Cancer is a general term for various disorders in which aberrant cells multiply and spread out of control. Cancer is one of the world's major causes of death, with an estimated 10 million deaths in 2020 [1]. The most diagnosed cancer among women is breast cancer (BC), with 2.26 million cases diagnosed each year. Hence, BC roughly accounts for one out of ten new cancer diagnoses worldwide, surpassing lung cancer. In addition, BC is the second leading cause of cancer death among women worldwide [2].

Breast cancer is divided into four primary categories based on distinct gene expressions that encode for hormone receptor status: estrogen receptor-positive (ER+) BC, including luminal types A and B, triple-negative/basal-like (TNBC), and HER-2 enriched molecular subtypes. The ER+ molecular subtypes account for approximately three-quarters of all BC cases [3]. Endocrine therapy, specifically tamoxifen (TAM), is the most often used treatment for ER+ BC, but its use has been limited due to the development of endocrine resistance[4]. More than half of advanced ER+ BC cases are intrinsically resistant to TAM, with another 40 % developing resistance during treatment [5]. Diverse mechanisms, including metabolic reprogramming, were involved in implementing TAM resistances [5], [6], [7].

Reprogramming of cellular metabolism is a well-recognized cancer characteristic nowadays. Changes in lipid metabolism, also known as "lipid metabolic reprogramming," can affect cellular processes such as cell cycle, proliferation, growth, differentiation, and the structural foundation of biological membranes, ultimately leading to carcinogenesis [8]. In malignancies, including BC, alterations in lipid metabolism, such as de novo lipogenesis, have reduced responses to traditional chemotherapies and targeted therapies [5], [9]. Besides, while most normal cells get most of their lipids from circulation, it's well-known that cancer cells assemble a significant portion of their lipids from de novo lipogenesis [10].

Increased de novo lipogenesis is particularly caused by overexpression of ATP citrate lyase (ACLY), a crucial enzyme that catalyzes the initial step of lipogenesis and connects aerobic glycolysis to FA synthesis, which is greatly activated in several types of malignancies, including BC [11], [12]. Besides, Zhang et al. indicated that the ACLY was overexpressed in TAM-resistant BC cells than sensitive and might be associated with TAM resistance and could serve as therapeutic targets in BC resistant to tamoxifen [13]. Also, another study indicated that targeting lipid-related enzymes could improve response to treatment in cancer, and they could be used as a target for cancer treatment [14]. ACLY inhibition, either genetically or pharmacologically, significantly reduces tumor growth [15]. According to our previous research, the inhibition of ACLY by hydroxycitric acid (HCA), the herb-derived component, potentiates the effect of TAM against sensitive BC cells [16].

Hydroxycitric acid is a derivative of citric acid, and it is the main acid of plant species native to South Asia, such as Garcinia cambogia, Garcinia indica, and Garcinia atroviridis family Clusiaceae (=Guttiferae); it is a potential metabolic regulator [17], [18]. Thus, HCA is usually sold as a weight-loss supplement either alone or in combination with other supplements. HCA exhibited anti-obesity activity, including reduced food intake and body fat gain by increased fat oxidation and decreased de novo lipogenesis [18], [19].

ACLY activity and expression are both regulated by HCA. Regarding inhibiting ACLY activity, HCA is structurally similar to citrate but has a significantly higher affinity for ACLY than citrate, making it a potent competitive inhibitor of the enzyme ACLY [20], [21], which links carbohydrates and lipids metabolism via catalyzing the conversion process of citrate to acetyl-CoA, which plays a key role in fatty acid, cholesterol, and TG syntheses. Concerning inhibition of ACLY expression, HCA can regulate the expression of the enzyme ACLY, is through the regulation of sterol regulatory element binding protein (SREBP), the upstream regulator of the transcription of genes encoding fatty acid synthesis enzymes [22], [23]. A previous report revealed that the supplementation of HCA inhibits SREBP expression, eventually leading to lipogenesis inhibition [24]. Also, a direct interaction between adenosine monophosphate-activated protein kinase is an enzyme (AMPK), and ACLY seems sensitive to HCA treatment. Additionally, HCA treatment resulted in the co-activation of AMPK and the mammalian target of rapamycin (mTOR) pathways [25]. Although HCA increments the TAM impact on sensitive BC cells, its ability to sensitize BC-resistant cells to TAM by targeting lipid metabolism has never been studied.

Accordingly, we will test the hypothesis that overexpression of the key lipid metabolizing enzymes contributes to TAM resistance in BC and that targeting lipid metabolic pathways may sensitize BC-resistant cells to TAM. Hence, we aimed to explore TAM efficiency on BC-resistant cells that had been pre-treated with HCA to target ACLY. This can lead to the discovery of novel therapeutic approaches and enhance the therapeutic outcomes of BC patients.