How Too Much Fat Disrupts Cell Cleanup, Leading to Long-Term Inflammation and Metabolic Disease

Macroautophagy is a highly conserved lysosomal degradation pathway that involves the formation of double-membrane vesicles, termed autophagosomes, which sequester cytosolic cargo and subsequently fuse with lysosomes for degradation [7, 36]. The process can be amplified by diverse stimuli such as nutrient withdrawal, radiotherapy, or pharmacological treatments [7]. It begins with the formation of a phagophore, which elongates and closes to generate an autophagosome. Upon fusion with lysosomes, the autolysosome exposes its cargo to lysosomal hydrolases [7, 37]. Initiation requires the autophagy-activating serine/threonine-protein kinase complex (ULK1), which integrates signals from the energy sensors mTORC1 and AMPK [7, 38]. Macroautophagy can be nonselective (random sequestration of cytoplasm) or selective (degradation of specific cargoes such as aggregates, mitochondria, peroxisomes, or lipid droplets) [39, 40]. Selectivity is mediated by autophagy receptors that link cargo to the phagophore—either ubiquitin-dependent or ubiquitin-independent [39, 40]. Most receptors bind via LC3-interacting regions (LIRs) to microtubule-associated protein 1A/1B-light chain 3 (LC3) proteins on the inner phagophore membrane [41], thereby tethering cargo to the nascent vesicle. LC3 belongs to the autophagy-related protein 8 (Atg8) family of ubiquitin-like modifiers that are covalently conjugated to phospholipids in the autophagosomal membrane, functioning as an “ubiquitin for membranes” that labels and organizes autophagic membranes [41, 42]. LC3 is commonly detected in two forms: the cytosolic, non-lipidated LC3-I and the membrane-bound, phosphatidylethanolamine-conjugated LC3-II. Conversion of LC3-I to LC3-II is required for autophagosome membrane expansion and cargo recruitment, making this conjugation step a critical functional and biochemical step of autophagy. Through this membrane-embedded ubiquitin-like system, LC3 proteins govern cargo selection, phagophore elongation, and closure; mature autophagosomes ultimately fuse with lysosomes to form autolysosomes [42].

In microautophagy, cytosolic material is taken up directly through invaginations or protrusions of the vacuolar or lysosomal membrane. In mammalian cells, two mechanisms have been described: protrusions of the lysosomal limiting membrane and lysosomal invagination [42]. In hepatocytes, type 1 microautophagy has been visualized as arm- or flap-like protrusions of the lysosomal membrane that extend into the cytosol and close around bulk cytoplasm and small organelles. By contrast, lysosomal invagination underlies microlipophagy in mammalian hepatocytes, where inward budding of the lysosomal membrane engulfs entire lipid droplets into the lysosomal lumen for degradation. Because experimental monitoring remains technically challenging, this process is still less well characterized than macroautophagy [43].

Lipophagy represents a selective form of autophagy in which lipid droplets (LDs) play a central role. During this process, LDs are specifically degraded and function as supplementary lipid reservoirs, providing energy substrates for cellular metabolism and systemic energy balance [46, 47]. LDs are unique lipid-storing organelles composed primarily of triacylglycerols (TAGs) and sterol esters. These neutral lipids form a hydrophobic core that is enclosed by a monolayer of specific phospholipids and surface proteins, separating it from the cytoplasmic environment. The surface proteins are essential for maintaining LD functionality, stability, and intracellular mobility [48].

In mammalian cells, the lipid droplet monolayer is enriched in phosphatidylcholine, which plays an important role in LD stability and turnover [49]. The phospholipid composition of the LD membrane plays a crucial role in regulating LD synthesis, maturation, and degradation. Another critical determinant is droplet size, which defines the pathway of lipid catabolism [47, 50]. Smaller droplets are predominantly degraded by lipophagy, whereas larger droplets are mainly hydrolyzed by cytosolic lipases such as adipose triglyceride lipase (ATGL) [47, 51].

Beyond their function in lipid storage, LDs are also involved in the biosynthesis of membrane components, the generation of signaling ligands, and the storage of metabolic intermediates. This lipid buffering capacity offers a dual benefit: serving as an alternative energy source and protecting against excess free fatty acids (FFAs) and sterols, which could otherwise disrupt membrane integrity, signaling pathways, and overall metabolic balance [52]. For lipid homeostasis, the liver plays a crucial role in lipophagy. Impaired lipophagy results in defective LD degradation, leading to a significant buildup of triglycerides in hepatocytes, which ultimately promotes the development of fatty liver disease. Three main pathways of lipophagy reflect the broader autophagic system and are classified as macrolipophagy, microlipophagy, and chaperone-mediated lipophagy (CML). These pathways mainly differ in how the lipid droplet is delivered to and degraded by lysosomes.

