Sorbitol dehydrogenase induction of cancer cell necroptosis and macrophage polarization in the HCC microenvironment suppresses tumor progression.

Hepatocellular carcinoma (HCC) is among the most common malignant cancers worldwide, with an increasing incidence associated with an increase in deaths due to liver cancer. HCC is typically detected at an advanced stage in patients with underlying liver dysfunction, resulting in high mortality. The identification of HCC-specific targets represents a desired but unmet need for liver cancer treatment. To identify potentially novel HCC therapeutic targets, we performed a secretome analysis using HCC spheroids. Sorbitol dehydrogenase (SORD) was identified as uniquely enriched in the secretomes and lysates derived from HCC spheroids, and high SORD expression in HCC tissues was associated with favorable effects on overall survival among patients with liver cancer. We found that the introduction of excess SORD in HCC cells inhibited tumor growth and stemness by enhancing necroptosis signal and bypassing energy-yielding pathways through regulation of lactate dehydrogenase A (LDHA) expression and mitochondrial dynamics. Treatment with human recombinant SORD (hrSORD) controlled HCC cell growth and regulated macrophage polarization in the tumor microenvironment. These results demonstrate that SORD plays critical functional roles in HCC suppression through polyol pathway-independent mechanisms, suggesting that targeting SORD expression might represent a promising therapeutic strategy for liver cancer therapy.