Sult2a1, the sulfotransferase family 2A member 1, is a phase II conjugating enzyme [2,3]. 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 involved in sulfonation processes, which can impact the metabolism of endogenous compounds and xenobiotics [3,4,5,6,7]. Nonsteroid nuclear receptors such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor-alpha, and vitamin D receptor mediate its transcription [4].

In hepatocellular carcinoma (HCC), Sult2a1 deficiency promotes chemotherapy resistance and stemness maintenance by activating the AKT signaling pathway, increasing c-Myc expression, facilitating NRF2 expression to reduce ROS accumulation, and knockdown of NR1I3 is involved in its transcriptional regulation in stemness maintenance. Also, Sult2a1 knockdown HCC cells promote the proliferation and activation of hepatic stellate cells, exerting a potential stroma remodeling effect [3]. In addition, the expression of Sult2a1 is extremely downregulated in human HCC tissues, and gain-and loss-of-function studies reveal that Sult2a1 suppresses the metastasis of HCC by regulating the level of 27-hydroxycholesterol (27-OHC), and Sult2a1-dependent alternation of 27-OHC activates the NF-κB signaling pathway to promote HCC metastasis [2]. Moreover, in CCl4-induced liver fibrosis in mice, mangiferin inhibits the expression of Sult2a1 along with other genes, alleviating liver fibrosis [1].

In conclusion, Sult2a1 is crucial for the sulfonation of various compounds, playing important roles in metabolism. In the context of liver-related diseases, especially HCC and liver fibrosis, studies on Sult2a1 knockout or knockdown models have revealed its significance in processes like cancer metastasis, stemness maintenance, and fibrosis alleviation, providing potential insights for therapeutic strategies [1,2,3].