In macrolipophagy, entire LDs are sequestered by autophagosomes and subsequently degraded following autophagosome-lysosome fusion, forming an autolysosome [53]. Microlipophagy is characterized by the direct engulfment of lipid droplets by lysosomes through membrane invagination, followed by lysosomal degradation. The size of the droplet is a decisive factor in determining the degradation route [47, 48]. Finally, chaperone-mediated lipophagy (CML) contributes to lipid-droplet turnover by selectively removing specific proteins from the LD surface. PLIN2 is a major LD coat protein that stabilizes lipid droplets and protects them from degradation. Its removal requires recognition by the chaperone HSC70/HSPA8 and delivery to the lysosomal receptor LAMP2A, thereby facilitating access of cytosolic lipases and autophagic machinery to the LD surface [54].

Over recent years, the concept of lipophagy has emerged as a central mechanism in lipid metabolism [55]. Although the molecular interfaces between individual lipoprotein fractions and the lipophagy machinery remain incompletely characterized, integrating these two systems provides a compelling mechanistic framework for understanding the interplay between extracellular lipid transport, intracellular lipid storage, and selective autophagy.

In particular, cholesterol-rich lipoproteins—including LDL, VLDL, and Apo(a)-containing particles—together with HDL as a cholesterol efflux partner, represent promising targets for elucidating how disturbances in lipid metabolism translate into cellular dysfunction. The concept of a direct interaction between lipophagy and lipoprotein pathways is highly attractive, as the classical lipoprotein fractions modulate intracellular lipid accumulation and thereby influence lipophagic activity. Triglyceride- and cholesterol-rich particles are internalized by macrophages and other cell types, via either scavenger receptors or ApoB/LDL receptor-dependent mechanisms, leading to the formation of cholesteryl ester (CE)-enriched lipid droplets [28]. Subsequently, lipophagy provides a pathway for breaking down these lipid stores, as LDs are moved to lysosomes via autophagosomes, where they are broken down by lysosomal acid lipase (LAL). The free cholesterol released then exits the cell through efflux transporters like ATP-binding cassette transporter (ABCA1), mainly to HDL [56]. HDL indirectly supports intracellular lipid clearance by accepting free cholesterol generated during LD mobilization and lysosomal lipid hydrolysis.

An imbalance in lipoprotein metabolism, such as elevated LDL/VLDL levels or reduced HDL-mediated efflux capacity, promotes excessive cellular lipid uptake and LD formation [57]. This overload can mechanically influence the lipophagic process. Studies show that prolonged exposure to oxidized LDL reduces lipophagic activity in endothelial cells [58]. When lipophagy is impaired, lipid droplets persist, cholesterol efflux is disrupted, and cellular stress or apoptosis increases, which promotes lipid-related diseases like atherosclerosis [29]. Overall, this creates a cycle: high lipoprotein uptake leads to LD formation, which triggers lipophagy and HDL-mediated cholesterol removal. When this cycle becomes dysfunctional, harmful lipid accumulation occurs, damaging cellular and organ functions.

Together, these mechanisms illustrate that lipophagy forms a central interface between extracellular lipoprotein metabolism and intracellular lipid clearance. However, when lipid influx chronically exceeds lysosomal and autophagic capacity, this adaptive system can shift into a maladaptive state characterized by impaired autophagic flux, lysosomal stress, mitochondrial dysfunction, and inflammatory activation.

