SKLB-D18 is a first-in-class, potent, and selective inhibitor of ERK1/2 and ERK5 with an IC50’s of 38.69 nM, 40.12 nM, and 59.72 nM, respectively, that also acts as an agonist of autophagy. It modulates mTOR/p70S6K and NCOA4-mediated ferroptosis, showing strong anti-tumor activity and offering a promising monotherapy strategy to overcome resistance in ERK1/2-targeted therapy for triple-negative breast cancer (TNBC).