Objective: The aldo-keto reductase (AKR) superfamily catalyzes the NAD(P)H-dependent reduction of aldehydes to less reactive alcohols, playing a critical role in detoxification and cellular redox homeostasis. AKR family members have been increasingly implicated in tumor progression across various cancers. However, the functional role and mechanism of AKR7A2 in hepatocellular carcinoma (HCC) progression remain poorly understood. Here, we identified an essential role of AKR7A2 in HCC progression.

Materials and Methods: The expression of AKR7A2 was analyzed in HCC tissues and human cell line models via immunohistochemistry (IHC) and Western blotting. The influence of AKR7A2 on HCC proliferation, migration, and invasion was assessed through CCK-8, colony formation, and Transwell assays. Potential molecular mechanisms were explored through bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases.

Results: We found that AKR7A2 expression was upregulated and significantly associated with poor prognosis. Elevated AKR7A2 expression was also linked to resistance to radiotherapy and sorafenib treatment. Knockdown of AKR7A2 suppresses HCC cell proliferation, migration, and invasion. Bioinformatics analysis further demonstrated that expression of AKR7A2 was positively correlated with oxidative phosphorylation (OXPHOS), mitochondrial biogenesis, PPARG expression, and tumor-associated macrophage polarization.

Conclusions: Taken together, our results indicate that AKR7A2 promotes HCC cell proliferation, migration, and invasion through PPARG-mediated OXPHOS and tumor-associated macrophage polarization. Therefore, AKR7A2 represents a promising therapeutic target for the treatment of HCC.