The SREBP family comprises three major isoforms: SREBP-1a, SREBP-1c, and SREBP-2. While SREBP mRNAs are ubiquitously expressed across tissues, their abundance and functional dominance exhibit significant tissue specificity. For instance, hepatic SREBP-1c expression surpasses SREBP-1a levels by approximately tenfold (25). Functionally, SREBP-1a primarily regulates both fatty acid and cholesterol biosynthesis, acting as a master transcriptional activator of rate-limiting enzymes such as ACC and HMGCR. In contrast, SREBP-1c serves as the principal regulator of fatty acid synthesis and energy storage, directly controlling the expression of key lipogenic enzymes including ACC, FAS, and SCD1. SREBP-2 operates with high specificity in cholesterol homeostasis, governing the transcriptional activation of HMGCR and LDLR (26). Beyond their canonical roles in lipid metabolism, SREBPs function as critical signaling hubs integrating diverse biological processes, including reactive oxygen species (ROS) generation, endoplasmic reticulum stress responses, autophagy regulation, and apoptosis modulation (27, 28).

The PPAR family comprises three distinct subtypes: PPARα, PPARβ/δ, and PPARγ. PPARα is predominantly expressed in brown adipose tissue, liver, heart, kidneys, and skeletal muscle. It coordinates lipid β-oxidation through synergistic interactions with PGC-1α, regulating key lipolytic enzymes including adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL). Additionally, PPARα activates thermogenic gene programs, notably upregulating uncoupling protein 1 expression to enhance energy expenditure. PPARγ, the most abundant isoform in adipose tissue, serves as a master regulator of white and brown adipocyte differentiation. It promotes lipid uptake by modulating lipid transporters CD36, FABPs, and FATPs, while stimulating lipogenesis through transcriptional activation of lipogenic enzymes such as lipoprotein lipase (LPL) (29). PPARβ/δ exhibits high activity in skeletal muscle, where it cooperates with PGC-1α to induce the expression of fatty acid catabolic enzymes and thermogenic regulators, thereby enhancing lipid oxidative metabolism and heat production (30).

ChREBP is a transcription factor that promotes lipogenic gene expression by sensing carbohydrates and is a hub for hepatic lipid synthesis (31). It is predominantly expressed in metabolically active tissues including the liver, intestine, and adipose tissue, where it orchestrates hepatic lipid biosynthesis through three distinct mechanisms: first, it regulates acetyl-CoA production via the pentose phosphate pathway and glycolysis-derived citrate cleavage. The second is direct transcriptional activation of the rate-limiting enzymes in fatty acid synthesis- ACC, FAS, and SCD1-thereby facilitating fatty acid synthesis, elongation, and desaturation. Third, it upregulates the expression of microsomal triglyceride transfer protein, which promotes the formation of very low-density lipoprotein (VLDL) particles. Notably, ChREBP exhibits functional crosstalk with PPARα, creating a metabolic switch that coordinates lipid anabolism and catabolism in response to nutritional status (32).

The nuclear receptor superfamily member, FXR, exists as four principal human isoforms (FXRα1-α4), with predominant hepatic and intestinal expression. Functioning as a monomer or heterodimer, FXR orchestrates transcriptional programs governing BA homeostasis and lipid metabolism through three primary mechanisms: (1) Suppression of bile acid synthesis via CYP7A1 downregulation; (2) Inhibition of cholesterol biosynthesis through Insig-2 activation; (3) Coordination of enterohepatic circulation by regulating BSEP/ABCB11 and intestinal bile acid-binding protein (33). Notably, hepatic FXRα2 exerts isoform-specific functions through selective binding to ER-2 response elements (34). Beyond its established roles, FXR modulates adipogenesis by repressing SREBP-1c expression (35), positioning it as a therapeutic target for metabolic disorders, hepatobiliary malignancies, and gastrointestinal cancers (36).

LXR, a pivotal member of the nuclear receptor superfamily, serves as a master coordinator of hepatic metabolic homeostasis. Its regulatory functions encompass two principal mechanisms: (1) promoting cellular cholesterol efflux through transcriptional activation of ATP-binding cassette transporters ABCA1 and ABCG1, and (2) modulating LDLR-dependent cholesterol uptake via induction of inducible degrader of LDLR (IDOL)-mediated receptor degradation, operating independently of the canonical SREBP pathway (37). Furthermore, LXR exerts cross-regulation of lipid metabolism by transcriptionally activating SREBP-1c (38), thereby bridging cholesterol homeostasis with fatty acid biosynthesis.