Lipids regulate autophagy at multiple stages—from membrane nucleation and autophagosome growth to cargo selectivity and lysosomal turnover, while autophagy safeguards lipid quality control, clearing damaged membranes and lipid droplets [73]. Atherosclerosis, a major contributor to the high mortality associated with cardiovascular disease, arises in part from impaired autophagy. Traditionally viewed primarily as a disorder of lipid accumulation, atherosclerosis is now understood as a chronic inflammatory disease in which lipid metabolism impacts the buildup of plaques, causing a higher risk of myocardial infarction, and strokes [74]. Atherosclerosis is multifactorially driven by the immune system, inflammation, lipid metabolism and the progression of the disease is strongly influenced by the underlying autophagic mechanisms and pathways governing these interactions [74]. In the early stages of atherosclerosis, autophagy inhibits the development of plaques, removing damaged organelles and reducing foam cell formation, but as the disease progresses, autophagy gets progressively impaired [75–77]. Under sustained lipid stress, impaired autophagy leads to the accumulation of damaged organelles, oxidized lipids, and inflammatory cargo, thereby promoting monocyte recruitment to the vascular wall. [78, 79]. The normally circulating monocytes are recruited to the arterial wall, where they differentiate into macrophages, which in turn clear and internalize modified lipoproteins. When cholesterol efflux to HDL is insufficient, these macrophages accumulate lipid droplets and transform into foam cells, promoting the growth of atherosclerotic plaques [56, 80]. Foam-cell apoptosis and defective efferocytosis promote accumulation of apoptotic and necrotic material, leading to necrotic core formation and plaque instability [81, 82]. Furthermore, inflammatory signaling amplifies arterial wall injury and contributes to plaque progression and instability [79, 83].

Increased and sustained expression of autophagy marker proteins Beclin1 and LC3-II induced by ox-LDL leads to elevated calcium ion concentration in the plasma membrane, induces endoplasmic reticulum stress, and activates pro-apoptotic factors, resulting in endothelial cell apoptosis. These apoptotic cells enhance platelet adhesion and promote thrombus formation after plaque rupture, linking impaired autophagy to myocardial infarction or strokes [13]. Severe oxidative stress promotes lipofuscin/ceroid-like material accumulation, which can further impair lysosomal hydrolase activity and autophagic degradation, disrupts lysosomal hydrolase function, and, in turn, leads to apoptosis and mitochondrial accumulation. This promotes increased oxidative stress and waxy pigmentation production, leading to a vicious circle that exacerbates cell death [84, 85]. Oxidative stress additionally induces mitochondrial damage, which can be cleared through mitophagy activation via the PINK/Parkin pathway. However, in advanced atherosclerosis, the mechanism becomes inefficient, further accumulating damaged mitochondria and elevating the oxidative stress levels [86]. These findings are consistent with the broader interpretation that increased autophagy marker levels do not necessarily indicate effective autophagic degradation; rather, in endothelial pathology, impaired or blocked autophagic flux may contribute to cellular dysfunction [61, 87].

Autophagy in obesity is highly context and cell-type-dependent. White adipose tissue (WAT) explants, containing adipocytes and fibroblasts, show elevated levels of autophagic markers in total, but the cell types differ remarkably. The mature adipocytes themselves show lower autophagic flux, reflected by reduced LC3-II accumulation [88–90]. Autophagic markers must be interpreted with caution, because their accumulation may reflect either increased autophagosome formation or impaired lysosomal degradation. Therefore, assessment of autophagic flux is essential for correct mechanistic interpretation [61]. Macrophages display decreased autophagic flux, infiltrating WAT during obesity, impacting insulin sensitivity, enhanced activation of inflammatory signaling pathways and defective clearance of damaged organelles [91, 92]. Additionally, other modifications occur, such as reduced expression of insulin receptor substrate (IRS-1) expression, impacting the PI 3-kinase, one of the key signal transducers in insulin-stimulated glucose uptake [93, 94]. Through insulin resistance, hyperglycemia, hypertension, dyslipidemia, hyperuricemia and endothelial dysfunction are caused. Continuously increasing insulin resistance will lead to Type 2 Diabetes Mellitus, metabolic syndrome, or metabolic dysfunction-associated steatotic liver disease, MASLD [95]. MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent clinical phenotypes of hepatic autophagy dysfunction, initiated and perpetuated by chronic systemic inflammation and metabolic stress [7, 8]. Lipophagy is critical in maintaining hepatic lipid homeostasis in MASLD/MASH patients by degrading lipid droplets and shuttling free fatty acids for mitochondrial oxidation [29, 96]. While autophagy is initially upregulated in response to early lipid overload, chronic nutrient excess (by Western-style diet) and lipotoxicity impair autophagic flux through the AMPK-mTOR axis, leading to the accumulation of dysfunctional organelles and lipid droplets, weaken lipophagic capacity and accelerate hepatic steatosis [96]. Cholesterol overload has been linked to lysosomal dysfunction and NLRP3 inflammasome activation, mechanisms that may also be relevant to MASLD/MASH progression [97]. Impaired lipophagy also drives overproduction of VLDL, promoting atherogenic dyslipidemia and increasing cardiovascular risk [98]. Altered VLDL metabolism may further intensify intracellular lipid loading ans systemic dyslipidemia, thereby reinforcing lipotoxic stress [98, 99]. Epidemiological data confirm that both MASLD and MASH independently elevate the risk for cardiovascular disease (CVD), underscoring hepatic autophagy dysfunction as a mechanistic link between metabolic liver disease and systemic inflammation [96]. Furthermore, lifestyle factors such as alcohol further disturb lipid metabolism through comparable pathogenic mechanisms [47]. Disease trajectory is further modified by sex, age, and hormonal status, but these factors are beyond the main mechanistic focus of this review [100–102].

