Hexavalent chromium (Cr(VI)), the most toxic valence state of chromium, is widely present in industrial effluents and wastes. Although previous study has reported that Cr(VI) can cause cytomembrane structure impairment by aggravating lipid peroxidation in the heart, the detailed mechanism of Cr(VI)-induced heart dysfunction is still unclear. Sesn2, a novel antioxidant and stress-inducible molecule, is evidenced to protect against various cardiometabolic diseases such as atherosclerosis and cardiomyopathy. To define the potential mechanism of heart dysfunction induced by chronic Cr(VI) exposure, Wistar rats were intraperitoneal injected with potassium dichromate (KCrO) for 35 d in the present study. The data showed that chronic KCrO exposure caused dose-dependently hematological variations, oxidative stress, dysfunction, and disorganized structure of heart, cardiomyocyte apoptosis, ATP depletion, and mitochondria impairment in rats. In addition, the expressions of Drp1 and Bax were increased by KCrO. However, the suppression of Mfn2, PGC-1α, Sesn2, nuclear Nrf2, HO-1, and NQO1 protein levels was observed in KCrO-treated rat hearts. In conclusion, these results demonstrate that chronic KCrO exposure dose-dependently causes heart dysfunction, and the molecular mechanism of this event is associated with the loss of Sesn2 mediated mitochondrial function and energy supply impairment.Copyright © 2020 Elsevier Ltd. All rights reserved.