The AMPK and mTOR signaling pathways are key regulators of lipophagy efficiency owing to their influence on lipid synthesis and oxidation processes (38). Analogous to that of autophagy, the initiation of lipophagy is governed by the inhibition of specific signaling pathways (particularly the PI3K/AKT/mTOR pathway). mTOR predominantly regulates the lipophagic process through its complex, mTORC1 (39). Lipophagy initiation is dictated by the dynamic interplay between AMPK and mTORC1, which are the primary cellular energy sensors (40). mTORC1 activation facilitates ULK1/2 and ATG13 phosphorylation, which in turn inhibits the formation of the ULK1/2-ATG13 complex (41,42). mTORC1 modulates lipophagy via two distinct mechanisms. Initially, lipophagy is inhibited through the modulation of TFEB nuclear translocation, and subsequently, suppression is accomplished by regulation of ATG14 activity (43,44). AMPK activation directly inhibits mTORC1 activity by phosphorylating and enhancing RHEB GTPase-activating protein activity, as well as by disrupting the stability of the mTORC1 complex through RAPTOR phosphorylation. Simultaneously, mTORC1 exerts negative feedback regulation by phosphorylating the AMPKα subunits at the Ser347 and Ser345 residues. This reciprocal modulation establishes a dynamically balanced metabolic regulatory network (45). In this process, lipophagy regulation is intricately linked to macrophage function as well as the overall status of systemic lipid metabolism. Moreover, disruptions in hepatic lipid metabolism are markedly associated with increased AS risk, underscoring the notable role of lipophagy in maintaining systemic lipid homeostasis (46). Heterogenous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1)-knockout hepatocytes exhibit increased co-localization of APs and LDs and enhanced LD lysosomal degradation, suggesting that lipophagy is crucial for reducing lipid deposition. The absence of hnRNPA2B1 decreases lipid droplet accumulation by preventing Atg5 degradation and boosting autophagy-driven lipophagy (47).

TFEB, recognized as a key regulator of autophagy and lysosome biogenesis, is considered to play a marked role in various pathological processes associated with the development of AS (48). TFEB is a marked regulator of lipid metabolism, overseeing transcriptional responses that control lysosomal biogenesis and autophagy. With roles in autophagy regulation, lysosomal formation, fusion and substrate degradation, TFEB promotes lipid breakdown and transport, making it a potential target for regulating lipophagy (49). TFEB has been shown to facilitate LD degradation and enhance lipid metabolic homeostasis by activating the lipophagy pathway. This mechanism may reduce lipid accumulation in macrophages and attenuate inflammatory responses, potentially impeding AS progression (50). TFEB transcriptional activity is tightly regulated by post-translational modifications, primarily phosphorylation and acetylation, which dictate its subcellular localization. Under nutrient-rich conditions, mTORC1 phosphorylates TFEB at specific residues (such as Ser211), promoting its interaction with 14-3-3 proteins and resulting in its cytosolic sequestration. Conversely, during lipid stress or atherogenic conditions, mTORC1 inhibition or AMPK activation leads to TFEB dephosphorylation (51). Concurrently, NAD+-dependent deacetylases, particularly SIRT1, deacetylate TFEB at key lysine residues (such as Lys116) (52). This synergistic dephosphorylation and deacetylation trigger the rapid nuclear translocation of TFEB, where it binds to coordinated lysosomal expression and regulation motifs. This binding markedly upregulates the expression of essential lipophagy and cholesterol efflux genes, including MAP1LC3B, SQSTM1 (p62) and ABCA1, thereby accelerating lipid droplet degradation and reducing lipotoxicity (53). TFEB enhances lipid breakdown and cholesterol removal via the autophagy-lysosome pathway and PPARα-PGC1α signaling while also stabilizing AS plaques by inhibiting NLRP3 inflammasome activation (38). Although the precise molecular mechanisms by which TFEB regulates AS are not yet fully understood, evidence suggests that TFEB expression levels vary among different cell types (48). These variations may affect AS pathological progression through cell-specific regulatory networks.