The impairment of hepatic autophagy extends beyond the liver, as dysfunctional hepatocytes release damage-associated molecular patterns (DAMPs) and additional proinflammatory cytokines that amplify hepatic and systemic inflammation [103]. In metabolic liver disease, chronic lipid overload in the setting of impaired autophagy and lysosomal dysfunction may also increase susceptibility to ferroptotic membrane damage. Under physiological conditions, lipophagy, mitophagy, and ferritinophagy buffer metabolic stress by removing ROS-producing mitochondria, controlling the cellular iron pool, and limiting the accumulation of peroxidation-prone membranes; when autophagy is impaired, this protective capacity is lost, resulting in increased ferroptotic vulnerability [104–106]. Of particular importance is NCOA4-mediated ferritinophagy, as its dysregulation can expand the redox-active iron pool and thereby enhance lipid peroxidation [105, 107]. In addition, lysosomal dysfunction under conditions of oxidative stress and lipid overload further aggravates mitochondrial injury and oxidative damage. In the context of MASLD/MASH, iron overload, lipid peroxidation, inflammatory cell death, and defective autophagy therefore converge into a self-reinforcing pathogenic mechanism [106, 108].

Beyond metabolic and inflammatory toxicity, defective autophagy and lipid overload increase ROS and lipid peroxidation, leading to intracellular accumulation of mutagens. Reactive aldehydes form highly mutagenic DNA adducts that are detected in MASLD and MASH patients, linking impaired autophagy to genomic instability and tumorigenesis [109, 110].

These mechanisms together enhance tissue oxidative stress, promote vascular foam cell formation, and compromise cellular clearance systems, ultimately contributing to disease progression rather than conferring metabolic benefits. Therefore, therapeutic strategies aimed at restoring autophagic competence not only improve hepatic function but also provide significant cardiovascular protection by interrupting these maladaptive metabolic-inflammatory cycles.

Defective autophagy and lipid overload lead to a reinforcing loop that can accelerate multiple neurodegenerative diseases [73, 111, 112]. When lipid regulation and autophagic lipid clearance are uncoupled, lipid droplets accumulate in neurons and glial cells, leading to impaired lysosomal flux and amplified neuroinflammatory signaling [73, 111, 112]. In Alzheimer disease (AD), this is driven by ceramide dysregulation, lipid-droplet-accumulating microglia, and APP-βCTF-mediated lysosomal dysfunction, all of which promote autophagic vacuole buildup, amyloid pathology, synaptic injury, and cognitive decline [111, 113, 114]. Genetic factors like APOE4 amplify this state by promoting maladaptive lipid handling even further and increasing lipotoxic stress [115, 116]. In Parkinson disease (PD), lipid droplets can act as nucleation sites for α-synuclein aggregation, while modified α-synuclein inhibits chaperone-mediated autophagy and disrupts macroautophagy through ATG9 and RAB1A, thereby impairing lysosomal clearance and lipophagy [117–120]. GBA1 loss-of-function further alters lysosomal lipid composition and increases α-synuclein accumulation [121]. In vascular dementia (VaD), autophagy defects in the neurovascular unit contribute to endothelial dysfunction, while impaired astrocytic and microglial lipophagy under ischemic stress promotes lipid droplet accumulation, oxidized lipid stress, defective debris clearance, and white matter injury [122–125]. Dysregulated LD dynamics can transform astrocytes from neuroprotective to pro-inflammatory states that exacerbate white matter injury typical of VaD [124].

Across Alzheimer disease, Parkinson disease, and vascular dementia, impaired autophagy—especially defective lipophagy—disrupts neuronal and glial lipid homeostasis, fosters lipid-droplet accumulation, and compromises lysosomal flux. These failures in lipid and proteostasis amplify neuroinflammation, synaptic dysfunction, and cognitive decline, with disease-specific factors such as ceramide dysregulation and APP-βCTF in AD, α-synuclein pathology and GBA1 loss-of-function in PD, and endothelial or astroglial autophagy defects at the neurovascular unit in VaD.

