Unlocking the lipid code: SREBPs as key drivers in gastrointestinal tumour metabolism

Abstract

In recent years, metabolic reprogramming has emerged as a significant breakthrough in elucidating the onset and progression of gastrointestinal (GI) malignancies. As central regulatory hubs for lipid metabolism, sterol regulatory element binding proteins (SREBPs) integrate dietary metabolic signals and carcinogenic stimuli through subtype-specific mechanisms, thereby promoting malignant tumour phenotypes. In this review, we first present the molecular background, structural characteristics, and posttranscriptional regulatory networks associated with SREBPs. We subsequently describe a systematic analysis of the distinct activation patterns of SREBPs in liver, gastric, colorectal, and other gastrointestinal cancers. Furthermore, we explore targeted intervention strategies for different SREBP subtypes, including small molecule inhibitors (such as fatostatin, which inhibits SREBP cleavage), natural compounds (such as berberine, which modulates the AMPK/mTOR pathway), and statin-mediated inhibition of the mevalonic acid pathway. These strategies may enhance tumour cell sensitivity to chemotherapeutic agents (such as 5-FU, gezil, and tabine) and improve the response to synergistic chemoradiotherapy by reversing adaptive metabolic resistance driven by the tumour microenvironment. Through this review, we hope to provide new insights into precise interventions targeting various subtypes of the SREBP molecule.

Introduction

Gastrointestinal (GI) tumours, which include malignancies such as oesophageal, stomach, colorectal, pancreatic, and liver cancer, have emerged as prevalent, life-threatening diseases that significantly impact quality of life in humans [1–4]. Although the pathogenesis of GI tumours remains largely elusive, modifications in lipid metabolism have been identified as distinctive characteristics of this type of cancer. Increasing attention has also been given to changes in lipid metabolism in cancer [5, 6]. Cancer cells rely on significant lipid synthesis and uptake to support their replication. A diverse array of enzymes, proteins, and transcription factors are involved in the reprogramming of lipid metabolism in GI tumours [6, 7]. These molecules, when expressed abnormally, can enhance lipid production and promote the clustering of lipid droplets through various mechanisms, thus affecting the development, spread, and growth of GI tumours.

Sterol regulatory element-binding proteins (SREBPs) serve as primary regulators of lipogenesis and significantly contribute to the maintenance of appropriate cellular lipid levels, including triglycerides and sterols, via intricate proteolytic processing mechanisms [8]. When highly expressed, SREBPs have been observed to be instrumental in lipid reprogramming across a diverse range of cancers [9]. Recent research has indicated a notable increase in lipid synthesis and uptake within gastrointestinal tumours, and this factor substantiates tumour growth. The range of cancers affected by the high expression of SREBPs includes prostate, liver, colorectal, stomach, and pancreatic malignancies [9, 10]. SREBPs function as pivotal transcription factors that govern lipid metabolism and modulate the expression of essential genes implicated in lipid synthesis and uptake, processes that may also be linked to oncogenesis [11]. Consequently, the utilisation of therapeutic strategies focusing on SREBPs in gastrointestinal tumours could provide promising molecular targets for cancer treatment.

In this review, we conducted a comprehensive search of PubMed for articles pertaining to the three subtypes of SREBPs (SREBP-1a, SREBP-1c, and SREBP-2) in relation to various gastrointestinal tumours. The search utilised both MeSH terms and free-text keywords, with the review being current as of July 2024. By examining the relationship between the aberrant regulation of SREBP molecular subtypes and the progression of gastrointestinal tumours, we offer new insights into their significant role in cancer biology and their potential as therapeutic targets in cancer treatment.

Biochemical background of SREBPs

SREBPs are integral to the regulation of lipid homeostasis, glycogenesis, and the biosynthesis of fatty acids, triglycerides, and cholesterol. In addition to functioning as transcription factors, they also control the expression of enzymes involved in endogenous cholesterol synthesis, fatty acid synthesis, triacylglycerol synthesis, and phospholipid synthesis. Moreover, as members of the bHLH-Zip transcription factor family, SREBPs possess basic helix-loop-helix-leucine zip structures, which are similar to those observed in their gene products [12].

In general, the SREBP precursors (each possessing approximately 1150 amino acids) are classified into the following three domains [13, 14]: (1) an NH₂ amino acid terminal domain that binds DNA, including the bHLH-Zip motif, which modulates the DNA-binding and dimerisation activities of mature SREBP transcription factors; (2) a short ring of approximately 30 amino acids between the two hydrophobic transmembrane segments that extends into the cavity of the endoplasmic reticulum, which is known as the membrane binding region; and (3) an approximately 590 amino acid COOH-terminal domain that regulates SREBP localisation and translocation within the cell (Fig. 2).

Fig. 2.

Structural diagram of different SREBP molecules (SREBP-1a, SREBP-1c, and SREBP-2) along with documented types of post-translational modifications

Currently, the SREBP family of proteins consists of two genes (SREBP1 and SREBP2), which are translated into three SREBP isoforms known as SREBP-1a, SREBP-1c, and SREBP-2 [15]. Among these isoforms, SREBP-1a and SREBP-1c are both products of the SREBP1 gene. However, due to alternative splicing at the transcription initiation site, the NH₂-terminal domain of SREBP-1a is 24 amino acids longer than that of SREBP-1c [16]. Consequently, these isoforms exhibit functional differences. Both SREBP-1a and SREBP-1c are involved in regulating fatty acid synthesis genes, whereas SREBP-2 regulates cholesterol synthesis genes [17–20]. Moreover, SREBPs are differentially distributed in mice and humans, with SREBP-1c most commonly expressed in the liver, white adipose tissue, adrenal gland and brain [21]. In contrast, SREBP-1a and SREBP-2 are predominantly expressed in cell lines, the nervous system and intestinal tissues [22, 23]. Unlike SREBP-1a, SREBP-1c possesses four unique amino acids rather than 28 amino acids. Therefore, SREBP-1c has a shorter N-terminal sequence, and its transcriptional activity is weaker [24, 25]. Furthermore, SREBP-2 possesses a robust activation domain analogous to that of SREBP-1a, whereas the shorter SREBP-1c isoform exhibits a comparatively weaker transcriptional activation domain than SREBP-1a [26].

Transcriptional regulation of SREBPs

To monitor sterol levels in the ER, two membrane-based proteins are involved in the SREBP pathway, including SREBP cleavage activation protein (SCAP) and insulin-inducing gene protein (INSIG) [27]. Sterol-sensing domains are present in SCAP molecules. The SCAP confines SREBPs to the endoplasmic reticulum when sterol levels are high in the cell; however, it escorts them to the Golgi apparatus when sterol levels are low [14]. Moreover, INSIG (as a regulatory protein) binds to the SCAP/SREBP complex and participates in the regulation of SREBP molecular function [28].

Notably, SREBPs synthesised in the ER are in their precursor form of 125 kDa, and enzyme processing is required for the precursor to become the mature form of 68 kDa, with the mature enzyme playing a role in lipid metabolism. Specifically, a precursor SREBP known as pSREBP is initially synthesised and subsequently inserted into the ER membrane, where it binds to the COOH terminal region of the SCAP [29]. This process also involves INSIG family proteins, which retain SREBPs in the ER along with cholesterol [30]. As a nuclear SREBP (nSREBP), the NH₂ terminal domain activates transcription by binding to nonpalindrosterol sterol response elements (SREs) in multiple target gene promoters/enhancers [13] (Fig. 1). The ACLY, ACC, FASN, and SCD genes (among others) regulated by SREBPs are highly expressed in cancer tissues compared with nontumour tissues and play important roles in cancer cell growth, metastasis, and survival. In summary, the modulation of the transcriptional activation process of SREBPs or the regulation of their downstream target molecules may represent promising therapeutic strategies in clinical settings.

