Oxidized phospholipids (oxPLs) were shown to be key players in the progression of numerous cardiovascular diseases including myocardial infarction, atherosclerosis, or cardiac ischemia reperfusion injury. However, the oxidized phospholipid-induced signaling mechanisms causing cardiac dysfunction remain elusive. We tested the hypothesis that oxPLs impact metabolism in cardiomyocytes and explored the involved signaling pathways. In vitro, treatment of h9c2 cardiomyocytes with a mixture of oxidized phosphatidylcholines (oxPAPC) led to activation of a mitogen-activated protein kinase (MAPK) pathway, namely phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2). Moreover, oxPAPC induced the expression of regulatory enzymes associated with the pentose phosphate pathway (PPP), such as PGD, G6PD, TALDO1, as well as genes connected to Nrf2-dependent oxidative stress, like HMOX-1. Metabolically, oxPAPC significantly reduced basal respiration and maximal oxygen consumption rate, as well as glycolytic capacity in h9c2 cardiomyocytes, as measured using a Seahorse extracellular flux analyzer. Treatment with a MEK inhibitor (PD98059, 10μM) resulted in a partial rescue of basal respiration and maximal oxygen consumption rate after incubation with oxPAPC. On the other hand, p38 inhibition (SB203580, 10μM) resulted in a change of oxPAPC-induced gene expression of PPP regulatory enzymes and HMOX-1. Ongoing studies including RNA-sequencing and pathway analysis will further explicate the scope of oxPL-induced gene expression and the involved mechanisms. In vivo , AAV8-mediated expression of the oxPL-recognizing scFv-E06 in albumin cre mice that had been fed a high fat high sucrose diet for 12 weeks, resulted in decreased expression of genes associated with GO Terms “glutathione metabolism” compared to AAV-GFP expressing counterparts, in their hearts. In summary, our study provides evidence that oxPLs significantly influence cardiomyocyte metabolism towards a redox-regulatory phenotype accompanied by the inhibited glycolysis and the decrease in oxidative phosphorylation by activating MAPK pathways. Future experiments will elucidate the relationship between MAPK signaling induced by oxPLs and cardiac dysfunction.