Sult2a1, the sulfotransferase family 2A member 1, is a cytosolic sulfo-conjugating phase II enzyme [3,4]. It is highly expressed in the liver, intestine, and adrenal tissue [4]. Sult2a1 preferentially acts on hydroxysteroids like dehydroepiandrosterone, testosterone/dihydrotestosterone, pregnenolone, and cholesterol-derived amphipathic sterol bile acids [4]. It is also involved in sulfonating several therapeutic drugs and xenobiotics [4]. Multiple nuclear receptors, such as the vitamin D receptor (VDR), liver X receptor α (LXRα), and constitutive androstane receptor (CAR), mediate its transcription induction in the enterohepatic system [4,5,6].

In hepatocellular carcinoma (HCC), Sult2a1 deficiency promotes chemotherapy resistance, stemness maintenance, and activates the AKT signaling pathway, increasing the expression of downstream stemness gene c-Myc and NRF2 to reduce ROS accumulation [3]. Also, its knockdown promotes the proliferation and activation of hepatic stellate cells (HSCs), potentially remodeling the stroma [3]. In HCC, Sult2a1 levels are extremely downregulated, and it suppresses HCC metastasis by regulating the level of 27-hydroxycholesterol (27-OHC), which activates the NF-κB signaling pathway [2]. In CCl4-induced liver fibrosis in mice, mangiferin treatment inhibited the expression of Sult2a1 along with other fibrogenic and bile acid metabolism genes [1].

In conclusion, Sult2a1 plays a crucial role in the sulfonation of endogenous and exogenous compounds. Its study in mouse models, especially in relation to HCC and liver fibrosis, has revealed its significance in cancer metastasis, stemness, and fibrosis development. These findings provide potential targets for therapeutic intervention in related diseases.