AMPK serves as a central energy sensor orchestrating systemic metabolic homeostasis through phosphorylation-dependent regulation of key metabolic nodes. This evolutionarily conserved kinase exerts multifaceted control over lipid metabolism via three principal mechanisms: (1) suppression of DNL through inhibitory phosphorylation of ACC1/ACC2 (39) and HMGCR (40), effectively blocking FA and cholesterol biosynthesis; (2) enhancement of lipolytic capacity via activation of ATGL phosphorylation, driving fatty acid β-oxidation (41); and (3) transcriptional regulation through phosphorylation-mediated inhibition of lipogenic transcription factors SREBP-1c (42) and ChREBP (43). By integrating glycolytic flux, mitochondrial energetics, and lipid storage/oxidation programs, AMPK maintains cellular energy equilibrium while preventing ectopic lipid accumulation (44).

ncRNAs, primarily encompassing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), lack protein-coding capacity but critically regulate lipid metabolism by modulating the expression of related genes through transcriptional, post-transcriptional, and post-translational mechanisms. miRNAs primarily function post-transcriptionally, directly targeting key enzymes and regulators (e.g., ACC, FAS, LDLR, HMGCR, ABCA1, CYP7A1) to inhibit FA synthesis and modulate cholesterol homeostasis. They also indirectly regulate lipid metabolism through core regulators like SREBPs, PGC1α, AMPK, and LXR. Notably, miR-33 is a key regulator of cholesterol homeostasis (45, 46). lncRNAs employ more complex mechanisms (e.g., signaling, scaffolding, decoying, enhancer, or guide functions) to bidirectionally regulate target genes across transcriptional, post-transcriptional, and epigenetic levels. They target central factors (e.g., ACC, FAS, SCD1, LDLR, ABCA1, ChREBP, SREBPs, AMPK, LXR, FXR) to inhibit lipid synthesis, promote cholesterol uptake, facilitate RCT and HDL synthesis, and enhance BA synthesis, typically yielding net beneficial effects. Conversely, lncRNAs can negatively regulate factors including CD36, HMGCR, ABCA1, and SREBPs. Additionally, lncRNAs modulate lipid metabolism by acting as miRNA sponges to sequester miRNAs (45, 47). Similarly, circRNAs can also function as miRNA sponges, adsorbing miRNAs to regulate key lipid metabolism molecules (e.g., FAS, PPARs, AMPK, SREBPs), thereby forming an antagonistic regulatory network with miRNAs (48, 49). Notably, HDL biogenesis is regulated by both miRNAs and lncRNAs, while HDL particles themselves serve as carriers for these ncRNAs (50, 51).

Cellular FA uptake is a key regulatory node in systemic lipid homeostasis. The scavenger receptor CD36 coordinates transmembrane fatty acid transport through dynamic plasma membrane-organelle transport (52). Pharmacological studies have shown that Pue exerts a multitissue lipid-lowering effect through the coordinated regulation of FA transporters. In cardiomyocytes, Pue inhibits Na⁺/K⁺-ATPase-driven expression of CD36, which reduces FA uptake and ameliorates cardiac steatosis in in vitro and in vivo models (53). In diabetic skeletal muscle, Pue attenuates CD36 membrane translocation while increasing mitochondrial β-oxidizing capacity, thereby reducing lipid accumulation in myocytes (54). Liver studies have shown that Pue has a dual inhibitory effect on CD36 and fatty acid transporter protein 5 (FATP5), which significantly reduces lipid deposition associated with NAFLD (55). Mechanistically, Pue disrupted the PPARγ-CD36 signaling axis and effectively counteracted environmental toxicant (bisphenol S)-induced lipid deposition in C57BL/6J mice (56).

