Abstract: The invention relates to small molecule inhibitors of GPR68, useful as therapeutic agents in conditions benefitted from inhibition of GPR68, such as cancers and acute lung injuries. Selective inhibition of GPR68 caused robust cell death in glioblastoma cell lines, without toxicity, as well as death of other cancer cells, such as lung and pancreatic cancers. Synergistic benefits are achieved using combination treatment of GPR68 inhibitor compounds with radiation therapy or traditional chemotherapies for cancers. Thus, GPR68 inhibition enhances the therapeutic efficacy of ionizing radiation and chemotherapies. GPR68 inhibition is a therapeutic approach to induce ferroptosis in glioblastoma multiforme and other cancers, in a synergistic manner with ionizing radiation. Since ferroptosis is a form of immunogenic cell death, GPR68 inhibition represents an attractive approach to enhance cancer immunotherapies, including check-point inhibitors and cancer vaccines.