Autophagy | DBI/ACBP Neutralization Strategy Treats Hepatocellular Carcinoma by Regulating Autophagy, Ferroptosis, and the Immune Microenvironment

This study reveals multiple pro-tumorigenic mechanisms of DBI/ACBP in hepatocellular carcinoma (HCC), providing new combinatorial intervention strategies to overcome resistance to HCC immunotherapy, suggesting that targeting DBI/ACBP could be a potential approach to enhance the efficacy of PD-1 blockade.

 

Literature Overview

The article titled 'Neutralization of the autophagy-repressive tissue hormone DBI/ACBP for the treatment of hepatocellular carcinoma,' published in the journal Autophagy, systematically investigates the central role of DBI/ACBP in the development and progression of hepatocellular carcinoma (HCC). The study reveals that this protein not only promotes tumor cell proliferation by inhibiting autophagy but also affects therapeutic responses through regulation of the immune microenvironment and ferroptosis pathways. These findings expand our understanding of metabolic-immune crosstalk in HCC and provide a theoretical basis for developing novel therapeutic strategies.

Background Knowledge

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with a complex pathogenesis involving intrinsic genetic mutations in hepatocytes, metabolic reprogramming, and extrinsic chronic inflammation and immunosuppressive microenvironments. Currently, immune checkpoint inhibitors (such as anti-PD-1/PDCD1) have shown efficacy in some HCC patients, but overall response rates remain limited, and most patients exhibit primary or acquired resistance. This suggests that other immunosuppressive factors within the tumor microenvironment may synergistically suppress anti-tumor immunity. DBI/ACBP, a tissue hormone that represses autophagy, has been reported to participate in steatosis and fibrosis in non-malignant liver diseases, but its role in HCC remains incompletely understood. Research has found that DBI/ACBP is overexpressed in HCC and promotes tumor progression by binding to its receptor GABRG2 and inhibiting autophagy. Additionally, DBI/ACBP may shape an immunosuppressive microenvironment by regulating immune cell subsets such as Treg and TH17 cells. Therefore, targeting DBI/ACBP may break immune tolerance and enhance the efficacy of PD-1 blockade, representing a promising new strategy to overcome immunotherapy resistance.

 

 

Research Methods and Experiments

The authors employed multiple HCC mouse models, including oncogene-driven, hepatotoxin (e.g., DEN)-induced, and high-fat-diet-induced liver cancer models. They systematically evaluated the impact of DBI/ACBP neutralization on tumor growth through hepatocyte-specific dbi gene knockout, GABRG2 receptor mutation, or treatment with anti-DBI/ACBP monoclonal antibodies. Spatial transcriptomics and immunofluorescence techniques were used to analyze changes in the tumor immune microenvironment and assess the proportions of T cell subsets such as Treg, TH17, and CTL. qPCR and Western blot were performed to examine the expression levels of ferroptosis-related genes (e.g., ACSL4, GPX4) and evaluate HCC cell sensitivity to ferroptosis inducers. Clinically, the relationship between DBI mRNA expression and patient prognosis was analyzed using databases such as TCGA, and plasma levels of DBI/ACBP protein in HCC patients were measured by ELISA to validate its potential as a biomarker.

Key Conclusions and Perspectives

• Hepatocyte-specific deletion of dbi or treatment with anti-DBI/ACBP antibodies significantly suppresses HCC tumor growth, indicating that DBI/ACBP is a viable therapeutic target in HCC
• Neutralization of DBI/ACBP activates autophagy and inhibits the AKT-MTORC1 pathway, leading to cell cycle arrest and inhibition of tumor cell proliferation
• The DBI/ACBP-GABRG2 signaling axis maintains its own expression via a PPARG-mediated positive feedback loop, forming a pro-tumorigenic positive circuit
• DBI/ACBP neutralization reduces hepatic fibrosis and inflammation, decreases infiltration of immunosuppressive T cells such as Treg, TH2, and TH17, and increases the CTL/Treg ratio, thereby reshaping the anti-tumor immune microenvironment
• Combining anti-DBI/ACBP antibodies with anti-PD-1 therapy significantly enhances anti-tumor efficacy, independent of changes in PD-L1 expression, suggesting it boosts immune responses through mechanisms distinct from classical checkpoints
• DBI/ACBP suppresses ferroptosis; its neutralization upregulates pro-ferroptotic genes (e.g., ACSL4) and downregulates anti-ferroptotic genes (e.g., GPX4), making HCC cells more susceptible to clearance by ferroptosis inducers
• Clinical data show elevated levels of DBI/ACBP in both tumor tissues and plasma of HCC patients, significantly correlating with tumor size, vascular invasion, AFP levels, and poor prognosis, supporting its value as a prognostic biomarker and therapeutic target

Research Significance and Prospects

This study systematically elucidates the multifaceted pro-tumorigenic roles of DBI/ACBP in HCC, linking three key processes—metabolic regulation (autophagy, lipid metabolism), cell death (ferroptosis), and immune escape—providing a novel target for comprehensive HCC therapy. Targeting DBI/ACBP can not only directly inhibit tumor cell proliferation but also reverse the immunosuppressive microenvironment and enhance the efficacy of PD-1 blockade, demonstrating significant clinical translational potential. Moreover, its detectability in plasma makes it a potential non-invasive biomarker for patient stratification and treatment response monitoring.

 

 

Conclusion

This study establishes DBI/ACBP as a pivotal molecular node in the treatment of hepatocellular carcinoma, driving HCC progression through inhibition of autophagy, promotion of immune escape, and suppression of ferroptosis. Neutralizing DBI/ACBP not only effectively inhibits tumor growth in multiple HCC models but also significantly enhances the efficacy of anti-PD-1 immunotherapy, offering a new strategy to overcome current immunotherapy resistance. Clinical data further support the value of DBI/ACBP as both a prognostic biomarker and a therapeutic target. From bench to bedside, targeting DBI/ACBP is poised to become an integral part of comprehensive HCC management, particularly for patient populations with high expression of this protein. Future research should advance the clinical development of anti-DBI/ACBP antibodies and explore their combination with existing therapies (e.g., immune checkpoint inhibitors, targeted drugs) to improve overall survival in HCC patients. This discovery lays a solid foundation for building a precision medicine framework based on DBI/ACBP expression levels and holds promise for reshaping the therapeutic landscape of liver cancer.

 

Sijing Li, Flavia Lambertucci, Isabelle Martins, Maria Chiara Maiuri, and Guido Kroemer. Neutralization of the autophagy-repressive tissue hormone DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) for the treatment of hepatocellular carcinoma. Autophagy.