GABRD promotes hepatocellular carcinoma progression via the IL-10RA/JAK2-STAT3 signaling axis.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, primarily owing to its capacity of metastasis, underscoring the urgent need to identify novel drivers of HCC progression. While neurotransmitter receptors are increasingly recognized as regulators of tumor biology, the role of the gamma-aminobutyric acid type A receptor delta subunit (GABRD) in HCC remains unexplored. Here, we show that GABRD is significantly upregulated in HCC tissues and cell lines, and high expression of GABRD correlates with poor prognosis in HCC patients. Loss- and gain-of-function studies demonstrated that GABRD promotes HCC cell proliferation, invasion, and migration in vitro, and accelerates tumor growth in both subcutaneous xenograft and spontaneous HCC models in vivo. Mechanistically, we find that GABRD physically interacts with the interleukin-10 receptor alpha subunit (IL-10RA). This interaction orchestrates the activation of the JAK2-STAT3 signaling axis, driving epithelial-mesenchymal transition (EMT). Inhibition of JAK2-STAT3 and IL-10RA partially reverses the tumorigenic effects of GABRD. Our study establishes the GABRD-IL-10RA-JAK2-STAT3 axis as a critical oncogenic driver in HCC and identifies GABRD as a promising therapeutic target for improving HCC outcomes.