Sirt6, a deacetylase enzyme, plays a notable role in lipophagy and lipid metabolism. It has been implicated in the pathogenesis of age-related diseases, cancer and diabetes (54–56), and Sirt6 regulation offers a new strategy for AS treatment. Sirt6 knockout increases plaque area in ApoE-/-mice, while its overexpression reduces plaque size and slows AS progression by downregulating MMP-2 and suppressing hypoxia inducible factor-1α, toll-like receptor-4 and von Willebrand factor. This enhances plaque stability by reducing intraplaque neovascularization (57). In macrophages, increasing Sirt6 expression boosts autophagy, reducing macrophagic interactions with ECs and decreasing adhesion and infiltration. This suppresses macrophage apoptosis and enhances atherosclerotic plaque stability (57). Studies have further highlighted the multifaceted protective roles of SIRT6 in autophagy regulation and inflammation resolution across different vascular cell types. For example, Li et al (58) demonstrated that SIRT6 epigenetically enhances macrophage efferocytosis, a specialized phagocytic and autophagic clearance mechanism, by hindering miR-216/217 cluster maturation, which promotes the resolution of chronic inflammation. Furthermore, Zi et al (59) showed that the protective role of SIRT6 extends beyond macrophages by revealing that SIRT6-induced autophagy effectively restricts TREM-1-mediated pyroptosis in oxidized low-density lipoprotein (ox-LDL)-treated ECs. This effect notably reduces endothelial damage and inflammatory cell death. These findings collectively underscore that SIRT6 not only prevents macrophage foam cell formation but also globally attenuates vascular inflammation by modulating autophagic flux, reinforcing its potential as a multidimensional epigenetic target for plaque stabilization. Sirt6 also promotes lipophagy by inhibiting the Wnt1 pathway, which reduces the accumulation of LDs and associated proteins, facilitating their degradation. These actions collectively reduce foam cell formation and inhibit AS development (35).

PLINs, the predominant proteins on LD surfaces, localize to specific binding sites to modulate lipid storage and hydrolysis (60). As notable surface proteins associated with LDs, PLINs initiate lipophagy by undergoing degradation (61). The PLIN protein family, consisting of PLIN1-5, regulates lipase binding to LDs during lipophagy, influencing both macroautophagy and CAM. PLIN1, required for LD function, plays a notable role in metabolic regulation. In adipocytes, its absence enhances liposome-lysosome fusion and LD-lysosome interactions, accelerating macroautophagy-mediated lipolysis (62). Structurally, the CMA pathway selectively recognizes KFERQ-like motifs within the amino acid sequences of PLIN2 and PLIN3, and the cytosolic chaperone heat shock cognate 70 kDa protein (Hsc70) specifically identifies and binds to these pentapeptide motifs. As a result of this structural interaction, the PLIN-Hsc70 complex is delivered to the lysosomal membrane, where it engages with the lysosome-associated membrane protein 2A (LAMP-2A) receptor for translocation and subsequent degradation. Moreover, PLIN2/3 removal via this process reveals the lipid droplet surface, which is a prerequisite for the macroautophagic machinery to recognize and engulf the lipid cargo. PLIN2 also facilitates AMPK signaling activation by interacting with the HSP70 chaperone protein, effectively coupling lipid droplet sensing to lipophagy upstream modulation (63). Beyond structural interactions, different PLIN family members exert distinct macroscopic effects on AS. Research on human carotid plaques and macrophage models shows that PLIN2 encourages early lipid droplet formation and proinflammatory macrophage behavior, with higher mRNA expression observed in symptomatic plaques (64). By contrast, PLIN1 stabilizes large LDs and supports the anti-inflammatory balance by reducing cholesterol efflux and markedly lowering TNFA, MMP2, ABCA1 and ABCG1 mRNA levels (64). Collectively, these functions demonstrate the pivotal roles of PLIN family proteins in the regulation of lipophagic processes.

