The overexpression of CD36 in cancer cells has reportedly been to enhance the transcription of genes associated with metastasis formation, facilitating the spread of cancer to lymph nodes in mice (Pascual et al., 2017). Feng and colleagues found that CD36 acted as a key player in resistance to lapatinib in human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells, and inhibiting CD36 restored sensitivity to lapatinib and triggered apoptosis in those lapatinib-resistant cells (Feng et al., 2019). Moreover, elevated CD36 levels were found to be correlated with unfavorable prognoses (Pascual et al., 2017; Koundouros and Poulogiannis, 2020). Correspondingly, CD36 may provide a promising therapeutic target (Zhao J. et al., 2017). Besides, literature showed that LPL had the potential to accelerate the growth of tumor cells (Kuemmerle et al., 2011) However, no inhibitors targeting enzymes implicated in FA uptake have been introduced into clinical practice yet, restricting the translational potential of these findings.

High expression of ACLY in breast cancer tissues is conversely proportional to disease stage and prognosis (Xiao et al., 2024; Chen et al., 2020). Furthermore, ACLY is implicated in the resistance to tamoxifen, palbociclib, and paclitaxel in breast cancer, whereas ACLY inhibition can re-establish sensitivity to these drugs and halts tumor progression (Chen et al., 2020; Ismail et al., 2022; Ismail et al., 2020; Velez et al., 2023). Besides cleavage of citrate by ACLY, the supply of cytosolic acetyl-CoA pool can be achieved via the conjugation of acetate with CoA under hypoxia and lipid-depleted conditions, catalyzed by acetyl-CoA synthetase 2 (ACSS2) (Schug et al., 2015). Hence, ACSS2 is essential for tumor growth under metabolic stress, and its expression can predict tumor staging and patient prognosis (Schug et al., 2015; Ling et al., 2022). As the rate-limiting enzyme of lipid biosynthesis, ACC definitely holds a pivotal position in breast cancer cell development (Brunet et al., 2008; Chajès et al., 2006), while silencing ACC hinders cell proliferation and triggers apoptosis in breast cancer cell lines (Chajès et al., 2006). Accordingly, ACC emerges as a potential target for suppressing FA biosynthesis in human cancers with pharmacological inhibitors exhibiting encouraging antitumor effects (Tong, 2005; Lally et al., 2019). As another crucial enzyme involved in DNL, FASN also contributes to breast cancer initiation, progression, and treatment resistance (Menendez and Lupu, 2017). Mechanistically, besides supplying energy to cancer cells, FASN exerts its pro-tumor effects through its positive feedback loop with HER2 (Menendez et al., 2021; Kumar-Sinha et al., 2003; Vazquez-Martin et al., 2008) as well as its interaction with nuclear factor-κB (NF-κB) (Liu et al., 2013; Wu et al., 2016), which affect downstream signaling pathways and cellular processes critical for cancer cell survival and resistance to treatment. Targeting FASN may therefore hold promise to inhibit tumor cell growth and enhance the vulnerability of breast cancer cells to traditional anticancer treatments (Menendez and Lupu, 2017).

ACSs are categorized into five groups based on the length of the FA chain they act upon. Among them, long-chain ACSs (ACSLs) are accountable for the catalyzation of intracellular free long-chain FAs, which are then transported by transporter proteins such as CD36 (Rossi Sebastiano and Konstantinidou, 2019). Among the ACSL family, ACSL4 has been widely researched and linked to tumor progression. ACSL4 exhibits an abnormal upregulation in triple-negative breast cancer (TNBC) cells and is correlated with unfavorable prognosis and metastasis in TNBC patients (Qiu et al., 2024). Preclinical studies have revealed that ACSL4 can be activated in drug-resistant breast cancer cells (Li et al., 2022). In turn, this activation can impede the apoptotic pathway and enhance the mTOR pathway, thereby promoting cancer growth and conferring resistance to chemotherapy, endocrinotherapy, and radiotherapy (Li et al., 2022; Wu et al., 2013; Orlando et al., 2019). Consequently, targeting ACSL4 presents a novel therapeutic strategy for breast cancer, while transferring the basic scientific discoveries into clinical practice poses a significant hurdle. As the rate-limiting enzyme in FAO, CPT1 serves as a key factor in the initiation, progression, and migration of cancer cells (Wang et al., 2021). This enzyme not only fulfills the energy demands of cancer cells by facilitating FAO but also exerts its influence through various signaling pathways, cytokines, or microRNAs (Wang et al., 2021). Elevated levels of CPT1 expression have been detected in recurrent breast cancer cases, which are associated with unfavorable patient outcomes (Han et al., 2019). Moreover, serum CPT1 levels reliably signify the disease progression in breast cancer patients (Tan et al., 2021), underscoring its potential utility as a biomarker in breast cancer management. Accumulating evidence suggests that a key mechanism underlying CPT1’s role in fostering treatment resistance is its ability to sustain stemness in stem cells (Wang et al., 2018; Han et al., 2019; He et al., 2019; Shim et al., 2022; Chen et al., 2023). Preclinical studies have demonstrated that etomoxir (a CPT1 inhibitor) can re-sensitize multiple cancers, including breast cancer, to conventional chemotherapy and radiotherapy (Han et al., 2019; Shim et al., 2022; Chen et al., 2023; Tan et al., 2018; Pucer et al., 2013). The mechanism by which CPT2 mediates radiotherapy resistance in breast cancer cells is analogous to that of CPT1 (Han et al., 2019). Unfortunately, despite their potential, none of the FAO-related therapeutic targets have been successfully translated into clinical practice for breast cancer treatment.