Fig. 1.

Transcriptional activation diagram of SREBPs molecule

PTMs in SREBPs

Significantly, the regulation of SREBPs'transcriptional activity is also influenced by posttranslational modifications (PTMs) (Fig. 2). Most studies have focused on SREBP-2 and SREBP-1a, which are sterol-dependent regulators of posttranslational proteolysis.

Protein phosphorylation, the most prevalent form of posttranslational modification, regulates a diverse array of biological processes. SREBP-1 is also regulated by phosphorylation. A recent study revealed that SREBP-1 is activated during cell transformation in Ras/PI3K mutants and that a reduction in SREBP-1 in cancer cells leads to decreased proliferation [31]. In addition, insulin-induced phosphorylation of SREBP-1c enhances transport from the endoplasmic reticulum (ER) to the Golgi and proteolytic processing [32]. For example, glycogen synthase kinase 3 directly phosphorylates Ser443 on SREBP-2 to mediate FBW7-induced ubiquitination and degradation [33]. Similarly, when nuclear SREBP-1a is phosphorylated at sites S430 and T426, FBW7 is able to interact with it and promotes its degradation and ubiquitination. Furthermore, FBW7 degrades nuclear SREBP-2 and SREBP-1c.

Transforming growth factor-β activated kinase 1 (TAK1), which is an inflammatory signalling protein, binds and phosphorylates full-length SREBPs in the ER or Golgi bodies in the cytoplasm, thus further reducing their DNA-binding capacity and weakening their transcription [34]. Via the ubiquitin–proteasome pathway, SREBPs are rapidly degraded in the nucleus. Additionally, the glycogen synthetase kinase-3B phosphorylates serine and/or threonine residues near the ubiquitination site in SREBP-1 and SREBP-2, which enhances their ubiquitination [35].

As a type II PRMT enzyme, protein arginine methyltransferase 5 (PRMT5) modifies target proteins through SDMA to cause tumour progression. Mass spectrometry has revealed that PRMT5 can symmetrically dimethylate mature SREBP1 (mSREBP1a, 68 kDa) at the R321 site, thereby increasing its transcriptional activity and stabilising SREBP-1a [36]. Methylated stable SREBP-1a enhances lipid synthesis and promotes the proliferation of cancer cells both in living organisms and under laboratory conditions. Conversely, AMPK prevents TDG-mediated DNA demethylation of the SREBP-1 promoter, thus indicating that TDG regulated by insulin or metformin could be a promising therapeutic target for cancers linked to type 2 diabetes [37].

SREBPs can undergo modification by a different protein known as small ubiquitin-like modifier (SUMO). The process of SUMOylation, which affects transcription factors such as SREBPs, generally reduces the ability of these factors to activate transcription [38, 39]. Mitsumi et al. demonstrated that SREBP-2 is modified by SUMO-2 or SUMO-3 molecules at Lys 464 and that SUMOylation reduces SREBP transcriptional activity by recruiting a corepressor complex containing HDAC3 [40]. Similarly, two major SUMO sites (Lys 123 and Lys 418) were identified in SREBP-1a. The absence of one or two SUMOylation sites also increases the transactivation capacity of SREBP-responsive promoters [41].

SREBP-1a and SREBP-2 can undergo acetylation mediated by the histone acetyltransferases known as p300 and CREB-binding protein (CBP), and this process is contingent upon the presence of the N-terminal p300/CBP binding domain. Further studies have revealed that acetylation affects the stability of K324 and K333 in the DNA-binding domain of SREBP-1a, thereby regulating their transcriptional activities [42]. Conversely, sirtuin-1 (SIRT1), which is a member of the deacetylase family, deacetylates SREBP-2, thereby reducing the abundance of SREBP-2 in the nucleus [43]. SREBP-1 has also been identified as a substrate for neddylation by UBC12. In addition to increasing the stability of SREBP-1, neddylation reduces ubiquitination, which promotes the aggressive characteristics of HCC and breast cancer [44].

The SREBPs in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents one of the most prevalent liver malignancies worldwide and is characterised by a poor prognosis and a dearth of potent and efficacious treatment modalities. Between 2010 and 2021, the global incidence and mortality rates of liver cancer increased by approximately 25%, with hepatitis B virus (HBV) persisting as the predominant cause of liver cancer-related morbidity and mortality worldwide [45]. Concurrently, nonalcoholic fatty liver disease (NAFLD) has emerged as a significant public health concern in Asia, with a prevalence rate of 34%; additionally, the incidence of NAFLD-associated HCC is increasing [46]. In the liver, SREBPs are involved in the pathogenesis of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hepatitis, and liver cancer. Moreover, SREBPs serve as central regulators in numerous physiological and pathophysiological cellular processes, thereby influencing both transcriptional and posttranscriptional regulation [17]. Numerous studies have demonstrated that de novo adipogenesis (which is regulated by the transcription factor SREBP-1) plays a crucial role in the progression of HCC [47, 48].

In cancer cells, genes and enzymes involved in lipid metabolism are significantly altered. By controlling the transcription of genes involved in lipid biosynthesis and absorption, SREBPs play crucial roles in regulating lipid metabolism in HCC [49]. ATP1A1/CA2, which has been identified as the target molecule of bufalin, exhibits significant antitumour activity against hepatocellular carcinoma. Bufalin exerts its effects by modulating the ATP1A1/CA2 axis, thereby leading to the downregulation of the SREBP-1/FASN/ACLY pathway in liver cancer [50]. This regulatory mechanism results in the inhibition of lipogenesis and tumourigenesis. Phosphorylation, which is recognised as the most prevalent type of posttranslational modification, is crucial in the pathogenesis and progression of cancer. Comprehensive investigations by Xu et al. have revealed that the phosphorylation of cytoplasmic phosphoenolpyruvate carboxykinase 1 (PCK1) at Ser90, as well as INSIG1 at Ser207 and INSIG2 at Ser151, is positively associated with the nuclear accumulation of SREBP-1 in HCC samples [51]. Moreover, this phosphorylation is significantly correlated with poor prognosis in HCC patients. Furthermore, the interaction between pyruvate kinase M2 (PKM2) and nuclear SREBP-1a facilitates the phosphorylation of SREBP-1a at threonine 59 residues [52]. This SREBP-1a/PKM2 complex is posited to play a significant role in the pathogenesis of hepatocellular carcinoma. The rapid growth of HCC creates an oxygen-poor tumour environment. Additionally, EFNA3 enhances HCC cell self-renewal, proliferation, and migration, with EphA2 acting as a crucial downstream mediator. The Ephrin-A3/EphA2 axis aids in SREBP-1 maturation and can regulate HCC cell metabolism under hypoxia [53]. Moreover, SLC25A47, which is a downregulated carrier protein in HCC mitochondria, affects energy metabolism by influencing the mitochondrial NAD⁺-dependent deacetylase known as SIRT3. The loss of SLC25A47 decreases mitochondrial NAD⁺ levels, thereby reducing SIRT3 activity and promoting HCC progression via the SIRT3-AMPKα-SREBPs pathway, which regulates lipid metabolism [54].

SREBP-1 is upregulated in hepatic carcinoma tissues, and its overexpression is correlated with unfavourable clinicopathological characteristics. The knockdown of SREBP-1 has been shown to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma cells [55]. Additionally, peroxidase 5 (Prx5) functions as an activator of AMP-activated protein kinase (AMPK), thus leading to the downregulation of SREBP-1 expression [56]. This regulatory mechanism can mitigate hepatic steatosis induced by excessive energy intake, thereby serving as a protective factor in the context of fatty liver diseases. Moreover, circPRKAA1, which is a circular RNA (circRNA) originating from the α1 subunit of AMPK, has the capacity to selectively recruit mSREBP-1, thereby increasing its transcription, enhancing fatty acid synthesis, and facilitating tumour growth [57]. Moreover, the membrane-bound transcription factor site-1 protease inhibitor known as PF-429242 induces autophagy-dependent cell death in HCC cells. Additionally, SREBP-1a/c are able to mitigate the cytotoxic effects induced by PF-429242 (to a certain extent) [58].