Research into metabolites as regulators has confirmed that gut microbiota metabolites directly modulate AS development through lipophagy. Pro-atherogenic substances such as trimethylamine N-oxide promote lipid accumulation by specifically inhibiting macrophage lipophagy. By contrast, beneficial metabolites such as short-chain fatty acids and secondary bile acids improve lipid metabolism by activating the GPCR/FXR signaling pathway (65,66). Additionally, ferulic acid restructures the gut microbiota by specifically reducing the abundance of Firmicutes, Erysipelotrichaceae and Ileibacterium, which subsequently modulates fecal metabolites, activating the AMPK/SREBP1/ACC1 signaling pathway (67). Activation of this pathway mitigates lipid accumulation by promoting lipophagy, highlighting a therapeutic mechanism involving the gut-vascular axis (67).

Through lipophagy, LDs in macrophages are transported to lysosomes, where they are hydrolyzed into free cholesterol by LAL. Subsequently, the free cholesterol is exported to the extracellular environment via the cholesterol reverse transport pathway, which is mediated by the ATP-binding cassette transporters ABCA1 and ABCG1 (68). The clearance of excess lipids via macrophagic lipophagy prevents the formation of foam cells, delaying the progression of AS (69). Macrophage ACE expression regulates lipid metabolism by activating PPARα, which boosts β-oxidation and cholesterol efflux. This increases mitochondrial respiration and ATP production, reducing foam cell formation and promoting M2 polarization and efferocytosis, notably slowing AS progression (70). While lipophagy initially plays an atheroprotective role by promoting cholesterol efflux, its role in advanced AS represents its capacity to act as a ‘double-edged sword’. Under conditions of severe lipotoxic stress, excessive or dysregulated lipophagy can overwhelm lysosomal capacity, leading to lysosomal membrane permeabilization, macrophage apoptosis and impaired efferocytosis (71). This transition ultimately contributes to necrotic core expansion and plaque instability. Therefore, understanding the temporal dynamics of lipophagy is required.

VSMCs are key in maintaining intravascular homeostasis, which includes processes such as contraction, dilation and vascular remodeling. As a result, VSMCs are recognized as cellular determinants in the pathology of arterial walls and are notably associated with cardiovascular diseases, including AS (72). Recent transcriptomic and multi-omics studies (15,57,67) have shown that VSMC proliferation and migration, which occur as a result of a switch from a contractile state to a synthetic state, cause arterial wall thickening. Subsequently, atherosclerotic plaques undergo growth and structural changes driven by the PDGF/BB signaling pathway and lncRNA-ITGA2-related 3D genome interactions, which are key in AS pathology (73). VSMCs are involved in vascular remodeling and markedly contribute to neointimal formation through their proliferative and migratory activities in AS (74). Enhanced lipophagy is intricately associated with VSMC proliferation; this relationship is particularly pronounced under hyperlipidemic conditions, wherein the proliferation of VSMCs and their transformation into foam cells are facilitated by the uptake of lipids, such as ox-LDL (75). Furthermore, peroxidase derived from millet bran markedly inhibits lipid phagocytosis and cell proliferation in human aortic smooth muscle cells (HASMCs). This enzyme facilitates the transition of HASMCs toward a contractile phenotype and concurrently suppresses their migratory capacity. This transition inhibits the phosphorylation of STAT3, which mediates inflammatory responses, reducing aortic plaque formation (76). Concurrently, lipid accumulation and enhanced lipophagy induce VSMC migration. Migration is particularly augmented within inflammatory microenvironments, where VSMCs express specific chemokines and cell adhesion molecules, enabling motility (77).

Lipophagy also plays a notable role in apoptosis regulation in VSMCs. AS progression is often associated with VSMC apoptosis, and the degree of lipophagy markedly affects this process (78). Excessive lipid uptake by VSMCs can initiate cellular clearance by inducing apoptosis. Nonetheless, excessive lipid accumulation and the lipophagy process may further exacerbate cellular death (79). PPARγ coactivator-1 alpha (PGC-1α) suppresses glucose-driven VSMC proliferation, migration and inflammation, which are crucial aspects of AS pathology. PGC-1α encourages VSMCs to differentiate into a macrophage-like form, potentially increasing the quantity of VSMCs-derived foam cells in plaques and aiding plaque stabilization (80). The gelsolin-mediated lipophagy-related signaling pathway is considered a necessary mechanism in safeguarding VSMCs against apoptosis, and this discovery offers new therapeutic insights supporting AS treatment (81).

