Xiaofeng Ma

Fatty acid synthase (FASN), a critical enzyme involved in lipid biosynthesis, is highly expressed in adipocytes and exhibits aberrant activity in diverse human cancers. Phloretin, a natural dihydrochalcone abundant in apple peels, crabapples, strawberries, and pears, has emerged as a potential modulator of FASN activity. This study investigates phloretin’s inhibitory effects on FASN and the underlying mechanisms. Biochemical assays revealed that phloretin inhibited FASN in a dose-dependent manner, with a half-maximal inhibitory concentration (IC₅₀) of 4.90 ± 0.66 μM. Kinetic analysis demonstrated distinct inhibition patterns: competitive inhibition against acetyl-CoA, mixed competitive/noncompetitive inhibition toward malonyl-CoA, and uncompetitive inhibition relative to NADPH. Molecular docking simulations further indicated that phloretin binds to the β-ketoacyl synthase (KS) domain of FASN, suggesting a mechanism distinct from that of typical flavonoid inhibitors. Notably, phloretin exhibited irreversible inhibition of FASN, in contrast with the inhibition observed for other flavonoids. To validate the cellular relevance, we demonstrated that phloretin suppressed FASN expression and enzymatic activity in breast cancer cells, concomitant with significant reductions in intracellular triglyceride (TG) accumulation and cancer cell viability. Although adipocytes were not studied in this work due to the long differentiation period required, future studies are planned to investigate FASN inhibition in adipogenesis models. Given FASN’s dual role as a therapeutic target in obesity and oncogenesis, these findings highlight phloretin’s translational potential as a multitarget agent for metabolic and neoplastic disorders. The well-characterized inhibition mechanism of phloretin, combined with its dual capacity to suppress lipogenesis and inhibit proliferation, establishes this natural compound as a compelling candidate for advanced preclinical evaluation in therapeutics for metabolic disorders.

Fatty acid synthase (FASN) is frequently overexpressed in human breast cancer and has emerged as a potential therapeutic target. Resveratrol has been shown to inhibit FASN activity in vitro through both fast-reversible and slow-irreversible mechanisms. In this study, resveratrol reduced intracellular fatty acid levels by inhibiting FASN activity and downregulating its expression across various breast cancer subtypes, including SK-BR-3, MCF-7, and MDA-MB-231 cells. Knockdown of FASN via small interfering RNA (siRNA) further enhanced resveratrol-induced cytotoxicity. Resveratrol significantly suppressed cell viability and triggered apoptosis, as evidenced by increased cleavage of poly(ADP-ribose) polymerase (PARP) and disruption of Bcl-2 family protein balance. Furthermore, resveratrol inhibited key signaling pathways involved in cell proliferation and survival, notably FAK, AKT, and ERK1/2. FASN silencing by siRNA also modulated the activation states of these signaling proteins. Collectively, these findings support resveratrol as a promising anti-cancer candidate that induces apoptosis in diverse breast cancer subtypes via FASN inhibition.

Fatty acid synthase (FASN) is highly expressed in multiple types of human cancers and is recognized as one of the targets for treating cancer metastasis. α-Linolenic acid is an omega-3 essential fatty acid and it possesses various biological activities. The present study was designed to reveal the effects of α-linolenic acid on osteosarcoma and to reveal whether the mechanism of α-linolenic acid in anticancer activity may be related to FASN inhibition. The cytotoxicity of α-linolenic acid was assessed in osteosarcoma MG63, 143B, and U2OS cells. Cell viability was detected by the MTT assay. The protein expression level was detected by western blotting. Flow cytometry, Annexin V/propidium iodide dual staining, and Hoechst 33258 staining were performed to assess the apoptotic effects. Wound healing assay was applied to detect the inhibitory effect of α-linolenic acid on osteosarcoma cells migration. The results showed that α-linolenic acid downregulated FASN expression. α-Linolenic acid inhibited osteosarcoma cell proliferation and migration in a dose-dependent manner. In addition, α-linolenic acid regulated endoplasmic reticulum transmembrane receptors and signal protein expression in osteosarcoma cells. The findings of the present study suggested that α-linolenic acid suppresses osteosarcoma cell proliferation and metastasis by inhibiting FASN expression, which provides a basis as a potential target for osteosarcoma treatment.

Acer truncatum Bunge is now widely cultivated throughout the world. Fatty acid synthase (FAS) is a potential target in the treatment of both obesity and cancer. Only a few FAS inhibitors have been reported. In this study, the inhibitory effect of A. truncatum seed coat (ESA) on FAS and the inhibition mechanisms were investigated using a FAS activity assay and an enzyme kinetics study. The main chemicals of ESA were analyzed with UPLC-MS/MS. The effects of ESA on 3T3-L1 adipocyte differentiation and lipid accumulation were investigated using Oil red O staining. We first identified seven main compounds (quinic acid, malic acid, gentisic acid, procyanidin dimer, procyanidin trimer, catechin, and quercetin) from 50% ethanol extracts of seed coats of A. truncatum (ESAs), which were then found to inhibit 3T3-L1 adipocyte differentiation at the concentration of 50 μg/mL. ESA obviously reduced the visible triglyceride droplets accumulation, and dramatically decreased the number of the adipocytes at a comparatively high concentration. It is suggested that the effects are due to the inhibition of FAS by ESA; FAS activity is inhibited by ESA at a half inhibition concentration (IC₅₀) of 0.57 μg/mL, which is lower than that of classically known FAS inhibitors. Meanwhile, ESA displayed different inhibition kinetics and reacting sites for FAS. These results provide new clues for the development of novel products for obesity treatment and a scientific basis for the full use of byproducts for future industrial production of vegetable oil.

