Neutralization of the autophagy-repressive tissue hormone DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) for the treatment of hepatocellular carcinoma.

DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein), which is a major macroautophagy/autophagy-repressive protein, is emerging as a key player in hepatocellular carcinoma (HCC) pathogenesis through multifaceted roles that encompass both cell-intrinsic and -extrinsic mechanisms. Beyond promoting cancer cell proliferation, DBI/ACBP contributes to a pro-tumorigenic microenvironment by sustaining inflammation and impairing immunosurveillance. Experimental models of HCC, whether induced by oncogenes, hepatotoxins, or diet, consistently reveal that hepatocyte-specific knockout of , systemic mutation of the DBI/ACBP receptor, which is GABRG2 (gamma-aminobutyric acid type A receptor subunit gamma2), or antibody-mediated neutralization of DBI/ACBP attenuates tumor growth. Mechanistically, DBI/ACBP inhibition reduces fibrogenesis, and the accumulation of immunosuppressive T-cell subtypes while enhancing antitumor immune responses in the context of PDCD1/PD-1 blockade. Simultaneously, DBI/ACBP inhibition increases the expression of pro-ferroptotic genes and proteins while decreasing those that are anti-ferroptotic in the liver, thereby sensitizing HCC cells to ferroptosis- a form of cell death associated with autophagy. Clinically, elevated mRNA expression in tumors and circulating DBI/ACBP protein correlate with poor prognosis in HCC patients. Hence, targeting DBI/ACBP offers a promising strategy to disrupt the metabolic, inflammatory, and immunosuppressive networks driving HCC progression.