Targeting DDOST improves the efficacy of lenvatinib and immunotherapy in hepatocellular carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options.
• Drug resistance and poor survival benefit hinder current HCC therapies.
• The role of Dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST) in HCC remains largely unknown.

Purpose of the Study:

• To investigate the role and therapeutic potential of DDOST in hepatocellular carcinoma.
• To elucidate the mechanism by which DDOST influences HCC progression and drug response.
• To evaluate the efficacy of targeting DDOST in combination with existing therapies.

Main Methods:

• Analysis of DDOST expression in HCC tissues and correlation with patient prognosis.
• In vitro and in vivo functional studies involving DDOST knockdown.
• Investigation of DDOST's impact on EGFR and PD-L1 glycosylation and downstream signaling pathways (AKT, ERK5, ERK1/2).
• Evaluation of the OST inhibitor NGI-1 and NGI-1-loaded nanoparticles as therapeutic agents.

Main Results:

• DDOST expression is upregulated in HCC and associated with poor prognosis.
• DDOST knockdown inhibits HCC cell proliferation, induces cell cycle arrest, and enhances lenvatinib sensitivity.
• DDOST depletion impairs EGFR N-glycosylation, suppresses AKT, ERK5, and ERK1/2 signaling, and reduces PD-L1 glycosylation.
• The OST inhibitor NGI-1 demonstrates antitumor effects and potentiates lenvatinib and immunotherapy efficacy.

Conclusions:

• DDOST is a key driver of HCC progression and chemoresistance.
• Targeting DDOST represents a promising therapeutic strategy for improving HCC treatment outcomes.
• Combined inhibition of DDOST with lenvatinib or immunotherapy may overcome treatment resistance in HCC.