DNL, a central metabolic pathway in hepatic and adipose tissues, is dynamically regulated by nutrient-hormonal crosstalk involving insulin, glucagon, and glucocorticoids. These endocrine signals converge on transcriptional activation of core lipogenic regulators—SREBP-1c and ChREBP—through kinase-mediated signaling cascades (2). Mechanistic studies reveal that Puel exerts potent anti-lipogenic effects via multi-target suppression of the DNL machinery: Transcriptional downregulation of master regulators SREBP-1c and ChREBP; Concomitant inhibition of rate-limiting enzymes including ACC, FAS, SCD1, and HMGCR. Functional validation across experimental models demonstrating attenuated lipid accumulation in both murine hepatocytes and human HepG2 cell lines (55, 57–59).

Hyperlipidemia, defined as a disturbance in the balance of plasma lipids, is most frequently manifested as hypercholesterolemia. This condition is a well-established risk factor for a variety of metabolic disorders, including obesity, T2DM, CVD, NAFLD, and acute pancreatitis (3). Experimental studies demonstrate that Pue ameliorates high-cholesterol diet-induced hyperlipidemia through CYP7A1 upregulation (64). Mechanistically, Pue exerts dual regulatory effects by suppressing HMGCR activity (reducing cholesterol biosynthesis) while enhancing CYP7A1 and LDLR expression, thereby promoting cholesterol excretion and LDL clearance. This dual mechanism underlies its protective effects against lead-induced hyperlipidemia (65). Notably, the JNK/c-Jun/CYP7A1 pathway has been identified as a critical mediator of Pue’s anti-hyperlipidemic activity in carbon tetrachloride (CCl4)-induced models (66). In diabetic models, Pue shows therapeutic potential through PPARα activation in gastrocnemius muscle tissue, effectively reducing lipid accumulation in streptozotocin (STZ)-induced diabetic mice (67). Cellular studies reveal that Pue inhibits lipid deposition in HepG2 hepatocytes via AMP-activated protein kinase (AMPK)-mediated suppression of acetyl-CoA carboxylase (ACC) activity, concurrently downregulating adipogenic markers (SREBP-1c, FAS, SCD, and HMGCR) (58). Interestingly, while Pue and its glycosides consistently upregulate LDLR expression in both HepG2 cells and C57BL/6J mice, their effect on CYP7A1 exhibits model specificity–significantly enhancing mRNA levels in murine liver without affecting in vitro systems (68).

Obesity is typically characterized by a state of energy imbalance, whereby energy intake exceeds energy expenditure, leading to excessive fat storage. Obesity is a significant risk factor for a number of diseases, including T2DM, NAFLD, CVD, and cancer (69). Current epidemiological data indicate over 600 million adults worldwide are clinically diagnosed with this condition (70). In high-fat diet/streptozotocin (HFD/STZ)-induced diabetic Sprague–Dawley rats, Pue administration significantly attenuated obesity-related metabolic derangements, manifested by reduced serum TG and FFA levels concomitant with decreased body weight (54). Notably, Pue demonstrated comparable efficacy in high-fat fructose diet-induced obese SD rats (58). Pue is also effective in modulating dyslipidemia through AMPK activation and coordinated regulation of key lipid-metabolizing enzymes: upregulating HSL while suppressing PPARγ (60). Pue enhances PGC-1α expression in skeletal muscle of HFD-fed mice, counteracting obesity-associated complications (71). Mechanistic studies further elucidate its multi-target effects: Inhibiting lipid absorption/synthesis via FXR-mediated downregulation of CD36, SREBP-1c, ACC, and FAS; Modulating bile acid homeostasis through CYP7A1 suppression and BSEP induction; Restoring gut microbiota composition, particularly Firmicutes/Bacteroidetes ratio and relative abundances of Firmicutes/Ascomycota phyla in HFD-induced obese C57BL/6 mice (57). Emerging evidence highlights Pue’s developmental programming effects–early intervention ameliorates hepatic steatosis and may mitigate adult-onset obesity in intrauterine growth restriction models (72). Recently discovered, Pue exerts central nervous system-mediated anti-obesity effects by binding to γ-aminobutyric acid type A receptor (GABA_AR), thereby suppressing dorsal motor nucleus of the vagus neuronal activity. This neuroendocrine mechanism leads to jejunal microvilli shortening and consequent inhibition of intestinal fat absorption (19).