Rapidly proliferating cancer cells fulfil their lipid and cholesterol requirements by augmenting the uptake of dietary lipids or by reprogramming intracellular lipid biosynthesis. Hyperglycaemia induces the production of reactive oxygen species (ROS), which subsequently increase the nuclear translocation of SREBP-1 through a series of signalling pathways, thereby promoting the progression of hepatocellular carcinoma [59]. Conversely, the inhibition of SREBP-1 activation not only impedes aerobic glycolysis in HCC cells but also augments the antitumour efficacy of radiofrequency ablation in xenograft tumours [60]. Therefore, the targeting of SREBP-1 activation may represent a promising therapeutic strategy for the treatment of advanced HCC. Additionally, several cytokines have been implicated in regulating hepatocellular cancer development and prognosis. The oncogene pleiotrophin has been demonstrated to upregulate the expression of SREBP-1c and adipogenic genes, thereby playing a critical role in HCC proliferation and metastasis [61]. Moreover, hepatoma-derived growth factor (HDGF) functions as a coactivator in SREBP-1-mediated lipogenic gene transcription. The coexpression of SREBP-1 and nuclear HDGF is associated with poor prognoses in HCC patients [62]. Additionally, ficolin 3 (FCN3) is a constituent of the complement system that functions as a recognition molecule targeting pathogens within the lectin pathway. FCN3 has the capacity to directly induce inactivation of insulin receptor β, thereby inhibiting the expression of SREBP-1c and promoting ferroptosis in hepatocellular carcinoma [63]. Drug resistance poses a significant challenge in treating HCC. Sorafenib (SFN), which is a drug used for advanced HCC, experiences resistance due to metabolic dysregulation in HCC cells, including increased mTOR activation and disrupted SREBP-1c inhibition [64]. Energy deficiency in susceptible HepG2 cells inhibits mTOR and SREBP-1c, thus contributing to SFN resistance and poor clinical outcomes. Furthermore, the inhibition of SREBP-1c may also help in treating tamoxifen-induced hepatocyte steatosis [65].

Recent proteomics research has indicated that key proteins involved in maintaining cholesterol homeostasis (such as SREBP-2) are significantly upregulated in the early stages of HCC [66]. NS5ABP37, which is a novel hepatitis C virus nonstructural protein (NS)5A-associated binding protein, has been observed to inhibit the promoter activities of both SREBP-2 and SREBP-1c [67]. The downregulation of these proteins at both the mRNA and protein levels has demonstrated antitumour effects. Pan et al. demonstrated that METTL3 facilitates the m6A modification of SREBP-2 cleavage-activating protein mRNA, thereby increasing its translation and subsequently activating cholesterol biosynthesis, which promotes HCC progression [68]. Concurrently, sapienate metabolism in cancer cells is regulated by mTOR and SREBPs. Similar to the well-characterised desaturase SCD1, fatty acid desaturase 2 (FADS2) serves as a target for both SREBP-1 and SREBP-2. The expression of FADS2 mRNA and protein can be modulated via mTOR signalling, thereby influencing cancer progression [69]. Emodin, which is an active component of Chinese herbal medicine, has been demonstrated to reduce cholesterol biosynthesis by inhibiting SREBP-2 transcriptional activity in HCC cells [70]. Additionally, the modulation of SIRT6 levels in HCC cells has been shown to influence SREBP activity, which is specifically achieved by inhibiting both SREBP-1 and SREBP-2, thereby limiting lipogenesis and reducing fibrosis [71]. Under typical physiological conditions, large tumour suppressor kinase 2 (LATS2) tumour suppressors function as regulators of SREBP activity, thereby maintaining cholesterol and lipid homeostasis. The downregulation of LATS2 results in the activation of SREBP-2 and subsequent accumulation of excess cholesterol [72]. Moreover, Liang et al. reported that the haploinsufficient tumour suppressor known as apoptosis-stimulating protein of p53-2 (ASPP2) interacts with SREBP-2 within the nucleus, thereby inhibiting the transcriptional activation of genes in the mevalonate pathway by SREBP-2 [73]. Intrahepatic cholangiocarcinoma (ICC) constitutes a significant component of primary liver cancer, and its high recurrence rate poses substantial challenges for clinical management. Recent research has indicated that elevated expression of myelin and lymphocyte protein 2 (MAL2) in ICC is correlated with unfavourable prognostic outcomes. The underlying mechanism of this effect involves the promotion of lipid accumulation within ICC cells via the stabilisation of EGFR membrane localisation and the subsequent activation of the PI3K/AKT/SREBP-1 signalling axis [74].

NAFLD has been identified as an early indicator of cirrhosis and HCC. Nonetheless, lipid metabolism is pivotal in regulating the balance between lipogenesis and fatty acid oxidation, which are processes that are advantageous for the therapeutic management of NAFLD.

Yang et al. demonstrated that exosomes derived from human umbilical cord mesenchymal stem cells (MSC-exs) inhibit fatty acid synthesis via calcium/calmodulin-dependent protein kinase 1 (CAMKK1) and SREBP-1c while simultaneously enhancing fatty acid oxidation via PPARα [75]. This dual regulatory mechanism leads to a reduction in lipid accumulation in an AMP-activated protein kinase (AMPK)-dependent manner. Similarly, SREBP-1 also directly upregulates histone deacetylase 8 (HDAC8), thereby increasing carcinogenic activity in NAFLD-associated hepatocellular carcinoma [76]. SREBP-1 is a key activator of apoptosis antagonising transcription factor (AATF) in the context of NAFLD, and therapeutic agents that reduce SREBP-1 activity can also reduce the risk of HCC development by reducing AATF [77]. Conversely, the phytochemical known as tetrahydropalmatine (THP) has been shown to ameliorate hepatic steatosis in NAFLD by activating the AMPK-SREBP-1c-Sirt1 signalling axis, thereby enhancing lipid oxidation [78]. In addition, octyl gallate (OG), which is a widely utilised food antioxidant, promotes the accumulation of lipid droplets in HepG2 cells via the modulation of SREBP-1c gene expression, thus potentially contributing to the pathogenesis of NAFLD when it is employed as a food additive [79]. Furthermore, ursodeoxycholic acid (UDCA) within bile acids has been demonstrated to mitigate lipid metabolism disorders induced by oleic acid (OA) via the inhibition of the AKT/mTOR/SREBP-1 signalling pathway [80]. In the hepatic tissues of obese patients with NAFLD, the intake of polyunsaturated fatty acids is correlated with increased levels of SREBP-1c, thereby potentially initiating a pro-lipogenic program that exacerbates hepatic lipid accumulation in these individuals [81]. In conclusion, the data derived from cellular and animal models, as well as clinical specimens, indicate that SREBPs play a critical role in the progression of pre-nonalcoholic fatty liver disease (pre-NAFLD). The targeting of SREBPs via various signalling pathways (including CAMKK1 and Sirt1) is anticipated to mitigate the metabolic transition from NAFLD to hepatocellular carcinoma.