In cancer patients, there is an increase in endogenous cholesterol synthesis, coupled with elevated circulating cholesterol levels (Kopecka et al., 2020). The heightened cholesterol levels can augment downstream oncogenic pathway signaling, including Hedgehog- and mammalian target of rapamycin complex 1 (mTORC1)-dependent pathways (Ding et al., 2019). Furthermore, by exerting its influence on membrane fluidity, lipid raft function, and transcriptional processes, cholesterol can also regulate the activity of drug efflux transporters, thereby contributing to drug resistance (Kopecka et al., 2020; Ding et al., 2019; Celestino et al., 2015). The overexpression of MVA pathway-related molecules was observed in breast cancer patients with a worse prognosis (Kuzu et al., 2016; Brown et al., 2016; Clendening et al., 2010; Kim et al., 2019; Bjarnadottir et al., 2020). Additionally, HMGCR may possess oncogenic properties, and perturbations within the MVA pathway could facilitate cellular transformation (Clendening et al., 2010). Research has indicated that HMGCR and SQLE represent compelling targets for cancer treatment, albeit clinical studies on the latter are still lacking (Feltrin et al., 2020).

Glycerophospholipids hold a critical position in the initiation and progression of cancer, and they mediate the resistance of cancer cells to chemotherapy via various mechanisms, encompassing modulating the composition of cellular membranes, influencing FA metabolism, acting as second messengers to activate DNA repair mechanisms, and upregulating drug efflux transporters (Kopecka et al., 2020). PS is a phospholipid confined to the inner leaflet of the cell membrane. In solid tumors, hypoxia and other pathophysiological stressors induce the externalization of PS, where it migrates to the outer leaflet (Gerber et al., 2018). The interaction between PS and its receptors critically regulates immuno-inflammatory responses, fostering an immune-evasive tumor microenvironment. Additionally, PS-receptor interaction mediates chemoresistance in cancer cells by the upregulation of drug efflux transporters and the activation of signaling cascades, e.g., phosphatidylinositol 3-kinase (PI3K)/Akt pathways (Zhou et al., 2020). These findings indicate the promising potential of PS-targeted therapy in combating tumor invasion and chemoresistance.

As mentioned above, despite the existence of numerous promising targets, their successful clinical translation remains elusive. Presently, the therapeutic strategies targeting lipid metabolism in breast cancer face several obstacles that require attention. Firstly, the inhibition of lipid metabolic pathways may raise safety concerns due to their potential to induce detrimental effects on normal cells, thereby limiting the development of safe and specific inhibitors (Ligorio et al., 2021). Secondly, the translation of preclinical findings into a clinical setting poses significant challenges, as experiment conditions utilized in preclinical studies may employ supra-physiological concentrations of lipid-modulating drugs (Goodwin et al., 2022). Thirdly, the metabolic adaptability of cancer cells may undermine the effectiveness of inhibiting a single enzyme or pathway alone in sustaining long-term tumor suppression (Ligorio et al., 2021; Fendt et al., 2020). Notwithstanding the challenges, some therapeutic strategies targeting lipid metabolism have still progressed into clinical trials, which will be exhaustively presented in the following section.

