 inhibitor, induces cellular senescence in multiple myeloma (MM) cells, characterized by SAHF formation, p21 upregulation, and increased SA-β-gal activity. • RRM2 overexpression inhibits EZH2 methyltransferase function and promotes its degradation via the ubiquitin-proteasome pathway, leading to senescence in MM cells. • EZH2 inhibition leads to aberrant accumulation of Lamin B1 and increased ERK1/2 phosphorylation; blocking ERK1/2 phosphorylation partially reverses senescence and restores Lamin B1 levels. • The study reveals a novel EZH2-RRM2-Lamin B1-ERK1/2 axis in MM senescence, offering potential therapeutic targets for relapsed/refractory multiple myeloma.