<p>Sepsis-associated acute kidney injury (SAKI) is the most common organ dysfunction in sepsis and a significant contributor to high mortality rates. Despite its clinical importance, the underlying pathogenesis of SAKI remains unclear, and effective therapies are currently lacking. This study aims to identify specific biomarkers for SAKI diagnosis by integrating bulk and single-cell RNA sequencing data from renal tissues in the SAKI model. We analyzed changes in mRNA/protein expression and cellular localization in kidney tissues affected by SAKI and confirmed that Hmox1 has potential as an indicator of proximal tubule (PT) injury in SAKI. Further validation across mouse models, and patient samples confirmed the role of Hmox1 in SAKI. Notably, we observed that Hmox1 high- and low-expressing PT cell subsets exhibit distinct phenotypes in SAKI. The Hmox1^hi PT cells are the principal cells undergoing injury and metabolic alterations, while Hmox1^low PT cells exert a major pro-inflammatory role through interactions with macrophages.</p>