Beyond classical cardiometabolic disease, emerging evidence suggests that defective autophagic clearance may also contribute to disease states characterized by disrupted temporal regulation. Autophagic flux is closely coupled to circadian timing cues such as feeding-fasting cycles, sleep, and light–dark exposure, and this coordination helps align nutrient sensing, lysosomal competence, and mitochondrial quality control with predictable metabolic demand [126–130]. When circadian organization is lost, mitophagic efficiency declines, inflammasome activity may become prolonged, and immunometabolic flexibility is reduced [127–130].

Another related concept has emerged in post-viral syndromes such as PASC, in which acute viral injury appears to disrupt autophagic and mitochondrial homeostasis beyond the period of active infection. SARS-CoV-2 interferes with autophagosome maturation and is associated with mitochondrial dysfunction and impaired mitophagy, thereby favoring persistent inflammatory signaling [35, 131–134]. EBV reactivation may represent an additional post-infectious modifier, as EBV also interacts with autophagic machinery and has been reported more frequently in COVID-19 and post-COVID cohorts [135–137].

Although the direct contribution of lipid overload is less well established than in atherosclerosis or MASLD/MASH, both circadian disruption and post-viral syndromes support the broader concept that failure to restore autophagic homeostasis after metabolic or infectious stress can promote chronic inflammation, fatigue, and multisystem dysfunction [127, 138, 139].

The primary therapeutic strategy for improving patient health is exercise and behavioral intervention, which also act as modulators of autophagy. In preclinical models, exercise improved lipid handling and lipid clearance [142]. Moderate exercise training has also been identified as an effective strategy to ameliorate MASLD progression, leading to increased mitochondrial function and lipid oxidation [143]. In addition, dietary modulation through intermittent fasting may represent another clinically relevant autophagy-inducing strategy, reducing lipotoxicity and supporting periodic activation of autophagic flux [144]. Chronobiologic alignment may provide an additional approach, as time-restricted eating can leverage endogenous circadian oscillations in hepatic and immune autophagy pathways [145].

Effective pharmacological intervention for autophagy collapse requires a “twin approach”; reducing lipotoxicity and restoring autophagic flux on one hand, and resolving inflammatory load on the other, because targeting only one arm of this pathogenic loop may not resolve the underlying cause of dysregulation [141].

For inducing autophagic functions, the AMPK-mTOR pathway represents a central therapeutic target.

Pharmacological inhibition of mTORC1 by rapamycin can activate autophagy, although precise tuning is required since excessive activation may lead to unwanted catabolic effects [146, 147]. Metformin activates autophagy as well through AMPK, but off-target and context dependent effects must be considered [32, 33]. As part of the AMPK-mTOR pathway, Beclin-1 and class III PI3K is another direct target for improving autophagosome biogenesis. Tat-Beclin-1, a Beclin-1 activating peptide, enhances hepatic autophagy and ameliorates MASLD-like phenotypes [148]. Another transcriptional node is TFEB, transcription factor EB. Recognized as a major transcriptional regulator of autophagy, targeted regulation may improve metabolic disorders, neurodegenerative diseases and inflammatory disease. Beyond AMPK-mTOR, SIRT1-dependent interventions may provide an additional regulatory layer by coupling nutrient sensing to deacetylation-driven autophagy and mitophagy, thereby supporting metabolic resilience [149].

Furthermore, selective pathways of autophagy are traceable in lipid-driven disease. Lipophagy therapies improve hepatic steatosis and systemic insulin sensitivity, thereby reducing the substrate burden that precipitates lipotoxic autophagy collapse. In this context, semaglutide showed beneficial changes in metabolic dysfunction-associated steatohepatitis, while tirzepatide improved MASH resolution without worsening fibrosis [150, 151]. Likewise, Mitophagy enhancement can reduce ROS-generating mitochondria and dampen inflammatory signaling. In the context of combined lipid overload and mitochondrial dysfunction, urolithin A has shown promising results after a randomized clinical study [152].