T2DM, defined as a chronic metabolic disorder characterized by persistent hyperglycemia, arises from pancreatic β-cell dysfunction coupled with systemic insulin resistance. Moreover, Emerging evidence indicates that chronic intracellular lipid accumulation (lip toxicity) contributes to β-cell dysfunction through multiple molecular mechanisms, including endoplasmic reticulum stress, oxidative stress, inflammatory responses, mitochondrial dysfunction, and impaired autophagy (73). Pue reduces TC, TG, LDL, PA, and Lysophosphatidylcholine (LysoPC) levels, increase HDL, PC, and PE levels, improve glucose-lipid metabolism and reduce inflammatory damage through AMPK-mTOR and PPARγ-NF-κB signaling pathways, thus treating diabetes mellitus (74). In skeletal muscle, Pue increased AMPK, SIRT1, PGC-1α, and CPT-1β levels and promoted fatty acid oxidation, thereby preventing lipid accumulation in diabetic models (54). Concurrently, hepatic insulin resistance is improved through Fetuin B suppression, AMPK phosphorylation, and inhibition of ACC activity (75). It is noteworthy that Professor Roy Taylor, a prominent British scholar, has underscored that lipid deposition in the liver and pancreas serves as the initiating factor that precipitates diabetes mellitus (76). This provides an important reference for Pue to target the regulation of lipid metabolism in the treatment of diabetes mellitus and its complications.

NAFLD affects approximately 25.24% of the global population (77), with pathogenesis driven by hepatic lipid dysregulation through enhanced FA uptake and DNL, ultimately triggering cellular stress, inflammation, tissue remodeling, and fibrosis. Experimental evidence demonstrates that Pue can reduce the expression of FATP 5, CD36, SREBF1, ChREBP, ACC, and FAS to decrease lipid uptake and biosynthesis, and up-regulate the expression of CPT 1a, ATGL, and ApoB100 to promote the degradation of lipids, which significantly improves the accumulation of lipids in the livers of rats with NAFLD (55). Mechanistic studies reveal Pue activates the FMO5/PPARα axis to stimulate PGC1α and CPT1a expression, thereby promoting FA oxidation and reducing lipid deposition in NAFLD mice (62). In vitro validation using oleic acid-treated HepG2 cells confirms Pue’s multi-target action: activation of PPARα and AMPK pathways concurrently inhibits SREBP1 and FAS expression while enhancing FA oxidation, effectively counteracting lipid accumulation (59).

CVD is the leading cause of death worldwide. Atherosclerosis (AS), the primary CVD manifestation, results from cholesterol deposition in arterial walls, leading to plaque formation and vascular dysfunction (78). LDL critically drives AS progression (79), underscoring lipid metabolism regulation as a key therapeutic target. Pue exerts anti-atherogenic effects by reducing serum TG, TC, and LDL levels while enhancing CYP7A1 expression in hypercholesterolemic models, thereby promoting cholesterol and bile acid excretion and lowering atherogenic indices (64). In vivo studies demonstrate Pue’s capacity to inhibit aortic intimal thickening and plaque formation in rabbits (80). In addition, Pue alleviate AS by inhibiting the production of Prevotella copri (P. copri) as well as trimethylamine (TMA) (81), while trimethylamine-N-oxide (TMAO) relies on the gut microbiota to improve lipid metabolism by regulating reverse cholesterol transport (82). At the cellular level, Pue combats foam cell formation through dual actions: (1) activating the AMPK-PPARγ-LXRα pathway to promote ABCA1-mediated cholesterol efflux (63), and (2) downregulating CD36 expression to limit lipid uptake in human THP-1 macrophages (83). Further studies reveal Pue’s activation of the PERK/Nrf2/thioredoxin 1 (Trx1) axis reduces scavenger receptor-A (SR-A) and lectin-type oxidized LDL receptor-1 (LOX-1) expression, inhibiting macrophage lipid accumulation (84). In cardiac pathophysiology models, Pue attenuates myocardial hypertrophy via PPARα/PGC-1α-mediated upregulation of CPT1a/b, enhancing fatty acid oxidation (85). It concurrently preserves cardiac function by increasing Na+/K+-ATPase activity and suppressing CD36-mediated fatty acid uptake (53). Notably, Pue supplementation demonstrates preventive efficacy against diet-induced metabolic syndrome and CVD complications by improving glucolipid homeostasis, attenuating cardiovascular remodeling, and reducing atherogenic indices (18), positioning it as a promising nutraceutical for cardiometabolic disease prevention.

