The Paleocene–Eocene thermal maximum (PETM), a transient period of global warming, is considered to be an important analog for future greenhouse conditions. It was accompanied by a significant carbon cycle perturbation. Although ocean deoxygenation across the PETM is reported widely, its mechanism in the open ocean remains uncertain. Here, we present magnetic and geochemical analyses of sediments from the eastern equatorial Pacific Ocean. We found that iron fertilization during the PETM by eolian dust and volcanic eruptions fueled eastern equatorial Pacific Ocean productivity. This process led to increased organic matter degradation and oxygen consumption in intermediate waters, leading to deoxygenation. Our findings suggest that iron fertilization could be an important driver of open-ocean oxygen loss, as a side effect of global warming.

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