Lowering atherogenic lipoproteins, primarily LDL cholesterol and Lp(a), is an essential strategy of reducing cardiovascular risk and, within the framework of this review, for reducing the upstream lipid burden that drives autophagic dysfunction. Current treatment typically begin with tolerated statin therapy, with add-on non-statin agents when LDL cholesterol remains above target [153]. Beyond lipid lowering, experimental studies suggest that statins may modulate autophagy-related pathways, including AMPK/mTORC1 signaling [154]. In macrophages, atorvastatin has shown to increase autophagic flux, while reducing inflammatory signaling and foam-cell formation [155]. If cholesterol remains above target despite statin therapy, PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors such as evolocumab or alirocumab can achieve a significant reduction in major adverse cardiovascular events [156, 157]. In hepatocytes, PCSK9 interacts with apoB and prevents its degradation, thereby contributing to increased apo-B-lipoprotein burden [158]. Conversely, inhibition of PCSK9 increases autophagic flux, reduces oxidative stress and inflammatory signals, and combines the previously mentioned “twin approach” of reducing inflammation while increasing autophagy and reducing lipotoxicity [159]. Beyond established approaches, newer lipid-centered therapies may indirectly improve autophagy and lysosomal function by reducing lipid burden. Olezarsen inhibits ApoC-III, reducing triglycerides in hypertriglyceridemia, and solbinsiran reduces atherogenic lipoproteins by silencing ANGPTL3 (Angiopoietin Like 3) in mixed dyslipidemia [160, 161]. For long-term LDL-lowering, inclisiran represents an additional siRNA-based strategy targeting PCSK9 [162].

To address these specific aspects, biomarkers must be identified for each target. While cholesterol and inflammatory markers are well-established diagnostic standards, biomarkers for autophagy are less thoroughly studied. Currently, there is no single universal biomarker for autophagy because the dynamic nature of "flux” means that static measurements can be misleading. Instead, it is better to use paired readouts that reflect cargo processing, such as LC3 turnover and SQSTM1/p62 degradation [61]. Additionally, at the pathway level, TFEB-driven CLEAR-network transcripts serve as a transcriptional indicator of autophagy-lysosome capacity [163]. In a lipid-focused context, combined readouts that integrate autophagy markers with lipid-droplet or lysosomal markers may help identify interventions that restore hepatic lipid turnover [7]. In addition, markers like ceramides and phospholipid ratios highlight downstream metabolic effects of impaired autophagy [8]. Exploratory studies suggest that Beclin-1 and selected autophagy-related non-coding RNAs may have future biomarker potential, although these approaches still require substantial validation [164, 165].

Emerging evidence suggests that autophagy dysregulation may also contribute to clinical conditions characterized by incomplete recovery after acute stress and by disturbed temporal organization of metabolism. In this context, post-viral syndromes such as Long COVID and related fatigue syndromes have gained increasing attention, as they appear to involve persistent alterations in mitochondrial homeostasis, inflammatory signaling, and autophagy-related pathways. Supporting the therapeutic relevance of this concept, a recent study in patients with ME/CFS reported that once-weekly low-dose rapamycin led to clinically meaningful improvements in fatigue, post-exertional malaise, and orthostatic intolerance, accompanied by increased plasma BECLIN-1 levels, consistent with restoration of autophagy signaling [147]. Because post-exertional symptom exacerbation and other clinical features overlap substantially between ME/CFS and Long COVID, these findings suggest that mTOR-dependent autophagy impairment may represent a shared mechanism and support autophagy-modulating strategies as a plausible therapeutic avenue in post-viral syndromes [147].

In parallel, nutritional and chronobiologic interventions may provide additional therapeutic entry points in these emerging contexts. A trial in individuals with Long COVID reported that intensified intermittent fasting produced greater improvements in global symptom burden and symptom count than milder time-restricted eating alone [166]. Although autophagy and lipophagy markers were not directly assessed, these findings are consistent with the hypothesis that periodic, prolonged fasting may help restore metabolic and organellar homeostasis in post-viral syndromes [166]. Chronobiologic alignment may further complement this approach, as time-restricted eating can reinforce endogenous circadian oscillations in hepatic and immune autophagy pathways [145]. Melatonin has likewise been discussed as a chronobiotic and cytoprotective signal with anti-inflammatory and redox-modulatory properties that could synergize with autophagy-restorative strategies in chronic inflammatory disease [167]. Together, these observations suggest that post-viral persistence and circadian disruption may represent emerging contexts in which defective autophagic recovery contributes to ongoing symptoms and may offer new therapeutic entry points.

As immunometabolism progresses, it becomes clearer that immune function is closely linked to the cell’s metabolic state and depends on effective autophagy. Understanding how specific types of lipids influence autophagy could lead to targeted therapies to address chronic inflammation and improve cell resilience.