Metabolic adaptation is an integral part of the organismal stress-response. In this study, we investigate the role of Hmox1 in mediating metabolic adaptation under both physiological and hemolytic stress conditions. Using an inducible Hmox1 deletion model (Hmox1^R26Δ/Δ), we demonstrate that Hmox1 expression is essential for preventing heme-induced kidney failure. Our integrative approach, combining bulk RNA sequencing and targeted metabolomics with in silico metabolic modeling, revealed a compromised pentose phosphate pathway (PPP) in failed renal adaptation after Hmox1 deletion. This study underscores the critical role of Hmox1 for PPP regulation and sheds light on the metabolic pathways involved in kidney dysfunction due to hemolytic diseases.