Background/Aims: Fatty acid synthase (FASN) is a multi-enzyme complex that synthesizes endogenous fatty acids. The overexpression of FASN has been reported in variety of cancers, including breast, ovarian, prostrate, and colon cancers, which strongly indicates the involvement of FASN in cancer progression. α-Linolenic acid (ALA) has many biological activities, including anti-cancer effects. The aim of the present study was to investigate the inhibitory effect of ALA on fatty acid synthesis pathway and apoptosis of human breast cancer cells. Methods: Cytotoxicity of ALA in human breast cancer cells (MDA-MB-231 and MCF-7 cells) was assessed by MTT assay. Changes in protein expression were detected by immunoblot analysis. Cell migration was detected by wound healing and cell transwell assay. Apoptotic effects, mitochondrial membrane potential and cell cycle analysis were detected by flow cytometry. Molecular docking was carried out with the AutoDockTools program suite to analyze the binding abilities of ALA on thioesterase (TE) domain of FASN. Results: We found that the expression levels of FASN decreased significantly in ALA treated breast cancer cells. Compared with palmitic acid (PA), ALA reduced cell viability in a dose-dependent manner. ALA showed a higher affinity with the TE domain than PA. ALA induced breast cancer cells apoptosis, which effects were similar with the knockdown of FASN. In addition, ALA inhibited the invasion and metastasis, and arrested cell cycle in breast cancer cells. Conclusion: We propose a hypothesis that ALA could contribute to the treatment of human breast cancer by inhibiting FASN.

One of the most important metabolic hallmarks of breast cancer cells is enhanced lipogenesis. Increasing evidences suggest that fatty acid synthase (FAS) plays an important role in human breast cancer. Previously we discovered that alpha-mangostin showed apoptotic effect on human breast cancer cells via inhibiting FAS activity. The endoplasmic reticulum (ER) stress and autophagy are involved in cell apoptosis. However, the role of ER stress and autophagy in FAS inhibition induced apoptosis still remains unclear. We evaluated the effects of alpha-mangostin on ER stress and autophagy in human breast cancer cells. Intracellular FAS activity was measured by a spectrophotometer at 340 nm of NADPH absorption. Cell Counting Kit assay was used to test the cell viability. Immunoblot analysis was performed to detect protein expression levels. Apoptotic effects were detected by flow cytometry. Alpha-mangostin induced endoplasmic reticulum stress and autophagy, both of which reduced the apoptotic effect of alpha-mangostin in MDA-MB-231 cells. Palmitic acid, the end product of FAS catalyzed reaction, rescued the ER stress and autophagy induced by alpha-mangostin. Cell apoptosis was markedly promoted by inhibiting ER stress and autophagy while treating cells with alpha-mangostin. We propose a hypothesis that a combination of FAS inhibition and ER stress and autophagy inhibition has an application potential in the chemoprevention and treatment of breast cancer.

Breast cancer is one of the most common cancers and the second leading cause of cancer mortality in women worldwide. Novel therapies and chemo-therapeutic drugs are still in urgent need to be developed for the treatment of breast cancer. One of the most important metabolic hallmarks of breast cancer cells is enhanced lipogenesis. Increasing evidences suggest that fatty acid synthase (FAS) plays an important role in the development of human breast cancer, for the expression of FAS is significantly higher in breast cancer cells than in normal cells. In addition, FAS inhibitors, such as curcumin, ursolic acid, and resveratrol, have shown anti-cancer potential. In the present study, we discovered that vitisin B, a natural stilbene isolated from the seeds of Iris lactea Pall. var. chinensis (Fisch.), was a novel FAS inhibitor. We found that vitisin B could down-regulate FAS expression and inhibit intracellular FAS activity in MDA-MB-231 cells. Also, we reported for the first time that vitisin B exhibited apoptotic effect on human breast cancer cells. Given all of this, we proposed a hypothesis that vitisin B has an application potential in the chemoprevention and treatment of breast cancer.

High levels of fatty acid synthase (FAS) expression have been found in many tumors, including prostate, breast, and ovarian cancers, and inhibition of FAS has been reported to obstruct tumor growth in vitro and in vivo. Curcumin is one of the major active ingredients of Curcuma longa, which has been proven to inhibit the growth of cancer cells. In the present study, we investigated the potential activity of curcumin as a FAS inhibitor for chemoprevention of breast cancer. As a result, curcumin induced human breast cancer MDA-MB-231 cell apoptosis with the half-inhibitory concentration value of 3.63 ± 0.26 µg/ml, and blocked FAS activity, expression and mRNA level in a dose-dependent manner. Curcumin also regulated B-cell lymphoma 2 (Bcl-2), Bax and p-Akt protein expression in MDA-MB-231 cells. Moreover, FAS knockdown showed similar effect as curcumin. All these results suggested that curcumin may induce cell apoptosis via inhibiting FAS.