ABSTRACT In the US, 1.5 million people are affected by sepsis with a mortality of more than 250,000 annually. Each year over 35,000 Veterans are hospitalized with sepsis, and high rates of post-sepsis mortality and significant increases in healthcare facility use are reported among Veterans surviving sepsis. We propose a bioenergetic approach to develop a novel treatment strategy for sepsis. The transcription factor BTB and CNC homology 1 (BACH1) is a repressor of NRF2 function and has been shown to negatively regulate NRF2 binding to ARE sequences. Our recent studies show that, Bach1 deletion improves organ function and survival following polymicrobial sepsis induced by cecal ligation and puncture (CLP) with a concomitantly increased liver HO-1 expression. In this proposal, we will determine whether HO-1 is the mediator for the salutary effect seen in Bach1-/- mice, whether there are other critical genes regulated by BACH1 independent of NRF2, and whether transient modulation of BACH1 can improve organ function and survival in sepsis. The proposed research is relevant to that part of VA’s mission that pertains to better understand the causes of and develop or improve treatments for injuries and illnesses that afflict Veterans. The outcome of this research will be significant because the fundamental knowledge gained from this study is expected to advance methods to promote our Veteran’s healthy living.