Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD) is increasing in prevalence worldwide and has become the greatest potential risk for cirrhosis and hepatocellular liver cancer. Currently, the role of gut microbiota in the development of MASLD has become a research hotspot. The development of MASLD can affect the homeostasis of gut microbiota, and significant changes in the composition or abundance of gut microbiota and its metabolite abnormalities can influence disease progression. The regulation of gut microbiota is an important strategy and novel target for the treatment of MASLD with good prospects. In this paper, we summarize the role of gut microbiota and its metabolites in the pathogenesis of MASLD, and describe the potential preventive and therapeutic efficacy of gut microbiota as a noninvasive marker to regulate the pathogenesis of MASLD based on the "gut-hepatic axis", which will provide new therapeutic ideas for the clinic.

Steatosis is characterized by an increase in free fatty acids, such as palmitic acid (PA), in hepatocytes and the accumulation of triglycerides in the liver. However, the role of intracellular autophagy in PA accumulation-induced hepatotoxicity is not clearly understood. Therefore, in this study, we investigated the effects of PA on autophagy in hepatocytes and its underlying mechanism of action. Treatment of HepG2 cells with PA induced a significant increase in intracellular p62 and LC3-II levels, suggesting inhibition of autophagy. Furthermore, PA inhibited autophagic flux in HepG2 cells, as monitored using GFP-RFP-LC3. Mechanistically, PA increased the phosphorylation of the Ser12 and Thr29 residues of LC3, which are autophagy inhibition markers, through protein kinase A (PKA) and protein kinase C (PKC) signaling. Finally, PKA and PKC inhibitors restored PA-induced autophagic flux inhibition, reduced intracellular lipid accumulation, and rescued the altered expression of lipogenic genes, such as SREBP-1c, in HepG2 cells. Thus, our study demonstrates the mechanism of autophagy inhibition by PA in hepatocytes and provides a potential therapeutic approach for preventing and treating hepatic steatosis.

Ibuprofen (IBU), a prevalent non-steroidal anti-inflammatory drug (NSAID), is extensively utilized in medical practices. Especially since the popularity of COVID-19, its use has become more widespread, coupled with its low degradation rate and high environmental residues. Thus, more focus is warranted on the possible detrimental impacts on non-target organisms, as well as the underlying mechanisms of toxicity. The present study investigated the relationships and molecular mechanisms between hepatic mitochondrial dynamics processes and lipid metabolism in the yellowstripe goby (Mugilogobius chulae) exposed to IBU at concentrations of 0.5, 5, 50, and 500 μg/L over 7 days. The results showed that IBU exposure inhibited mitochondrial biogenesis and fusion but promoted mitochondrial fission by interfering with the SESN/PGC/ULK signaling pathway, causing an imbalance in mitochondrial dynamics. Thus, high concentration of IBU exposure caused mitochondrial dysfunction and oxidative stress. Molecular biological evidences suggested that IBU caused a decrease in ATP production and lipogenesis, leading to an energetic crisis in M. chulae. Hepatic tissue also showed a significant decrease in relative weight, an increase in mitochondrial damage and adipocyte degeneration. Correspondingly, the exposed organism attempted to mitigate these crises by promoting mitophagy and lipophagy via the Pink-Parkin pathway. Overall, IBU exposure interfered with mitochondrial dynamics processes and caused abnormalities in hepatic lipid metabolism in M. chulae. The present study highlighted the discovery of mitochondrial dynamics imbalance to lipid dysregulation cascade mechanism. We emphasized the negative effects of NSAIDs such as IBU on aquatic non-target organisms at different levels. It provided valuable insights into the ecological risk assessment of IBU in aquatic environments.

Autophagy, a critical intracellular degradation and recycling pathway mediated by lysosomes, is essential for maintaining cellular homeostasis through the quality control of proteins and organelles. Our research focused on the role of proximal tubular autophagy in the pathophysiology of aging, obesity, and diabetes. Using a novel method to monitor autophagic flux in kidney tissue, we revealed that age-associated high basal autophagy supports mitochondrial quality control and delays kidney aging. However, an impaired ability to upregulate autophagy under additional stress accelerates kidney aging. In obesity induced by a high-fat diet, lysosomal dysfunction disrupts autophagy, leading to renal lipotoxicity. Although autophagy is initially activated to repair organelle membranes and maintain proximal tubular cell integrity, this demand overwhelms lysosomes, resulting in "autophagic stagnation" characterized by phospholipid accumulation. Similar lysosomal phospholipid accumulation was observed in renal biopsies from elderly and obese patients. We identified TFEB-mediated lysosomal exocytosis as a mechanism to alleviate lipotoxicity by expelling accumulated phospholipids. Therapeutically, interventions such as the SGLT2 inhibitor empagliflozin and eicosapentaenoic acid restore lysosomal function and autophagic activity. Based on these findings, we propose a novel disease concept, "Obesity-Related Proximal Tubulopathy." This study underscores autophagic stagnation as a key driver of kidney disease progression in aging and obesity, offering insights into the pathophysiology of kidney diseases and providing a foundation for targeted therapeutic strategies.