As a pivotal regulator of VSMC function, lipophagy is a prospective therapeutic target for AS (26,82). The dual role of lipophagy in VSMCs must be considered in the context of overall plaque stability. Specifically, the lipophagic flux in VSMCs serves as a determinant of plaque structural integrity. While physiological lipophagy prevents the transdifferentiation of VSMCs into foam cells by mobilizing intracellular lipids, excessive or dysfunctional autophagic flux can trigger VSMC apoptosis (82). This depletion of VSMCs within the fibrous cap directly compromises its mechanical strength, as these cells are the primary source of the extracellular matrix, particularly interstitial collagen (83). A reduced VSMC population leads to a net loss of collagen fibers and progressive thinning of the fibrous cap, thereby transforming a stable lesion into a vulnerable plaque prone to rupture. Thus, the ‘double-edged sword’ of lipophagy in VSMCs represents a pivotal link between cellular lipid homeostasis and macroscopic plaque stability (84,85). Thus, the net effect of VSMC lipophagy depends on the disease stage and the intensity of autotoxic stress.

ECs are notable contributors to AS and serve as regulatory centers throughout the progression of the disease. These cells participate in various physiological processes, such as intracellular signal transduction, cell adhesion, immune response and inflammation (38). EC dysfunction (ECD) involves a compromised endothelial barrier, increased inflammation, oxidative stress imbalance and decreased nitric oxide availability, leading to lipoprotein leakage, monocyte recruitment and plaque formation. As plaques progress, ECD exacerbates inflammation by releasing proinflammatory and prothrombotic factors, contributing to plaque instability (86). Research has elucidated the notable role of lipophagy in preserving EC function, and ECD is acknowledged as an early indicator of AS. Lipophagic deficiency can produce lipid accumulation within ECs, triggering oxidative stress and inflammatory responses, which further aggravates ECD (87). ox-LDL binds to specific receptors on ECs, facilitating EC lipid uptake; this mechanism induces lipid overload and subsequently leads to EC apoptosis (88). Enhanced lipophagy in ECs helps clear excess lipids, improving EC function and vascular health. It also reduces inflammation, a key factor in AS development, by suppressing EC levels of pro-inflammatory cytokines (89). For example, lipophagy mitigates ox-LDL-induced inflammatory responses in ECs by facilitating intracellular ox-LDL clearance, thus providing protection against EC damage (90,91). Lipophagy mitigates inflammatory responses by facilitating EC repair and regeneration through the modulation of specific autophagy-related signaling pathways, such as the CaMKKβ/AMPK, SOCE and PI3K/AKT pathways (92,93). The role of lipophagy in EC inflammation extends beyond lipid clearance; it also encompasses regulation of cytokine expression and signaling pathway activity (93,94). Enhanced lipophagy markedly improves EC function and augments resistance to oxidative stress and inflammation. Certain natural compounds, such as naringenin, have been shown to facilitate EC lipophagy, thereby mitigating ox-LDL-induced cellular damage (95). Lipophagy is integral to EC functional recovery; consequently, lipophagy modulation has considerable therapeutic potential in the context of AS.