Pue exhibits therapeutic potential for central nervous system (CNS) disorders through multimodal mechanisms (86–88). Emerging research highlights the intersection of lipid metabolic dysregulation and CNS pathophysiology (89). Hypercholesterolemia exacerbates neuroinflammation, accelerating neuronal degeneration and cognitive decline (90). Dietary supplementation with Pue attenuates the metabolic syndrome and associated neurological damage induced by a high-fat/high-sugar diet by restoring glycolipid homeostasis and improving cortical/hippocampal vascularity and neuronal density (18). In addition, Pue modulates phospholipid metabolism and attenuates inflammation associated with depression by inhibiting TLR4 and repairing the intestinal barrier (91). Gut-brain axis studies reveal Pue’s microbiota remodeling capacity in chronic stress models: Enriching beneficial taxa (Firmicutes, Lactobacillus) and Depleting pathogenic genera (Proteobacteria, Desulfovibrio) (92). These commensal microbes enhance intestinal integrity and immunomodulation through short-chain fatty acid (SCFA) production (93, 94). Notably, recent advances position cellular senescence as a therapeutic frontier for CNS disorders (95), with lipid metabolic alterations driving senescence progression (10). Pue’s dual targeting capability—modulating lipid metabolism while clearing senescent cells—presents a novel strategy for treating age-related neurological diseases.

Osteoporosis is characterized by low bone mass and deterioration of bone micro-structure. Pue exerts anti-osteoporotic effects by regulating the type and abundance of intestinal flora, increasing the content of SCFAs in the colon, especially acetic acid and butyric acid, maintaining the dynamic balance of the colonic mucosa, and reducing the inflammatory response (96). Pue influences gut microbial diversity by modulating Alloprevotella, Rodentibacter, Alistipes, and Fusobacterium flora, remodels gut flora, and regulates alpha-linolenic acid metabolism and glycerophospholipid metabolism, thereby inhibiting pioglitazone-mediated bone loss (97). Pue can also improve OVX-induced osteoporosis by activating the Wnt 3a/β-catenin signaling pathway, inhibiting the PPARγ signaling pathway, regulating phospholipid metabolism and the biosynthesis of PUFAs, and modulating the differentiation of bone mesenchymal stem cells to osteoblasts (98).

Lipid signaling critically regulates tumor progression and microenvironment remodeling, with Pue emerging as a multi-target anticancer agent since its initial antitumor activity in colon cancer was reported in 2006 (99). Subsequent studies validate Pue’s efficacy across esophageal (100), lung (101, 102), hepatic (103), breast (104), and bladder cancers (105) through five core mechanisms: suppressing cancer cell proliferation/migration (105), inducing apoptosis (106), reprogramming glucose metabolism (107), overcoming chemoresistance, and modulating tumor immune landscapes (108). Mechanistically, Pue reverses multidrug resistance (MDR) in human breast cancer MCF-7/adr cells by upregulating AMPK and ACC, thereby inhibiting MDR1 expression (109). This finding holds particular significance given that phospholipid/cholesterol-mediated MDR pathways represent major obstacles in chemotherapy (110). Crucially, Pue’s ability to target lipid metabolic nodes—including MDR1 suppression and chemoresistance reversal—positions it as a promising candidate for developing lipid-centric anticancer strategies, offering novel therapeutic opportunities for oncology patients.

Pue reverses alcohol-induced metabolic disturbances, including sphingolipid metabolism, resulting in hepatoprotective effects (111). In alcoholic fatty liver disease (AFLD), Pue ameliorates hepatic lipid accumulation in zebrafish larvae by suppressing fatty acid synthesis via the AMPKα-ACC pathway, while concurrently restoring sphingolipid homeostasis to exert hepatoprotective effects (112). Beyond hepatic protection, Pue counteracts sarcopenia by remodeling the gut-muscle axis: enhancing gut microbiota diversity, elevating SCFA production, and boosting ATP synthesis to improve skeletal muscle strength (113). Additionally, in alcohol-related osteopathology models, Pue reduces PPARγ expression in both murine bone marrow stromal cells and Kunming mice, effectively inhibiting bone marrow adipogenesis while preserving osteogenic differentiation capacity, thereby mitigating alcoholic osteonecrosis (114).