In summary, the development and progression of HCC are linked to SREBPs (particularly SREBP-1 and SREBP-2), which increase tumour growth by activating lipid production pathways such as FASN/ACLY and cholesterol synthesis pathways such as SCAP-m6A modification (Table 1). Notably, during the transformation from NAFLD to HCC, SREBPs play crucial roles in mediating lipid metabolism imbalance via the coordination of the AMPK/mTOR/Sirt1 signalling pathways. Targeted intervention strategies, including the use of AMPK activators and METTL3 inhibitors, have demonstrated efficacy in disrupting this process. Future approaches that involve the multipathway regulation of SREBPs, along with their upstream and downstream effector molecules such as HDAC8 and AATF, may offer promising avenues for overcoming drug resistance in HCC treatment and achieving precise metabolic intervention.

Table 1.

Related mechanisms of SREBPs molecular types in hepatocellular carcinoma

Type of Cancer	Targets of SREBPs	Key molecules/mechanism pathways	Main cell lines/sample sizes	Reference
Hepatocellular carcinoma	SREBP-1	Bufalin/ATP1A1/CA2	PLC/PRF/5, Huh6, Huh7	[50]
	SREBP-1	PCK1/INSIG1/INSIG2	Huh7, Hep3B, SNU-398/HL7702, THLE-2/CHL-1, U87, H1993/90 human HCC tissue samples	[51]
	SREBP-1	Ephrin-A3/EphA2 axis	Huh7, PLC/PRF/5, MHCC97L, HepG2/97 paired HCC/non-tumourous liver samples	[53]
	SREBP-1	Prx5/circPRKAA1	HepG2	[56]
	SREBP-1	ROS	HepG2, Hep3B, HuH-7	[59]
	SREBP-1	HDGF	HepG2, HEK293 T,7721	[62]
	SREBP-1	HDAC8	LO2, HepG2, Bel-7404, PLC5/24 paired NAFLD-associated HCC samples	[76]
	SREBP-1	AATF	HepG2, Hepa1–6, Huh7, QGY-7703/18–20 human samples	[77]
	SREBP-1	UDCA/AKT/mTOR	L02	[80]
	SREBP-1a	PKM2	HEK293 T, HepG2, SW480, A549, MCF7/75 patient samples	[52]
	SREBP-1c	Pleiotrophin	HepG2, Huh-7, LX-2, LO2/80 HCC patient tissue samples	[61]
	SREBP-1c	FCN3/insulin receptor β	Huh7, HepG2, HEK-293 T, SM-386, YY-8103, MHCC97-H/133 human samples	[63]
	SREBP-1c	SFN, Tamoxifen	HepG2, Huh7, Hep3B/126 patients who received SFN therapy	[64]
	SREBP-1c	Exosomes derived from MSC-ex	L02, HFL1, AML12, HEK293 T	[75]
	SREBP-1c	THP/AMPK/SIRT1	SMMC-7721, BEL-7402	[78]
	SREBP-1c	OG	HepG2	[79]
	SREBP-1a/c	PF-429242	PLC/PRF/5, HepG2	[58]
	SREBP-2	METTL3	HKCI2, HKCI10, RIL-175, Hepa1-6	[68]
	SREBP-2	Emodin	Hep3B, HepG2, SK-HEP-1, Huh7, PLC/PRF5	[70]
	SREBP-2	LATS2	HepG2	[72]
	SREBP-2	ASPP2/MVA	HEK293 T, HCC-LM3, HepG2, Huh-7	[73]
	SREBP-1/2	FADS2/mTOR	HUH7, U87 MG glioblastoma cells, U2OS osteosarcoma cells	[69]
	SREBP-1/2	SIRT6	HepG2, Huh-7	[71]
	SREBP-1/2	SLC25A47/SIRT3/AMPK	L02, HepG2, Huh7, Hela, HEK293 T	[54]
	SREBP-1c/2	NS5ABP37	HepG2, L02/10 HCC cases of different stages and 10 normal pancreatic tissue samples	[67]

SREBPs in colorectal cancer

Lipid metabolic reprogramming is thought to be an important aspect of tumour metabolism, thus suggesting that SREBPs may be effective targets for cancer therapy. Many studies have demonstrated that SREBPs are elevated in many cancers, including colorectal cancer (CRC); moreover, their high expression has been observed to accelerate cancer progression. According to statistical data from 2020, CRC ranks as the second leading cause of cancer-related mortality in the United States. Additionally, both the incidence and mortality rates of CRC are increasing annually in Asian countries, with a pronounced increase being observed in East Asia [82]. Protein tyrosine phosphatase receptor type O (PTPRO) functions as a tumour suppressor across various cancer types. The silencing of PTPRO facilitates AKT/mTOR phosphorylation, which subsequently induces the expression of SREBP-1 and its downstream target gene ACC1, thereby increasing fatty acid synthesis and lipid accumulation; these effects may further contribute to the tumourigenesis and progression of CRC [83]. Aspirin enhances the susceptibility of CRC cells to ferroptosis by inhibiting the PI3K/AKT/mTOR signalling pathway, which subsequently suppresses SREBP-1/SCD1-mediated lipogenesis [84]. Furthermore, the genetic ablation of SREBP-1 or SCD1 increases the sensitivity of cancer cells to ferroptosis induction. In alignment with prior research, the selective PI3Kδ inhibitor known as TYM-3–98 has been demonstrated to inhibit CRC by inducing ferroptosis via the suppression of SREBP1 and its downstream targets. Notably, the overexpression of SREBP-1 diminishes the efficacy of TYM-3–98. These findings indicate that TYM-3–98 exhibits promise as a potential therapeutic agent for targeting CRC [85]. Moreover, brexpiprazole has been shown to markedly suppress the proliferation, lipogenesis, and cell cycle progression of colorectal cancer cells. The underlying mechanism of these effects likely involves the inhibition of colorectal cancer cell proliferation and adipogenesis via the AMPK/SREBP-1 signalling pathway [86].

SREBP-1 expression is elevated in colorectal tumour tissues, particularly at the invasive front and tumour budding sites, in contrast to normal tissues. This differential expression implies a potential role for SREBP-1 in the invasion and metastasis of colorectal cancer. Mechanistically, SREBP-1 facilitates endothelial cell angiogenesis through the augmentation of ROS and enhances the invasive and metastatic capabilities of colon cancer cells by upregulating matrix metalloproteinase 7 (MMP7) via p65 phosphorylation [87]. Liver metastasis often leads to death in advanced colorectal cancer patients. Yuan et al. reported that the cyclic RNA known as circNOLC1 (which is linked to the oxidative pentose phosphate pathway) interacts with zinc-alpha2-glycoprotein (AZGP1) to activate mTOR/SREBP-1 signalling [88]. This effect correspondingly induces glucose‐6‐phosphate dehydrogenase (G6PD), thus further activating the pathway and playing a crucial role in colorectal cancer liver metastasis.

Radiation resistance (both acquired and intrinsic) poses a significant challenge in treating CRC. High cholesterol levels enhance this resistance effect. External cholesterol intake increases radioresistance in CRC cells; however, the inhibition of the SREBP-1/FASN pathway reduces cholesterol synthesis and increases radiation-induced cell death in CRC [89]. The knockdown of SREBP1 has been shown to significantly inhibit the proliferation, migration, and invasion of CRC cells by controlling lipid metabolism and enhancing their apoptotic sensitivity [90]. This observation is corroborated by the study conducted by Gao et al., which demonstrated that SREBP-1 can inhibit apoptosis. Furthermore, the inhibition of SREBP1 overexpression also results in the suppression of apoptosis. The underlying mechanism of this effect likely involves the regulatory effect of SREBP-1 on the caspase-7 apoptosis signalling pathway and the concurrent inhibition of poly(ADP-ribose) polymerase-1 (PARP1) cleavage, thereby mitigating the apoptosis of colon cancer cells [91]. The knockdown of SREBP1 or SREBP2 significantly hampers cell proliferation and tumour growth; alters cell metabolism by reducing glycolysis, mitochondrial respiration, and fatty acid oxidation; and diminishes the tumour-forming ability of colon cancer cells while also reducing cancer stem cell gene expression [92]. Moreover, ZNFX1 antisense RNA 1 (ZFAS1), which is overexpressed in various cancers, functions as an oncogene by regulating miRNAs and is vital for CRC proliferation and metastasis. In CRC cells, ZFAS1 enhances fat metabolism reprogramming by binding to poly(A)-binding protein 2 (PABP2), thus facilitating the interaction of PABP2 with SREBP-1 [93]. This effect stabilises SREBP-1 mRNA and activates its downstream genes SCD1 and FASN, thus promoting CRC progression. Additionally, acyl-CoA synthetase 3 (ACSL3) is an enzyme that converts long-chain fatty acids into fatty acyl-CoA esters for lipid synthesis and fatty acid oxidation. Transforming growth factor beta 1 (TGFβ1) can upregulate ACSL3 via the SREBP-1 pathway, thereby leading to energy metabolic reprogramming in CRC cells [94]. This process supports EMT and metastasis and provides energy for cancer cell invasion and distant metastasis.