Vascular remodeling is a pathological mechanism critical to AS progression, characterized by structural reorganization of the vascular wall, diminished elasticity, tissue calcification, plaque rupture and luminal narrowing. These phenomena are manifested through a range of pathological processes (70). For example, as a key regulator of lipid metabolism and inflammatory responses, lipophagy is crucial for VSMC remodeling in AS (96). VSMCs not only function as structural support cells but also play a role in lipid metabolism during atherogenesis. By promoting lipid degradation, lipophagy mitigates lipid accumulation within VSMCs, thereby limiting AS progression (97). Macrophages are the primary cells responsible for lipid accumulation within arterial walls. In macrophages, lipophagy mitigates the intracellular accumulation of CEs and TG through LD degradation via lysosomal pathways, thereby preventing foam cell formation and promoting cholesterol efflux (6,68,98). LAL is crucial in the lipophagy pathway, and reduced LAL expression decreases its activity in macrophages, resulting in more LDs, faster foam cell formation and vascular thickening. Conversely, LAL overexpression reduces lipid buildup by boosting the expression of genes such as Hmgb1, Hmgb2, Hspa5 and Scarb2. This also decreases cholesterol efflux and enhances lipophagy coordination (6,99). Lipophagic deficiency has been shown to expedite the progression of unstable atherosclerotic plaques. Impaired lipophagy within macrophages causes increased lipid core size, diminished collagen content and thinning of the fibrous cap in plaques, collectively enhancing the risk of plaque rupture (66). Vascular endothelial injury triggers vascular remodeling; however, lipophagy shields ECs from ox-LDL and advanced glycation end product damage by maintaining redox balance, clearing damaged mitochondria and lipotoxic products, preventing lipid droplet buildup and reducing lipid deposition. In addition, lipophagy also decreases inflammatory cell secretion, further protecting vascular ECs (100). Preclinical studies indicate that lipophagy activators, including berberine (BBR), decrease the levels of inflammatory factors such as TNF-α and IL-6 through a SIRT3-mediated lipophagy pathway. This mechanism enhances endothelium-dependent vasodilation and attenuates the progression of vascular stiffening (101). Enhancing lipophagic activity may therefore constitute a pivotal strategy for improving the structural integrity of the vascular wall and preventing AS.

Beyond macrophages and VSMCs, emerging evidence suggests that lipophagy serves as a notable metabolic rheostat in other non-canonical cell types, notably T lymphocytes and fibroblasts (102). In T lymphocytes, lipophagy--mediated mobilization of triacylglycerols provides free fatty acids for mitochondrial fatty acid oxidation, an energetic process essential for T-cell activation and the maintenance of regulatory T cell populations. A deficiency in autophagic lipid processing can impair Treg suppressive function and promote a pro-inflammatory Th17 phenotype, thereby intensifying the inflammatory milieu within the plaque. Similarly, in vascular fibroblasts, lipophagy-mediated lipid turnover maintains intracellular lipid proteostasis, thereby suppressing cellular senescence and the pathological fibroblast-to-myofibroblast transition by mitigating oxidative stress (102–104). By governing the availability of lipid-derived signaling molecules, lipophagy influences the production of the extracellular matrix, which is required for the structural integrity of the adventitia and media (105). These emerging insights suggest that lipophagy represents a universal metabolic hub across diverse cell populations in the progression of AS.

Autophagy activators are compounds employed to stimulate or augment autophagy. These agents operate by activating autophagy-related signaling pathways or modulating the expression of notable autophagy-associated proteins. The underlying mechanisms encompass negative regulation of the mTOR signaling pathway and activation of AMPK, among others (108). mTOR is a highly conserved serine/threonine protein kinase with a pivotal role in the regulation of fundamental biological processes such as cell growth, proliferation, protein synthesis, energy metabolism and autophagy (109). Everolimus, the most extensively researched mTOR inhibitor, has been thoroughly investigated to determine its therapeutic potential against AS, owing to its autophagy-inducing properties (110). It notably enhances plaque stability, and the application of everolimus-eluting cobalt-chromium platforms to cardiac stents facilitates the development of a stable plaque phenotype (110,111). Everolimus has been shown to inhibit AS progression, and its therapeutic efficacy appears to be more pronounced in the early stages of AS than in the advanced stages (112). However, the clinical translation of broad mTOR inhibitors such as everolimus, whose therapeutic efficacy varies between early and advanced lesions in LDL-R-deficient mice and clinical studies, is markedly limited by systemic immunosuppressive effects and metabolic side effects, including treatment-induced hypercholesterolemia, systemic immunosuppressive effects and metabolic side effects, emphasizing the need for cell type-specific delivery systems (109–111).

Metformin (Met) is commonly prescribed as a first-line pharmacological treatment for type 2 diabetes mellitus, and it is acknowledged as an AMPK activator (112). Patients with AS exhibit AMPK and ERK pathway suppression, which contributes to abnormal lipid metabolism and inflammation (113). Met reduces plaque buildup caused by a high-fat diet, exerting a protective effect against AS. Mice fed a high-fat diet exhibit an increased proportion of Ki67-positive proliferating cells and α-SMA-positive VSMCs within the arterial media. Met decreases abundance of these dual-positive cells and ERK levels while increasing AMPK and Pdlim5 levels. This finding indicates that Met selectively counteracts the pathological VSMC proliferation promoted by a high-fat diet, thereby stabilizing the vascular wall and mitigating AS (112).

Atorvastatin is a primary therapeutic agent for lipid reduction and plaque stabilization that exhibits anti-oxidative, anti-inflammatory, anti-thrombotic and anti-atherosclerotic properties (114). Additionally, it enhances endothelial function and contributes to plaque stabilization (115). It inhibits foam cell formation by promoting lipophagy, marked by increased Atg protein expression, a higher LC3-II/LC3-I ratio and reduced p62 levels. It also enhances LC3 and LD co-localization in treated foam cells, suggesting an ability to induce autophagy in macrophages and reduce intracellular lipid buildup (116). Clinically, while atorvastatin is widely prescribed for systemic lipid-lowering at standard doses of 20–80 mg/d, ongoing clinical evaluations are required to determine whether these conventional regimens are sufficient to optimally induce macrophage lipophagy within the complex plaque microenvironment (117,118). Furthermore, the dose-dependent risk of statin-associated muscle symptoms necessitates the exploration of localized targeted delivery strategies (119,120).

Increased research into the anti-AS effects of TCM extracts has confirmed the efficacy of numerous herbal monomers against AS. Additionally, synergistic combinations of multiple TCM/natural products (such as multicomponent botanical compositions) demonstrate greater anti-AS activity and fewer side effects than isolated compounds used alone (121). Geniposide (GE), a water-soluble iridoid glycoside also referred to as genipin-1-β-gentiobioside, has been identified in >40 plant species, and it exhibits a range of pharmacological effects and biological activities (122). GE boosts lipophagy by inhibiting the PARP1/PI3K/AKT pathway, accelerating LD breakdown and reducing lipid buildup. This slows AS development by preventing apoptosis and foam cell marker expression in VSMC-derived foam cells (123).

Epigallocatechin gallate (EGCG) is the most abundant and biologically active compound in tea polyphenols; it exhibits multiple biological effects, including anti-inflammatory and anti-oxidant (124), anti-obesity (121), as well as anti-infection and anti-tumor activities (125). EGCG activates autophagic flux via the Ca²⁺/CaMKKβ/AMPK pathway, reducing lipid buildup in vascular ECs by promoting lipophagy. EGCG releases Ca²⁺ from the endoplasmic reticulum, triggering CaMKKβ and AMPK/ULK1 phosphorylation (bypassing mTOR) and subsequently increasing LC3-II formation and p62 degradation (126). EGCG enhances lysosomal degradation by co-localizing LDs with LC3 and lysosomes, ultimately reducing palmitate-induced lipid accumulation, improving endothelial lipotoxicity and mitigating AS (127,128).

BBR, an isoquinoline alkaloid derived from Coptis chinensis and various Berberis species, demonstrates anti-atherosclerotic properties through a range of mechanisms such as lipid regulation, anti-inflammatory effects, oxidative stress reduction, vascular endothelial dysfunction mitigation, modulation of VSMC proliferation and migration and anti-thrombotic activity (129). BBR boosts the intracellular NAD+/NADH ratio by activating NAD+ biosynthesis pathways, enhancing SIRT1 deacetylase activity (130,131). Activated SIRT1 then deacetylates TFEB, increasing the LC3-II/LC3-I ratio and Beclin 1 expression (132). This process promotes autophagosome formation, inducing lipophagy and promoting LD degradation while delaying cell apoptosis. Together, these effects intervene in AS lipid metabolism. Despite these promising in vitro mechanisms, the clinical translation of BBR is significantly hindered by its poor oral bioavailability. Achieving sustained therapeutic concentrations specifically within atherosclerotic plaques remains a major challenge, emphasizing the necessity for advanced cell-type-specific delivery systems (130,131). Future clinical applications will likely depend on the development of novel nanoparticle-based delivery systems that enhance lipophagic efficacy in vivo.

The therapeutic landscape of natural compounds targeting AS is rapidly expanding beyond traditional signaling pathways to encompass epigenetic regulation and intercellular communication. Recent comprehensive studies have emphasized that natural medicinal active ingredients and TCMs can effectively prevent and treat AS by directly targeting epigenetic modifications (133). For example, intercellular crosstalk via extracellular vesicles (EVs), such as EV-derived miR-146a targeting SMAD4, has recently been identified as a novel pathogenic mechanism in high-fat diet-induced AS (134). Botanical extracts possess a profound capacity to modulate such epigenetic networks, evidenced by their ability to mitigate chronic inflammatory diseases by markedly altering micro RNA expression profiles (135). Consequently, future investigations into natural lipophagy modulators should explore their potential to concurrently regulate EV miRNAs and the epigenetic landscape, which would offer a multi-dimensional, systemic approach to plaque stabilization.

Research examining the therapeutic effects and underlying mechanisms of TCM interventions in the context of AS has markedly increased in recent years (136,137). TCM formulations demonstrate efficacy in alleviating AS symptoms and decelerating disease progression, attributed to multi-component actions, multi-target mechanisms and minimal side effects (138). Tianxiangdan enhances lipophagy by inhibiting the PI3K/Akt/mTOR pathway, reducing p85/Akt/mTOR phosphorylation. This activates TFEB and the autophagy proteins ULK1/LC3-II, boosting LD degradation. Tianxiangdan also increases ABCA1 expression and suppresses expression of p62, raising lipophagy levels, reducing foam cell formation, decreasing arterial plaque lipid deposition and slowing AS progression (139). Recent molecular docking and pharmacological analyses indicate that rather than acting as a simple generalized inhibitor, the Huoxue Qutan Formula contains primary active constituents such as specific flavonoids and saponins that directly interact with upstream nutrient-sensing kinases. This targeted interaction persistently suppresses mTORC1 phosphorylation, thereby mechanically uncoupling mTORC1 from TFEB and enhancing TFEB nuclear translocation, increasing LC3-II/I and Beclin1 levels, and reducing p62 levels. This process leads to improved co-localization of LDs with autophagosomes and upregulates the expression of the cholesterol efflux proteins ABCA1 and SCARB1 through TFEB pathways, reducing foam cell formation and lipid deposition in atherosclerotic plaques (140). The Gualou-Xiebai herbal combination inhibits P2RY12 activation, downregulating p62 and Plin2 expression and upregulating LC3II expression. The quantity of autophagosomes is also increased, markedly enhancing lipophagy activity. Consequently, foam cell formation is reduced, and anti-atherosclerotic effects are achieved (141).

In conclusion, accumulating evidence suggests that pharmacological agents and active compounds that modulate lipophagy exhibit notable therapeutic potential for AS prevention and treatment. Research priorities in this domain include autophagy inducers, monomeric TCM components and TCM compounds. Mechanistically, these agents operate by activating autophagy-related signaling pathways, regulating the activity of key autophagy proteins, improving dysregulated lipid metabolism and inflammatory responses, inhibiting foam cell formation, exerting anti-inflammatory and antioxidant effects, ameliorating vascular endothelial dysfunction and modulating VSMC proliferation and migration (Table I). Further investigation is necessary to elucidate the precise mechanisms and assess the clinical feasibility of these pharmacological agents.

As illustrated in the regulatory network (Fig. 2), pharmacological agents modulate lipophagy through two distinct but converging signaling axes. First, in the inhibitory axis, agents such as everolimus and the TCM formula Tianxiangdan function by inhibiting the PI3K/Akt/mTOR pathway. This inhibition suppresses mTORC1 phosphorylation, thereby relieving the suppression of ULK1/2 and TFEB, which subsequently activates autophagy proteins and increases LD degradation. Second, in the activating axis, natural compounds such as BBR and EGCG predominantly target the AMPK-SIRT1 axis. BBR activates NAD+ biosynthesis, which enhances SIRT1 deacetylase activity and leads to TFEB deacetylation, ultimately increasing the LC3-II/LC3-I ratio. Similarly, EGCG activates the CaMKKβ/AMPK pathway, bypassing mTOR and directly stimulating autophagic flux. These interventions ultimately converge to upregulate the expression of cholesterol efflux proteins (ABCA1) and reduce foam cell formation.