Nuciferine Suppresses Inflammatory Hepatocarcinogenesis by Targeting cPLA2-Dependent Arachidonic Acid Metabolism

Chronic inflammation is a hallmark of hepatocellular carcinoma (HCC) and is closely linked to aberrant arachidonic acid (AA) metabolism; however, whether AA mobilization is driven by defined upstream regulatory mechanisms and can be therapeutically targeted remains largely unresolved. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central regulator of AA-dependent inflammatory signaling in hepatocarcinogenesis and a direct pharmacological target of nuciferine (NF). Using diethylnitrosamine (DEN)/carbon tetrachloride (CCl₄)-induced HCC mouse models with transcriptomic and lipidomic profiling, we show that cPLA2 activation is progressively elevated during tumorigenesis, leading to excessive eicosanoid production that fuels NF-κB-driven inflammation. NF markedly suppresses tumor burden, fibrosis, and inflammatory signaling, accompanied by broad inhibition of AA metabolism. Mechanistically, NF directly binds to the C2 domain of cPLA2, disrupting Ca^{2 +}-dependent membrane translocation and attenuating its activation. Importantly, Pla2g4a deficiency significantly attenuates hepatocarcinogenesis and abolishes the therapeutic effects of NF, establishing cPLA2 as essential for its antitumor activity. In human HCC, increased cPLA2 activation correlates with increased AA metabolism, inflammatory signatures, and poor patient survival. These findings uncover cPLA2-dependent AA metabolism as a critical inflammatory axis in HCC and identify NF as a direct cPLA2-targeting agent, highlighting a pharmacologically actionable metabolic node for liver cancer therapy.