Increasing evidence also suggests that SREBP-1 may play an important role in tumour progression and malignancy [95]. SREBP-1 promotes CRC cell growth, migration, and invasion by upregulating snail family transcriptional repressor 1 (SNAIL) and accelerating EMT. This process relies on the oncogene known as c-Myc, with which SREBP-1 interacts to increase the binding of c-Myc to the SNAIL promoter, thereby increasing SNAIL levels and enhancing EMT and cell migration [96]. Drug resistance continues to pose a significant challenge to the prognoses and survival rates of patients with colorectal cancer. SREBP-1 is also overexpressed in CRC patient samples that are resistant to chemotherapy. SREBP-1 negatively regulates caspase-7 and sensitises CRC cells to chemotherapy [97]. Conversely, low SREBP-1 expression in CRC samples is associated with elevated caspase-7 levels. Therefore, the targeting of SREBP-1 may increase the sensitivity of colorectal cancer cells to gemcitabine. Similarly, when CRC cells are cultured in adipocyte-conditioned media, SREBP-1 levels increase via the Akt and p70S6K pathways, thereby reducing sensitivity to 5-FU and increasing drug resistance [98]. Similarly, mutations in PIK3 CA-mutated tumours lead to sustained activation of the PI3K/Akt signalling pathway, which correspondingly promotes the nuclear accumulation of SREBP-1 and the transcription of apolipoprotein A5 (APOA5) [99]. This transcriptional activation can further stimulate the peroxisome proliferator-activated receptor γ (PPARγ) signalling pathway, thus resulting in a reduction in the production of reactive oxygen species and consequently enhancing the chemoresistance of CRC.

Oridonin, which is a diterpenoid compound isolated from Rabdosia rubescens, exhibits notable anti-proliferative activity against cancer. Empirical evidence has demonstrated that oridonin effectively suppresses the expression of FAS and SREBP1 mRNAs and proteins in human colorectal cancer cells, thereby exerting its anticancer effects [100]. Berberine, which is traditionally utilised in Chinese medicine, has been demonstrated to inhibit the growth and lipogenesis of colon cancer xenografts via a SCAP-dependent mechanism [101]. This inhibition occurs via the suppression of SREBP-1 activation and SCAP expression, thus ultimately leading to the downregulation of associated lipogenic enzymes. Furthermore, the natural cyclic peptide known as RA-XII suppresses the expression of the novel fatty acid-synthesising proteins FASN and SCD by downregulating SREBP-1 expression, thereby inhibiting the proliferation and metastasis of colorectal tumours [102]. Ilexgenin A, which is known for its substantial lipid-lowering properties, has been demonstrated to reduce the expression of SREBP-1 and its target genes in the colon tissues of colorectal cancer model mice [103]. This compound may facilitate the early prevention of colorectal cancer by modulating lipid metabolism via the HIF1α/SREBP-1 pathway.

B7H3, which is a member of the B7 cosignaling molecule family, enhances resistance to ferroptosis by modulating SREBP-2-mediated cholesterol metabolism [104]. Both the administration of exogenous cholesterol and the application of the SREBP-2 inhibitor betulin effectively counteracted the influence of B7H3 on iron-induced apoptosis in colorectal cancer cells. Furthermore, the interaction between YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) and SREBP-2 facilitates enhancer-promoter interactions and promotes the recruitment of the mediator complex, thereby upregulating genes associated with the mevalonate (MVA) pathway, which correspondingly increases the susceptibility of patients to colorectal cancer [105]. Yu et al. reported that increased SREBP-2 and cholesterol due to lower atypical protein kinase C (PKC) levels are crucial for managing metaplasia and producing aggressive cell subpopulations in serrated tumours [106]. Thus, the targeting of cholesterol biosynthesis could serve as a chemoprophylaxis strategy. Similarly, polyunsaturated fatty acids such as docosahexaenoic acid and oleic acid may enhance CRC progression by activating SREBP-2 and inhibiting its target genes, which can occur independently of cholesterol levels and ER stress [107]. Sorting nexin 10 (SNX10) is crucial for maintaining intestinal stem cells (ISCs). Moreover, the deletion of SNX10 increases SREBP-2 activation, increases cholesterol production and aids in ISC recovery for mucosal healing [108]. Additionally, studies have demonstrated that the interaction between polyamine metabolism and the cholesterol synthesis pathway via SREBP-2 regulates colorectal cancer cell growth and malignancy [109]. Curcumin, a constituent of traditional Chinese medicine, induces activation of the transient receptor potential cation channel subfamily A member 1 (TRPA1), leading to enhanced calcium influx. This process subsequently upregulates peroxisome proliferator-activated receptor gamma (PPARγ) while concurrently downregulating the SP-1/SREBP-2/NPC1L1 pathway, thereby ultimately inhibiting cholesterol absorption [110].

SREBPs are central to CRC metabolic reprogramming and promote malignancy via lipid synthesis, cholesterol balance, and signalling activities. The targeting of SREBP and effectors such as SCD1 and NPC1L1 can hinder metabolic adaptation, EMT, and drug resistance (Table 2). Moreover, the combination of natural compounds with synthetic inhibitors could offer new CRC treatment strategies. Future research should explore the interactions of SREBPs with the tumour microenvironment to enable precise metabolic interventions and personalised therapies.

Table 2.

Related mechanisms of SREBPs molecular types in colorectal cancer

Type of Cancer	Targets of SREBPs	Key molecules/mechanism pathways	Main cell lines/sample sizes	Reference
Colorectal cancer	SREBP-1	PTPRO/AKT/mTOR	DLD1, HCT116, SW480, SW620, LoVo, RKO/276 patients with CRC	[83]
	SREBP-1	Aspirin	DLD-1, HCT 116, HepG2, PANC-1, AGS	[84]
	SREBP-1	TYM-3–98	HCT 116, LoVo, SW620	[85]
	SREBP-1	Brexpiprazole	HCT116	[86]
	SREBP-1	MMP7/AMPK	HT29, SW620, HUVEC/60 primary carcinoma specimens	[87]
	SREBP-1	circNOLC1, AZGP1/mTOR, G6PD	HCT116, LoVo, LS174 T	[88]
	SREBP-1	FASN	HT‐29, HCT‐8	[89]
	SREBP-1	Caspase-7, PARP1	HT29, SW620/30 primary carcinoma specimens	[91]
	SREBP-1	ZFAS1, PABP2	SW480/30 CRC and adjacent tissues, blood samples were obtained from 218 patients with CRC and 238 healthy people	[93]
	SREBP-1	TGFβ1, ACSL3	HCT116, LoVo	[94]
	SREBP-1	c-Myc, SNAIL/EMT	SW480, HT29, HCT116, SW620, LS180/44 patient fresh CRC and matched adjacent non-cancerous tissues	[96]
	SREBP-1	Akt/p70S6K, 5-FU	DLD-1, SW480	[98]
	SREBP-1	APOA5, PPARγ	HCT15, HCT116, SW480, SW620, LOVO	[99]
	SREBP-1	Oridonin	SW480, SW620	[100]
	SREBP-1	Berberine, SCAP	DLD-1, Caco-2	[101]
	SREBP-1	RA-XII	HCT116	[102]
	SREBP-1	Ilexgenin A/HIF1α	HT29, HCT 116	[103]
	SREBP-2	B7H3	NCM460, HCT116, HT29, SW480, SW620	[104]
	SREBP-2	ZMYND8/MVA	HEK293 T, HCT116, DLD1	[105]
	SREBP-2	PKC	HEK293 T, HCT116/483 CRC tissues from patients	[106]
	SREBP-2	SNX10	HCT116	[108]
	SREBP-2	Curcumin/SP-1, NPC1L1	Caco-2	[110]