Despite strong evidence supporting FASN as a promising target for breast cancer therapy, only a few compounds inhibiting FASN have entered clinical studies to date. TVB-2640 is a small molecule that stands as the first highly selective human FASN inhibitor to progress into clinical trials (Falchook et al., 2021). A phase I clinical trial have confirmed the biological activities and safety of the TVB-2640 in solid tumors, including breast cancer (Falchook et al., 2021). Accordingly, an ongoing Phase II clinical study (NCT03179904) will further investigate the efficacy and safety profile of TVB-2640 administered in conjunction with trastuzumab plus paclitaxel or endocrine therapy in the management of advanced HER2-positive breast cancer (Table 1). Besides the FASN inhibitor TVB-2640, several other clinical medications or plant-derived polyphenols have been demonstrated to block FASN, among other targets, and enhance the effectiveness of numerous traditional therapies. Examples include omeprazole (Sardesai et al., 2021), conjugated linoleic acid (CLA) (McGowan et al., 2013), and epigallocatechin-3-gallate (EGCG) (Brusselmans et al., 2003), which have undergone corresponding clinical trials. Notably, research results for the former two have been published (Table 2). Consequently, the combination of omeprazole and neoadjuvant chemotherapy has yielded a promising pathological complete response (pCR) rate (Sardesai et al., 2021), and preoperative administration of CLA for ten to 28 days resulted in significant reductions in Spot 14 and Ki67 levels (McGowan et al., 2013).

Statins, functioning via the inhibition HMGCR, are commonly prescribed for patients with cardiovascular disease and high cholesterol levels to lower their cholesterol (Clendening and Penn, 2012). In recent years, growing trials have focused on their promising anticancer benefits (Kamal et al., 2024; Yulian et al., 2021; Dewidar et al., 2022; Yulian et al., 2023; Garwood et al., 2010; Feldt et al., 2015; Bjarnadottir et al., 2015; Nielsen et al., 2012). Currently, clinical trials for drugs such as fluvastatin, atorvastatin, simvastatin, and pitavastatin have been initiated worldwide, primarily for use before surgery in early breast cancer. The potential of these drugs, either as monotherapy or in addition to traditional standard therapy, is being evaluated through clinical or pathological responses (Tables 1, 2). Among them, results from three window-of-opportunity studies have been published, generally finding that short-term monotherapy with statins could suppress tumor growth and enhance apoptotic processes (Kamal et al., 2024; Garwood et al., 2010; Feldt et al., 2015; Bjarnadottir et al., 2015). Additionally, two published studies in the neoadjuvant setting suggested that statins combined with standard neoadjuvant chemotherapy could, to some extent, enhance clinical and pathological responses compared to placebo, although the statistical differences were not always significant (Yulian et al., 2021; Dewidar et al., 2022; Yulian et al., 2023). Ongoing trials will delve deeper into the therapeutic potential of statins as monotherapy, alongside chemotherapy or with endocrine therapy for early- and advanced-stage breast cancer. For instance, the ongoing Phase III MASTER trial (NCT04601116) aims to determine whether long-term statin therapy can enhance the prognosis of women with early breast cancer.

Metformin, a frequently prescribed biguanide, stands as a cornerstone medication in managing hyperglycemia and type 2 diabetes (Pernicova and Korbonits, 2014). Increasing evidence suggests a potential effectiveness of this compound as an anticancer agent (Pernicova and Korbonits, 2014; Thompson, 2014). A fundamental way in which metformin exerts its influence encompasses the stimulation of AMP-activated protein kinase (AMPK), a vital metabolic modulator essential for maintaining energy balance and regulating cellular growth (Ben Sahra et al., 2010). Of note, AMPK has an impact on inhibiting ACC activity (Fullerton et al., 2013; Svensson et al., 2016). Accordingly, the antitumor activity of metformin could be at least partially facilitated by hindering FA biosynthesis (Ligorio et al., 2021). Herein, we also provide an overview of the clinical studies regarding the application of metformin in breast cancer (Table 1 and 2). Unfortunately, the research findings remain controversial. Some studies have found that preoperative monotherapy with metformin for 2-4 weeks could significantly reduce Ki67 levels and oncogenic signaling (Hadad et al., 2011; Dowling et al., 2015; Niraula et al., 2012; DeCensi et al., 2014). Furthermore, a study conducted by Serageldin et al. demonstrated that metformin could provide an additional benefit in terms of clinical and pathological responses compared to neoadjuvant chemotherapy alone (Serageldin et al., 2024). However, most research, including a phase III trial (MA.32) involving 3,649 patients (Goodwin et al., 2022), has indicated that metformin offered no advantage in antitumor effect, whether in early-stage (El-Khayat et al., 2021; Goodwin et al., 2022; Goodwin et al., 2023; Barakat et al., 2022; Kalinsky et al., 2014; Huang et al., 2023; Martin-Castillo et al., 2018; Cuyàs et al., 2019a; Cuyàs et al., 2019b; Lopez-Bonet et al., 2019; Bonanni et al., 2012; Cazzaniga et al., 2013; DeCensi et al., 2015; Rocca et al., 2021) or late-stage (Zhao Y. et al., 2017; Essa et al., 2022; Nanni et al., 2019; Pimentel et al., 2019; Yam et al., 2019) breast cancer, and regardless of whether the treatment was administered as monotherapy or in addition to conventional regimens. Notably, preclinical studies on ACC inhibition have exhibited contradictory outcomes regarding its anticancer effectiveness (Ligorio et al., 2021). Furthermore, Liu et al. discovered that the conjunction of metformin and simvastatin exhibits synergistic inhibition of various cancer cells, suggesting its potential in antitumor therapy when used in conjunction (Liu et al., 2023).

Bavituximab represents an unconjugated chimeric immunoglobulin G1 (IgG1) monoclonal antibody specifically binds to PS (Gerber et al., 2018). The unique external exposure of PS on tumor cells makes bavituximab an effective agent for targeting tumor specifically (Jennewein et al., 2008). Preclinical studies have shown that chemotherapy and radiation therapy could increase the exposure of PS, further enhancing bavituximab binding and immune activation (Huang et al., 2005; He et al., 2007). Therefore, bavituximab may serve as an ideal partner for chemotherapy and radiation therapy. A phase I clinical trial has thus far confirmed the safety of bavituximab administration in breast cancer (Chalasani et al., 2015). Additionally, two ongoing phase Ⅱ trials (NCT00669565 and NCT00669591) have completed their investigation into the potential value of combining bavituximab with chemotherapy in advanced breast cancer, although the research data have not yet been disclosed (Table 1). However, a randomized phase III trial comparing docetaxel plus bavituximab to docetaxel alone in patients with previously treated advanced non-squamous non-small-cell lung cancer failed to demonstrate survival benefit for the combination therapy (Gerber et al., 2018).

Despite contradictory research findings regarding its direct anticancer effects in breast cancer, lipid pathway-targeted therapy has been widely accepted for its crucial role in managing complications associated with treatments such as chemotherapy. For instance, metformin has been shown to alleviate chemotherapy-induced peripheral neuropathy neutropenia, cardiac toxicity, oral mucositis, and fatigue in non-diabetic breast cancer patients (Serageldin et al., 2023; Nanni et al., 2019; Bakry et al., 2023). Based on the preclinical evidence, statins appear to have the potential to mitigate chemotherapy-induced cardiotoxicity (Padegimas et al., 2020; Pecoraro et al., 2023; Bjørnstad et al., 2022). However, results from published clinical studies indicate that statins did not affect declines in left ventricular ejection fraction among certain breast cancer patients (Hundley et al., 2022; Makhlin et al., 2024; Thavendiranathan et al., 2023). An ongoing study is currently assessing the use of atorvastatin for prophylactic cardioprotection in patients undergoing anti-HER2 targeted therapy (NCT05559164). Lipid pathway-targeted therapy is also capable of protecting patients from the side effects of radiation therapy. In a phase Ⅱ double-blind, placebo-controlled randomized trial, the prophylactic application of EGCG solution significantly decreased both the occurrence and magnitude of radiation-induced dermatitis among breast cancer patients receiving adjuvant radiotherapy (Zhao et al., 2022). Statins are also believed to alleviate radiation-related complications (Ricco and Kron, 2023), however, clinical studies related to statin protection during radiotherapy in breast cancer patients have been terminated (NCT04385433, NCT00902668).

Furthermore, there are currently numerous completed as well as ongoing clinical trials exploring the potential of lipid pathway-targeted therapy in breast cancer prevention. The omega-3 preparation Lovaza was reported to reduce breast cancer risk in obese women (Manni et al., 2017). Although many observational analyses have found that metformin therapy did not practically influence cancer incidence (Dankner et al., 2019; Dickerman et al., 2023), there are also studies that supported a potential beneficial impact of metformin on reducing cancer risk (Evans et al., 2005; Muszyńska-Ogłaza et al., 2017; Tapia et al., 2021; Tseng, 2014). A clinical trial that is still ongoing will specifically explore the potential of metformin in preventing the development of invasive breast cancer among patients with a history of breast carcinoma in situ or atypical hyperplasia (NCT01905046). Similarly, there is no definitive conclusion pertaining to the association between statin administration and breast cancer risk (Higgins et al., 2012; Vinayak et al., 2013). Of note, several studies have indicated that lipophilic statins (i.e., simvastatin, fluvastatin, and lovastatin) may offer superior breast cancer prevention benefits compared to hydrophilic statins (i.e., atorvastatin and pravastatin) (Ahern et al., 2011; Cauley et al., 2006).

Based on the above, the clinical evidence projecting lipid pathway-targeted therapy as an anticancer or cancer chemopreventive strategy is variable. Nonetheless, it is recognized that certain breast cancer patients can indeed benefit from lipid pathway-targeted therapy (Serageldin et al., 2024; El-Khayat et al., 2021; Kamal et al., 2024; Yulian et al., 2021; Dewidar et al., 2022; Yulian et al., 2023; Serageldin et al., 2023). Consequently, we advance the Selective Lipid Metabolism Therapy Benefit Hypothesis, suggesting that therapeutic strategies targeting lipid metabolism may selectively benefit a subset of patients. This hypothesis neither unconditionally advocates for the absolute benefits of targeting lipid metabolism nor conclusively denies its significance based solely on negative trial results. Instead, it offers a more objective and dialectical understanding of the clinical value of lipid pathway-targeted therapies. This hypothesis highlights the need for a more precise identification of the patient subpopulation that may potentially benefit from such treatment, which is of paramount importance. Currently, some clinical trials have identified potential biomarkers capable of predicting the treatment response to lipid metabolism-targeting therapies, which will be comprehensively summarized in the next section.

Currently, a number of clinical trials have identified a panel of promising biomarkers (Feldt et al., 2015; Cuyàs et al., 2019a; Hadad et al., 2015; Pimentel et al., 2021; Goodwin et al., 2015; Goodwin et al., 2021a; Feldt et al., 2020; Ahern et al., 2020; Goodwin et al., 2021b). Based on an exploratory analysis of a window-of-opportunity breast cancer trial, Feldt and colleagues suggested that the expression levels of cyclin D1, p27, and low-density lipoprotein receptor in tumor tissues might influence the anti-proliferative efficacy of atorvastatin (Feldt et al., 2015; Feldt et al., 2020). Furthermore, evidence exists indicating that HER2 overexpression and genetic variations in ABCB1, CYP3A4, SLCO1B1, and CYP3A5 serve as biomarkers for predicting the response of breast tumors to simvastatin (Yulian et al., 2021; Ahern et al., 2020). Regarding Metformin, studies have found it to be more effective in patients with a BMI ≥25 (El-Khayat et al., 2021), although this finding remains controversial (Kalinsky et al., 2014). The Phase Ⅱ METTEN trial suggested that the C allele of ataxia telangiectasia mutated (ATM) rs11212617 might function as a predictive biomarker to guide the personalized use of metformin in patients with breast cancer (Cuyàs et al., 2019a); however, subsequent findings from the Phase Ⅲ MA.32 trial refuted this notion (Goodwin et al., 2021b). This controversy may stem from differences in the patient populations included in the two studies, as some research indicates that the anticancer effects of metformin in breast cancer exhibit subtype specificity (Yulian et al., 2021; Bonanni et al., 2012). Specifically, the METTEN trial exclusively enrolled HER2-positive breast cancer patients, whereas the MA.32 trial included patients regardless of their subtype. Additionally, the METTEN trial proposed that serum homocysteine levels might serve as an indicator connecting the antifolate-mimicking effects of metformin with tumor response (Cuyàs et al., 2019b). An observable trend towards differing metformin efficacy, based on insulin resistance status, is also noted (Bonanni et al., 2012; Cazzaniga et al., 2013). Further exploration and validation of stable biomarkers for lipid pathway-targeted therapy in large-scale clinical trials are warranted.