Hypoxia‐Induced ADAM23 Drives Neuron–Tumor Crosstalk and Therapeutic Resistance in Hepatocellular Carcinoma

ABSTRACT Hypoxia and nutrient deprivation are fundamental drivers of tumor aggressiveness and therapeutic resistance in hepatocellular carcinoma (HCC). While the involvement of neural components in the tumor microenvironment (TME) is increasingly recognized, the molecular transducers linking metabolic stress to neuron–tumor crosstalk remain elusive. Here, we identify ADAM23 (A disintegrin and metalloproteinase 23) as a hypoxia‐responsive mediator that mediates communication between HCC cells and neuronal cells. ADAM23 expression was markedly upregulated in HCC cells under both chemical (CoCl 2 ) and physical hypoxia (1% O 2 ), a process further amplified by glucose deprivation and directly modulated by HIF‐1α. Functional assays revealed that ADAM23 overexpression promotes epithelial–mesenchymal transition (EMT) and enhances cell viability under metabolic stress. Notably, sorafenib‐resistant HCC cells (Huh7SR) exhibited high levels of ADAM23 secretion, which triggered proliferative and metabolic activation in neuronal SH‐SY5Y cells. In 3D co‐culture spheroid models, Huh7SR cells mixed with SH‐SY5Y cells displayed significantly larger spheroid volumes and enhanced neuronal fluorescence compared with parental controls, suggesting that ADAM23‐mediated interactions facilitate a supportive neural niche. Analysis of The Cancer Genome Atlas (TCGA) datasets and patient microarrays confirmed that ADAM23 is significantly overexpressed in HCC and positively correlates with HIF‐1α expression. Moreover, elevated expression of ADAM23 was significantly correlated with poor overall survival. Collectively, our findings underscore ADAM23 as a critical metabolic‐neural linker that promotes HCC progression and drug resistance. These findings suggest that the ADAM23‐mediated neuron–tumor axis may represent a potential therapeutic target in aggressive HCC.