SREBPs in pancreatic ductal adenocarcinoma

The prevalence and mortality of pancreatic ductal adenocarcinoma (PDAC) vary throughout the world, particularly in Asia. The Global Burden of Disease Study indicated a notable increase in pancreatic cancer cases and deaths from 1990 to 2017, especially in high-income areas [111]. In Southeast Asia, both the incidence and mortality of this type of cancer are increasing and are projected to significantly increase by 2050 [112]. The initiation of abnormally activated lipid metabolic reprogramming plays a key role in the development of PDAC, which can develop into a deadly malignant tumour with a high probability of recurrence and distant metastasis [69]. The expression of oxysterol binding protein-associated protein 5 (ORP5) is correlated with increased invasiveness and poor prognoses in patients with pancreatic cancer. ORP5 upregulates the expression of SREBP-2 and activates downstream genes associated with sterol response elements [113]. This regulatory mechanism influences the expression levels of tumour suppressor genes, thereby promoting the invasion and proliferation of pancreatic cancer cells. Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) alpha and beta play key roles in regulating intermediate metabolism. Hannes et al. reported that PGC-1α increases SREBP-1c and SREBP-2 expression in beta cells, thus impairing insulin secretion by increasing UCP2 transcription [114]. Conversely, a reduction of PGC-1β decreases the impact of SREBP-1c on granulophilin transcription, thereby enhancing glucose-stimulated insulin release. Moreover, sodium medroglutarate is enzymatically converted to farnesyl pyrophosphate (FPP), which is a precursor of cholesterol and sterols, and to geranyl pyrophosphate. These lipids are involved in tumourigenesis and progression. Dysregulation of the MVA pathway may activate SCAP and transcription factors such as SREBPs and HIF-1 [115]. As inhibitors of the MVA pathway, statins have the ability to reduce cancer risk and/or treat cancer by interfering with essential cell functions such as proliferation and differentiation. Kubota et al. demonstrated that synergistic apoptosis can be achieved when PDAC cells are treated with both statins and SREBP inhibitors and that this effect is dependent on geranylgeranyl diphosphate (GGPP), which is produced in the MVA pathway [116].

Diabetes is a significant risk factor for PDAC, with over 50% of individuals who are diagnosed with PDAC also presenting with diabetes. Research has demonstrated that elevated insulin secretion is correlated with the induction of SREBP-1c and augmented lipid synthesis in murine islets cultured under high-glucose conditions [117]. Type 2 diabetes mellitus (T2DM) is characterised by impaired glucose-stimulated insulin secretion (GSIS) due to glycolipid toxicity. The downregulation of SREBP-1c partially reverses GSIS injury induced by palmitate [118]. According to a recent report, transcolloin-2 expression is higher in PDAC tissues than in normal tissues [119]. Additionally, insulin activates SREBP-1-mediated transcription in PDAC cells to upregulate transgelin-2 expression. Moreover, the aberrant expression of cellular retinoic acid binding protein II (CRABP-II) enhances the stability of SREBP-1c mRNA and upregulates the downstream genes of SREBP-1c, thereby facilitating the absorption and accumulation of cholesterol in lipid rafts [120]. This increased accumulation of cholesterol in lipid rafts subsequently promotes AKT survival signalling and contributes to PDAC resistance. In addition, in the context of pancreatic cancer, liver X receptor (LXR) and SREBP-1 levels are notably lower in tumour tissues than in adjacent tissues. Furthermore, triptonide can further reduce LXR and SREBP-1 levels in tumours by activating p53 and causing DNA strand breaks, thus resulting in cell death [121].

In summary, the targeting of SREBPs and related pathways (such as MVA and CRABP-II) can effectively hinder metabolic adaptation and resistance (Table 3). Additionally, the combination of statins with natural compounds (such as triptonide) could enhance the effectiveness of PDAC treatment. Upcoming studies should concentrate on the dynamic interactions between SREBPs and the metabolic environments of tumours, including those associated with diabetes and cholesterol metabolism, to create targeted interventions and improve clinical treatments.

Table 3.

Related mechanisms of SREBPs molecular types in pancreatic ductal adenocarcinoma

Type of Cancer	Targets of SREBPs	Key molecules/mechanism pathways	Main cell lines/sample sizes	Reference
Pancreatic ductal adenocarcinoma	SREBP-1	Triptonide/P53	Patu8988, Panc-1/100 primary PC tumour tissues and 80 paired normal pancreatic tissues	[121]
	SREBP-1c	CRABP-II	BxPC3, Capan-1, Panc-1, Panc10.05, HEK293 T/12 primary PDACs samples	[120]
	SREBP-2	ORP5	Capan-1, Capan-2, Hs700 T, MiaPaCa2, Panc-1	[113]
	SREBP-1c/2	PGC-1α/β/UCP2	INS-1E	[114]
	SREBPs	MVA/GGPP	Pa02c, Pa03c, Pa16c, Pa20c, HEK293 T	[116]

SREBPs in gastric cancer

The prevalence and mortality rates associated with gastric cancer (GC) in Asia represent a significant public health concern. Empirical studies have indicated that Asia is among the regions with the highest incidence and mortality rates of gastric cancer, particularly regarding East Asian countries such as China, Japan, and South Korea [122]. Moreover, lipid metabolism plays a crucial role in the pathogenesis of GC, which is complex and diverse. SREBP-1c is activated in human gastric cancer and promotes the expression of a series of fatty acid synthesis-related genes, such as SCD1 and FASN [123]. SREBP-1c gene knockdown can restore the migration and invasion defects of gastric cancer cells. A similar increase in FASN and SREBP-1c protein and gene expression in gastric adenocarcinoma (GA) patients is associated with the overexpression of the hypoxia-inducing factor known as HIF-1α. The activation of SREBP-1c by HIF-1α can facilitate the upregulation of FASN in GA, which has diagnostic and prognostic significance [124]. The transcriptional cofactor RPRD1B (regulation of nuclear pre-mRNA domain containing 1B) has been identified as being a promoter of lymph node metastasis in gastric cancer both in vivo and in vitro. The underlying mechanism of this phenomenon likely involves the upregulation of fatty acid uptake and synthesis via transcriptional activation of the c-Jun/c-Fos pathway and subsequent activation of the c-Jun/c-Fos/SREBP1 axis [125]. Consequently, the targeting of this pathway represents a promising therapeutic strategy for the treatment of gastric cancer. Indeed, many types of drugs are also involved in treating gastric cancer via the lipid metabolism pathway related to SREBPs. For example, apatinib, which is a vascular endothelial growth factor 2 (VEGFR2) inhibitor, has antiangiogenic and anticancer effects. Specifically, it induces lipid peroxidation via the antioxidant enzyme glutathione peroxidase 4 (GPX4), which is mediated by SREBP-1a, thereby negatively regulating iron-induced apoptosis in GC cells, including those cells resistant to multiple drugs [126]. Natural compounds such as flavonoids, alkaloids and saponins can also inhibit the de novo synthesis of lipids in GC by regulating SREBP-1, reducing lipid accumulation levels, and subsequently inhibiting the occurrence and development of GC [127]. Statins can inhibit the MVA pathway, trigger apoptosis in cancer cells in vitro, and reduce tumour incidence in animals. Research has demonstrated that statins induce apoptosis in HGT-1 human gastric cancer cells, which is regulated by SREBP-1 and SREBP-2, with caspase-7 being activated under mevalonic acid restriction [128]. In summary, SREBPs are key regulators of lipid reprogramming in gastric cancer and promote malignant traits by integrating hypoxia, metastasis pathways, and drug responses. The targeting of SREBPs and their downstream effectors (such as FASN and GPX4) can effectively inhibit metabolic adaptation and metastasis (Table 4).

