Cardiac Remodeling and Cancer Interplay: Investigating the Role of OSM and MEK/ERK Pathway Inhibitors

All articles of this category (opens in new window) Background: Oncostatin M (OSM) potently activates the MAP Kinase pathway, which is central to cardiac regeneration and is activated in inflammatory heart diseases. Furthermore, it is mutated in over half of cancers. MAPK signaling is essential for heart development, homeostasis, and protective remodeling. MEK1/2 and ERK1/2 inhibitors (e.g., trametinib and ulixertinib) target this cascade in cancer therapy, but they carry a risk of cardiotoxicity. In this study, we investigated how MEK/ERK inhibition modulates OSM-induced signaling and secretomes in cardiac and cancer cells. Methods: Neonatal rat cardiomyocytes were treated with OSM with or without the MEK1/2 inhibitor trametinib or the ERK1/2 inhibitor ulixertinib. Changes in gene expression were assessed by RNA sequencing, and the phosphorylation of signaling proteins was analyzed by immunoblotting. To study paracrine crosstalk, conditioned media from A549 carcinoma cells treated with OSM ± inhibitor were applied to the cardiomyocytes, and vice versa. Results: Treatment with OSM induced dedifferentiation of cardiomyocytes, re-expression of fetal genes, and reduced contractile genes. Transcriptomic analyses confirmed the upregulation of immune responses, MAPK activity, and macrophage activation, as well as the downregulation of sarcomeric, contractile, cell cycle, and cardiac conduction genes. Trametinib and ulixertinib blunted these responses, but with distinct profiles. Both inhibitors suppressed OSM-induced fetal gene activation and partially preserved contractile function. However, ulixertinib did not block ERK phosphorylation, though it reduced p90RSK signaling downstream. In contrast, trametinib blocked MEK1/2 and ERK1/2 phosphorylation. OSM-stimulated A549 cells decreased cardiomyocyte beating frequency. Trametinib blunted this effect, whereas ulixertinib allowed partial recovery of contractility. Conclusion: We found that using OSM as a physiologic activator of MAPK signaling resulted in the mitigation of OSM-induced dedifferentiation and gene expression changes by both MEK and ERK inhibitors, while producing distinct transcriptomic and signaling signatures. Trametinib abolished beating completely in OSM-stimulated cardiomyocytes, whereas ulixertinib reduced beat frequency while preserving residual contractility. Cross-talk experiments recapitulated these contractility differences. These findings highlight the importance of balancing MAPK inhibition with cardiotoxic risk when using these agents in personalized cancer therapy. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany