Cancer is defined as a systematic metabolic dysfunction disease [
1]. Lipid metabolism is activated and significantly upregulated during cancer development and progression, providing energy and material for cancer cell proliferation and metastasis [
2]. Therefore, reprogrammed lipid metabolism is seen as a new hallmark of cancer malignancy, and targeting this pathway has become a promising cancer therapeutic strategy [
3‐
5].
Cancer cells obtain lipids mainly through de novo lipid synthesis and uptake, which are both activated [
6,
7]. Lipids are sequentially synthesized by a series of enzymes. ATP citrate lyase (ACLY) converts citrate into acetyl-CoA, whose conversion to malonyl-CoA is catalyzed by acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN) catalyzes palmitate synthesis from malonyl-CoA. Stearoyl-CoA desaturase-1 (SCD1) produces monounsaturated fatty acids from saturated fatty acids. In addition to de novo lipid synthesis, fatty acid uptake from the exogenous environment is essential in cancer cells. Lipid uptake occurs mainly through the membrane glycoprotein CD36, which binds fatty acids and transports them into the cells [
8]. Several proteins regulate the lipid metabolism pathway. For instance, SREBP is a direct master regulator of lipid synthesis enzyme expression, including ACLY, ACC1, and FASN, which thereby enhances de novo lipid synthesis. The Myc oncoprotein can synergistically enhance lipid synthesis via SREBP [
9]. Liver X receptor, pregnane X receptor, and peroxisome proliferator-activated receptor γ regulate CD36 [
10]. Overexpression of enzymes and regulators involved in the lipid metabolic pathway has been reported in cancer, correlating with the clinical outcomes of cancer patients. ACLY is overexpressed in patients with hepatocellular carcinoma (HCC), indicating shorter overall survival (OS), compared with low ACLY levels [
11,
12]. SB-204990, an ACLY inhibitor, has shown anticancer effects in vivo [
5,
7]. FASN is highly expressed in lung cancer, and its expression is negatively correlated with the clinical outcomes of HCC patients [
13]. The FASN inhibitor TVB-2640 has been used to treat non-small cell lung cancer and colon cancer in clinical studies [
14]. SCD1 inhibition prevents HCC [
15]. Furthermore, anti-CD36 antibodies have shown a significant antimetastatic effect in oral cancer xenograft models [
16]. SREBP1 overexpression has been observed in various human cancers, and its specific inhibitor 25-hydroxycholesterol suppresses cancer cell migration and proliferation [
6,
17]. However, inhibitors targeting lipid synthesis or uptake alone cannot fully inhibit cancer progression. As cancer cells acquire fatty acids primarily through de novo synthesis and uptake, targeting both lipid synthesis and uptake is a promising anticancer strategy. However, the regulatory factors targeting both lipid synthesis and uptake have not been clearly studied. Therefore, it is urgent to explore these regulators.
MiRNAs are small non-coding RNAs containing approximately 22 nucleotides that regulate gene expression, and they have been reported as key lipid metabolism regulators. MiR-4310 inhibits lipid synthesis by suppressing FASN and SCD1, thus suppressing HCC growth and metastasis [
18]. MiR-192-5p regulates lipid synthesis in nonalcoholic fatty liver disease through SCD-1 [
19]. MiR-195 inhibits proliferation, invasion, and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA, and CYP27B1 [
20]. MiR-758-5p regulates cholesterol uptake by targeting the CD36 3’-UTR [
21]. MiR-9 directly targets the 3’-UTR of cholesterol acyltransferase, an enzyme that converts cholesterol into cholesterol esters for storage along with triglycerides in the cores of cytosolic lipid droplets [
22]. However, miRNAs that target both lipid synthesis and transport pathways have not been investigated.
In this study, we found that miR-3180 inhibits both de novo lipid synthesis and uptake by targeting SCD1 and CD36. Further investigation indicated that miR-3180 inhibits HCC cell proliferation, migration, invasion, and metastasis in vitro and in vivo in a lipid synthesis- and uptake-dependent manner. Therefore, miR-3180 plays an important role in HCC development and progression and may be a promising target for HCC therapy.