Table 4.

Related mechanisms of SREBPs molecular types in gastric cancer

Type of Cancer	Targets of SREBPs	Key molecules/mechanism pathways	Main cell lines/sample sizes	Reference
Gastric cancer	SREBP-1	RPRD1B/c-Jun/c-Fos/SREBP1 axis	HGC27, AGS/42 paired fresh specimens of tumour and adjacent non-tumour tissues	[125]
	SREBP-1a	Apatinib	MGC803, AGS, GES-1	[126]
	SREBP-1c	HIF-1α	AGS/112 GA patients and 156 control cases	[124]
	SREBP-1/2	MVA pathway	HGT-1, HCT116, HepG2, L50	[128]

SREBPs in oesophageal cancer

Oesophageal cancer is linked to risk factors such as smoking and obesity. The Global Burden of Cancer report estimated 511,054 new cases of oesophageal cancer and 445,391 deaths worldwide in 2022, with approximately 75% of the cases occurring in Asia [129]. Obesity is frequently linked to the dysregulation of lipid metabolism, whereas cancer cells are commonly characterised by metabolic reprogramming. Tumour cells require high levels of cholesterol during development to perform membrane biosynthesis and undergo rapid proliferation. In oesophageal tumours, SREBP1 overexpression is associated with lower survival rates and levels of miR142-5p, which is a tumour suppressor [130]. The inhibition or silencing of SREBP-1 in oesophageal cancer cells resulted in significant reductions in tributary characteristics, decreased expression of EMT markers, and increased expression of miR-142-5p. Additionally, the targeting of SREBP-1 molecules with the SREBP-1 inhibitor fatostatin can significantly inhibit tumourigenesis both in vitro and in vivo. Recently, AKT-dependent PCK1 was demonstrated to promote SREBP1-dependent adipogenesis. In patients with oesophageal squamous cell carcinoma (ESCC), PCK1 pS90, INSIG1 pS207/INSIG2 pS151 or nuclear SREBP-1 levels were observed to be positively associated with a poor prognosis [131]. A combined expression value for these indicators demonstrates better prognostic value for oesophageal cancer compared with a single protein expression value. By disrupting redox homeostasis, trace zinc can increase the level of intracellular Fe²⁺ and prevent ferroptosis in oesophageal cancer cells. A mechanism explaining this change could be related to the inhibition of p-AMPK and the induction of SREBP1 and SCD1, which increase the production of monounsaturated fatty acids exhibiting antiferroptotic characteristics [132]. In addition, the upregulation of SREBP1 in ESCC tumours and cells is closely related to proliferation and metastasis. As a result of SREBP1 depletion, SCD1 and Wnt/β-catenin signalling pathway activity are inhibited, thereby diminishing in vivo metastasis [133]. In ESCC, lysophosphatidylcholine acyltransferase 1 (LPCAT1) is highly expressed and reprograms cholesterol metabolism. Additionally, LPCAT1 regulates cholesterol synthesis by two mechanisms: the activation of PI3K to facilitate SP1/SREBP2 nuclear entry and the activation of EGFR to reduce INSIG-1 expression and promote SREBP-1 nuclear entry [134]. Moreover, the reduction of SREBP-2 expression in oesophageal cancer cells decreases their survival, migration, and colony formation. This scenario occurs via the interaction of SREBP-2 with c-Myc and the joint activation of HMG-CoA reductase (HMGCR) expression [135]. Thus, a focus on SREBPs and their effectors (such as SCD1 and HMGCR) can collectively impede metabolic adaptation and metastasis, whereas interventions such as fatostatin and zinc metabolism provide potential methods to combat drug resistance. Future research should focus on the interaction between SREBPs and activities in the tumour microenvironment (such as redox balance and EGFR/PI3K signalling) to develop multitarget therapies for overcoming clinical treatment challenges in oesophageal cancer (Table 5).

Table 5.

Related mechanisms of SREBPs molecular types in oesophageal cancer

Type of Cancer	Targets of SREBPs	Key molecules/mechanism pathways	Main cell lines/sample sizes	Reference
oesophageal cancer	SREBP-1	miR-142-5p	OE21, OE33	[130]
	SREBP-1	PCK1/INSIG1/INSIG2	200 ESCC patient samples	[131]
	SREBP-1	Trace zinc	EC109, EC9706, Het-1 A/31 pairs of ESCC patients and healthy control	[132]
	SREBP-1	SCD1/Wnt/β-catenin signaling pathway	TE-1, ECA-109, KYSE-150/77 paired ESCC tumour and adjacent normal tissue samples	[133]
	SREBP-1/2	LPCAT1/PI3K/EGFR	HEEC, EC9706, TE1/Tumour tissue from 154 patients with ESCC	[134]
	SREBP-2	c-Myc/HMGCR	Het-1 A, HEK 293 T, Eca109, KYSE150/samples from 52 patients(oesophageal cancer and adjacent non-tumour samples)	[135]

Strengths and limitations

The exploration of SREBPs in GI tumour metabolism has unearthed a wealth of knowledge, yet it also confronts certain challenges.

One of the significant strengths lies in the comprehensive understanding of SREBPs' role in lipid metabolic reprogramming across multiple GI tumours. In HCC, SREBPs intricately regulate lipid-related genes, with SREBP-1 playing a pivotal part in tumour progression by modulating pathways like FASN/ACLY for lipid production. In CRC, SREBPs are involved in various processes such as angiogenesis, metastasis, and drug resistance. This in-depth understanding of their functions provides a solid foundation for developing targeted therapies.

Furthermore, the identification of various intervention strategies targeting SREBPs represents a significant advancement in the field. Small molecule inhibitors have the capacity to directly inhibit SREBP activation, thereby disrupting lipid synthesis associated with tumour promotion. Natural compounds, with their multi-target regulatory capabilities, can modulate pathways related to SREBPs, providing a more comprehensive approach to treatment. Additionally, statins, through their interference with the mevalonate pathway, not only impact lipid metabolism but also demonstrate potential in augmenting the effectiveness of other anticancer therapies.

However, the current body of research is not without limitations. A major drawback is the heavy reliance on cellular and animal models for mechanistic investigations. These models, while valuable, cannot fully recapitulate the complexity of the human tumour microenvironment. The differences in metabolic regulation, immune-tumour interactions, and genetic backgrounds between models and human patients may lead to inaccurate predictions of treatment efficacy in the clinical setting.

