AKR1C3 promotes bile acid production and contributes to the occurrence and development of liver cancer by upregulating HMG-CoA reductase

Abstract Objectives Among the large number of members in the aldo-keto reductase families, aldo-keto reductase family one member C3 (AKR1C3) has been identified as a key player in hepatocellular carcinoma (HCC) progression, yet the specific regulatory mechanisms are still being unraveled. We aimed to validate the effects of AKR1C3 on cholesterol and bile acid (BA) metabolism both in vivo and in vitro , and to investigate its novel mechanisms in HCC progression. Methods The differential expression of AKR1C3 in HCC and normal liver tissues was assessed using a public database and validated through cell experiments. The effects of AKR1C3 on liver cancer cell proliferation, migration, and invasion were verified using a cell counting kit-8 (CCK-8) assay, a plate clone formation experiment, and Transwell assays. The specific mechanism was predicted by RNA sequencing, and pathway proteins were validated by western blotting. Subcutaneous tumor formation experiments were used to confirm the effect of AKR1C3 on liver cancer proliferation in nude mice. Furthermore, the effect of AKR1C3 on lung metastasis was evaluated through the pulmonary metastasis model. Results AKR1C3 is overexpressed in liver cancer and is positively correlated with poor prognosis. HCC cells showed a marked reduction in both proliferative activity and metastatic potential (migration and invasion) after AKR1C3 knockdown. RNA sequencing suggested that AKR1C3 was involved in cholesterol and BA metabolism. Western blotting showed that AKR1C3 promoted the expression of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase (HMGCR) and cholesterol 7α-hydroxylase (CYP7A1). Subsequently, knocking down AKR1C3 decreased cholesterol and BA levels. In vivo experiments confirmed that AKR1C3 knockdown inhibits tumor growth, suppresses lung metastasis, and lowers cholesterol and BA levels. Conclusions AKR1C3 promotes cholesterol and BA synthesis through the HMGCR–CYP7A1 axes, thus accelerating liver cancer pathogenesis.