Multi-omics dissection of RAD21-PON1 axis reveals metabolic-immune crosstalk and prognostic significance in hepatocellular carcinoma.

RAD21, a key cohesin subunit, participates in chromatin regulation and may influence tumor metabolism and immunity. Its role in liver HCC remains unclear. We investigated whether RAD21 regulates PON1 and how this axis integrates metabolic and immune signals in HCC. Multi-omics integration (transcriptomic, ChIP-seq, and scRNA-seq) datasets to identify the RAD21-PON1 regulatory axis, with immune infiltration, metabolic remodeling, and prognostic impact assessed via GSVA, TIDE, and LASSO modeling. RAD21 upregulation inversely correlated with PON1 expression. RAD21 binds the promoter of PON1, impacting metabolic pathway activity and shaping the immune microenvironment. Low PON1 expression was linked to immunosuppressive patterns and poor prognosis. A RAD21-PON1 risk signature robustly stratified survival. Our findings highlight the RAD21-PON1 axis as a central regulator connecting metabolism and immunity in HCC, providing prognostic and therapeutic insights.