Another limitation is the incomplete understanding of the functional divergence among SREBP subtypes. SREBP-1a, SREBP-1c, and SREBP-2 demonstrate distinct functions and expression patterns across various gastrointestinal cancers. Their differential roles in lipid metabolism, such as the variable influence of SREBP-1c on fatty acid and cholesterol metabolism in different tumours, necessitate more comprehensive investigation. This gap in understanding impedes the development of highly specific and effective targeted therapies. Clinically, the utility of SREBPs as reliable biomarkers is challenged. Although their expression levels correlate with patient prognosis, the presence of metabolic disorders, such as NAFLD and T2DM, complicates this relationship. Furthermore, certain SREBP-targeting intervention strategies may induce unintended side effects in normal tissues, thereby limiting their clinical applicability.

In conclusion, although substantial advancements have been made in understanding the role of SREBPs in gastrointestinal tumour metabolism, it is imperative to address existing limitations by employing more sophisticated research models, conducting comprehensive subtype analyses, and enhancing biomarker validation. These steps are crucial for the successful translation of research findings into effective clinical therapies.

Summary

As central regulators of lipid metabolic reprogramming, SREBPs exhibit a multifaceted cancer-promoting mechanism across various gastrointestinal solid tumours. The role of SREBPs extends beyond facilitating the synthesis of fatty acids and cholesterol. Furthermore, a dynamic regulatory network is established by integrating metabolic signals with classical oncogenic pathways, such as the AKT/mTOR, Wnt/β-catenin, and epithelial-mesenchymal transition (EMT) pathways. For example, in HCC, SREBP-1 enhances nuclear translocation through its interaction with PKM2 and the Ephrin-A3/EphA2 axis. In CRC, SREBP-1 collaborates with c-Myc to activate the SNAIL/EMT pathway. Additionally, in ESCC, LPCAT1 activates SREBP-1/2 via a dual pathway to reprogram cholesterol metabolism. The shared metabolism-signalling interactions in various cancers suggest that the targeting of SREBPs could be widely effective against tumours. Intervention strategies include small molecule inhibitors such as fatostatin, which block SREBP activation; natural compounds such as lamonidin and berberine, which inhibit SREBP via pathways such as the AMPK/mTOR pathway; and statins, which disrupt the substrate supply via the MVA pathway. The combination of SREBP targeting with other metabolic targets (such as SCD1 or HMGCR) or treatments such as chemotherapy/radiotherapy has demonstrated promise in overcoming resistance, such as 5-FU resistance in CRC and iron death resistance in ESCC.

Nevertheless, the current body of research is subject to notable limitations. First, a substantial portion of the mechanistic evidence is derived from cellular or animal models, which possess metabolic microenvironments that are distinct from those of human tumours. This discrepancy may lead to an overestimation of the therapeutic efficacy of the targeting of a single pathway. Second, the functional heterogeneity among members of the SREBP family (including SREBPs-1a/1c-2) that is observed across various cancer types remains inadequately understood. For example, SREBP-1c predominantly influences fatty acid synthesis in GC, whereas it is more closely linked to cholesterol metabolism in PDAC, thus necessitating precise targeting strategies to differentiate between the subtypes. From a clinical translation perspective, although SREBP expression is significantly correlated with prognosis, it lacks specificity as a biomarker, particularly in patients with metabolic disorders such as NAFLD and T2DM. Furthermore, certain intervention strategies (such as cholesterol deprivation) may induce off-target toxicity in normal tissues. Thus, the advancement of metabolic targeted therapy necessitates the interdisciplinary integration of metabolic biology, pharmaceutical engineering, and clinical oncology to overcome existing limitations and facilitate a paradigm shift from"pathway inhibition"to"metabolic microenvironment reshaping".

Abbreviations

GI

Gastrointestinal tumour

SREBPs

Sterol regulatory element-binding proteins

SCAP

SREBP cleavage activation protein

INSIG

Insulin-inducing gene protein

SREs

Nonpalindrosterol response elements

ACLY

ATP citrate lyase

ACC

Acetyl-CoA carboxylase

FASN

FA synthase

SCD

Stearoyl-CoA desaturase

ER

Endoplasmic reticulum

Golgi

Golgi apparatus

FBW7

F-Box And WD Repeat Domain Containing 7

TAK1

Transforming growth factor-β activated kinase 1

PRMT5

Protein arginine methyltransferase 5

SUMO

Small ubiquitin-like modifier

HDAC3

Histone deacetylase 3

CBP

CREB-binding protein

SIRT1

Sirtuin-1

UBC12

Ubiquitin Conjugating Enzyme E2 M

HCC

Hepatocellular Carcinoma

ATP1A1/CA2

ATPase Na⁺/K⁺ Transporting Subunit Alpha 1/ Carbonic Anhydrase 2

PCK1

Phosphoenolpyruvate carboxykinase 1

PKM2

Pyruvate kinase M2

EFNA3

Ephrin A3

EphA2

Ephrin Type-A Receptor 2

SLC25A47

Solute Carrier Family 25 Member 47

SIRT3

Sirtuin 3

Prx5

Peroxidase 5

AMPK

AMP-activated protein kinase

ROS

Reactive oxygen species

HDGF

Hepatoma-derived growth factor

FCN3

Ficolin 3

SFN

Sorafenib

NS5ABP37

Novel hepatitis C virus non-structural protein 5A-associated binding protein

LATS2

Large Tumour Suppressor Kinase 2

NAFLD

Non-alcoholic fatty liver disease

MSC-ex

Exosomes derived from human umbilical cord mesenchymal stem cells

CAMKK1

Calcium/calmodulin-dependent protein kinase 1

AATF

Apoptosis antagonizing transcription factor

THP

The phytochemical tetrahydropalmatine

UDCA

Ursodeoxycholic acid

OA

Oleic acid

OG

Octyl gallate

CRC

Colorectal cancer

PTPRO

Protein tyrosine phosphatase receptor Type O

MMP7

Matrix metalloproteinase 7

AZGP1

Alpha-2-Glycoprotein 1, Zinc-Binding

ZFAS1

ZNFX1 antisense RNA1

ACSL3

Acyl-CoA synthetase 3

5-FU

5-Fluorocrail

PPARγ

Peroxisome Proliferator Activated Receptor Gamma

B7H3

B7 homolog 3 protein

ZMYND8

Zinc finger MYND-type containing 8

MVA

Mevalonate

PKC

Atypical protein kinase C

ISCs

Intestinal stem cells

SNX10

Sorting nexin 10

TRPA1

Transient receptor potential ankyrin 1

NPC1L1

Niemann-Pick C1-like 1

ORP5

Oxysterol binding protein-associated protein 5

PGC-1

Peroxisome proliferator-activated receptor-gamma co-activator-1

UCP2

Uncoupling Protein 2

FPP

Farnesyl pyrophosphate

GGPP

Geranylgeranyl diphosphate

PDAC

Pancreatic ductal adenocarcinoma

T2DM

Type 2 diabetes mellitus

GSIS

Glucose-stimulated insulin secretion

CRABP-II

Cellular retinoic acid binding protein II

LXRs

Liver X receptors

HIF-1α

Hypoxia Inducible Factor 1 Subunit Alpha

RPRD1B

Regulation Of Nuclear Pre-MRNA Domain Containing 1B

VEGFR2

Vascular endothelial growth factor 2

GPX4

Glutathione Peroxidase 4

GC

Gastric cancer

LPCAT1

Lysophosphatidylcholine Acyltransferase 1

EGFR

Epidermal Growth Factor Receptor

HMGCR

3-Hydroxy-3-Methylglutaryl-CoA Reductase

ESCC

Oesophageal squamous cell carcinoma

ORP5

Oxysterol binding related proteins 5

Authors’ contributions

HWT conceived the idea and wrote the manuscript. YTZ, DNZ and MJG drew the diagrams and tables. XY and XW (corresponding author) revised and edited the manuscript. The author(s) read and approved the final manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (No. 32170910) and the Projects from Social Development of Zhenjiang (SH2024024).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.