Inflammatory bowel diseases (IBD) are diseases of intestinal epithelial cell (IEC) death and mucosal damage. High mobility group box 1 (HMGB1) is a multifunctional protein whose intracellular expression is decreased in IEC from active IBD lesions. During microbial stress, intracellular HMGB1 regulates the cellular autophagy/apoptosis checkpoint to promote cell survival. Thus, HMGB1-regulated cell survival pathways represent potential therapeutic targets for this disease.,In this study, treatment of primary IEC (enteroids) with the bacterial components muramyl dipeptide (MDP), lipopolysaccharide (LPS), flagellin (FLA), lipoteichoic acid (LTA) or the bacteria DNA CpG-ODN increased HMGB1 protein levels. However, these same microbial stimuli activated apoptosis in HMGB1-deficient cells. Treatment with MDP likewise increased ATP production and Akt phosphorylation in wild type, but not HMGB1-deficient cells. We utilized this model of HMGB1-deficient enteroids to screen the Prestwick Chemical Library for drugs with the capacity to increase ATP production during MDP-induced cellular stress. The goal was to identify drugs that could increase survival of HMGB1-deficient IEC during microbial stress, a model of the mucosal epithelium of patients with active IBD. Nineteen drugs satisfied screening criteria for increased ATP production. One candidate drug, lovastatin was investigated further and found to restore Akt phosphorylation and autophagy in MDP-stressed HMGB1-deficient cells. Therefore, we developed a novel drug screening and validation pipeline to rapidly identify existing drugs or novel compounds that potentially preserve IEC functions and survival during IBD. This pipeline and the drugs identified through the screening could provide new opportunities for IBD therapies that improve patient outcomes while minimizing side effects related to immunosuppression.