C/EBP alpha agonist ICCB280 overcomes doxorubicin resistance in osteosarcoma through mitochondrial dynamics-dependent GREM1-MAPK activation

The resistance of doxorubicin (DOX), the first-line chemotherapeutic drug for osteosarcoma (OS), stands as a pivotal obstacle in the effective treatment of OS. Alterations in mitochondrial dynamics and thereby affecting reactive oxygen species (ROS) accumulation play critical roles in DOX-induced cell death. However, the novel targets and pharmacological agents combating DOX resistance in OS via mitochondrial homeostasis and DOX-induced cell death manipulation is poorly understood. Herein, we showed that the C/EBPα/GREM1/p-ERK signaling pathway sensitizes OS to DOX by promoting mitochondrial fission and causing ROS-induced apoptosis. C/EBPα agonist ICCB280 and ERK pathway inhibitor PD98059 both played a DOX sensitivity augmentation role in OS in vitro and in vivo. The combined application of these two agents synergistically amplifies the cytotoxic impact of DOX, potentially overcoming DOX resistance and offering innovative therapeutic strategies for treating DOX-resistant OS.SCHEME： ICCB280 and PD98059 co‑administration counteracts doxorubicin resistance in osteosarcoma. When ICCB280 and PD98059 are co-administered, the activation of GREM1 by C/EBPα and the inhibition of ERK phosphorylation are intensified. This suppresses OPA1 expression, promotes mitochondrial fission, and effectively counteracts chemotherapy resistance in osteosarcoma.