<p>Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) and presents significant challenges during kidney transplantation. Due to the detrimental effects of IRI on kidney function and the lack of effective intervention strategies, we conduct a multi-omics study in male mice with surgically induced renal IRI, revealing a modulatory role for the metabolite S-adenosylmethionine (SAM) in AKI development. Our metabolic analysis of clinical samples establishes a link between various AKI conditions and marked elevations in serum SAM, underlying its potential as a biomarker for diagnosis. Furthermore, we find that short-term dietary methionine deprivation, which reduces circulating methionine and kidney SAM levels, effectively enhances renal resilience against IRI. In vivo isotopic tracing demonstrates that this diet preconditions kidney metabolic programs, enhancing glucose and fatty acid oxidation in preparation for IRI. Particularly, the activation of pyruvate dehydrogenase, which produces acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle, highlights an energy-efficient strategy of glucose metabolism that is essential for the protective effects of dietary methionine deprivation.</p><p></p>