Lipids metabolism is crucial in regulating aging and metabolic diseases. Lipid droplets (LDs) are dynamic, complex organelles responsible for the storage and release of neutral lipids, essential for maintaining lipid homeostasis and energy metabolism. Aging accelerates the accumulation of LDs, functional deterioration, and metabolic disorders, thereby inducing age-related metabolic diseases (ARMDs). This review examines published datasets on the association between LDs and ARMDs, focusing on the structure and function of LDs, their interactions with other organelles, and associated proteins. Furthermore, we explore the potential mechanisms by which LDs mediate the onset of ARMDs, including Alzheimer's disease (AD), sarcopenia, metabolic cardiomyopathy, non-alcoholic fatty liver disease (NAFLD), and cancer. Lastly, we discuss intervention strategies aimed at targeting LDs to improve outcomes in ARMDs, including exercise, dietary, and pharmacological interventions.

Lipids, which are indispensable for cellular architecture and energy storage, predominantly consist of triglycerides (TGs), phospholipids, cholesterol, and their derivatives. These hydrophobic entities are housed within dynamic lipid droplets (LDs), which expand and contract in response to nutrient availability. Historically perceived as a cellular waste disposal mechanism, autophagy has now been recognized as a crucial regulator of metabolism. Within this framework, lipophagy, the selective degradation of LDs, plays a fundamental role in maintaining lipid homeostasis. Dysregulated lipid metabolism and autophagy are frequently associated with metabolic disorders such as obesity and atherosclerosis. In this context, peroxisome proliferator-activated receptors (PPARs), particularly PPAR-γ, serve as intracellular lipid sensors and master regulators of gene expression. Their regulatory influence extends to both autophagy and lipid metabolism, indicating a complex interplay between these processes. This review explores the hypothesis that PPARs may directly modulate autophagy within the realm of lipid metabolism, thereby contributing to the pathogenesis of metabolic diseases. By elucidating the underlying molecular mechanisms, we aim to provide a comprehensive understanding of the intricate regulatory network that connects PPARs, autophagy, and lipid homeostasis. The crosstalk between PPARs and other signaling pathways underscores the complexity of their regulatory functions and the potential for therapeutic interventions targeting these pathways. The intricate relationships among PPARs, autophagy, and lipid metabolism represent a pivotal area of research with significant implications for understanding and treating metabolic disorders.

Tubulointerstitial fibrosis (TIF), a critical pathological hallmark in progressive chronic kidney disease (CKD), may be potentiated by renal lipid metabolism dysregulation and ectopic lipid deposition, though these processes likely exhibit bidirectional interactions with fibrotic progression Lipophagy is a type of selective autophagy that specifically recognizes lipid droplets and is accountable for lipid stability and metabolism. It serves as a link between lipid metabolism and autophagy. It was found that a positive correlation between elevated LARS1 expression and the severity of renal interstitial fibrosis in CKD patients. In Lars1+/- mice, we observed that the absence of LARS1 significantly reduced lipid deposition and TIF. Mechanistically, stimulation of HK-2 cells with TGF-β1 resulted in LARS1-mediated activation of mTORC1 and suppression of lipophagy, consequently leading to increased lipid accumulation and epithelial mesenchymal transition (EMT) through a defined mechanistic pathway. Collectively, our studies demonstrate that LARS1 plays a pivotal role in renal fibrosis at least in part by inhibiting lipophagy, suggesting that targeting LARS1 may represent a novel therapeutic strategy for patients with CKD.

Dehydroepiandrosterone (DHEA), a precursor of sex hormones, has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH), with studies suggesting a strong correlation between DHEA levels and disease severity. In this study, we demonstrated that DHEA alleviated lipotoxicity-induced hepatic damage by promoting autophagy. Our findings demonstrate that DHEA-induced autophagy is mediated by estrogen receptor alpha (ER-α) and androgen receptor (AR) activation and protects hepatic cells against palmitate-induced apoptosis, steatosis, and inflammasome activation. DHEA treatment in a murine NASH model induced significant autophagy in the liver, further supporting the hepatoprotective role of DHEA. Collectively, our results identified DHEA as a pro-autophagic hormone with therapeutic potential for the treatment of lipotoxicity in NASH.

The aim of this study was to investigate the regulation of triptolide on Rab7-mediated lipophagy to elucidate the potential association between lipophagy and ferroptosis in triptolide-induced hepatotoxicity. Human normal liver HL7702 cells and C57BL/6J mice were treated with triptolide to establish in vitro and in vivo models. The results revealed that triptolide caused a severe hepatic cell damage in vitro and in vivo. Concurrently, triptolide induced the remarkable activation of Rab7-mediated lipophagy, as evidenced by the decreased levels of lipid droplets and p62, the increased Rab7, microtubule-associated protein light chain 3Ⅱ (LC3Ⅱ) and phosphorylated adenosine monophosphate-activated protein kinase (AMPK) levels, as well as the increased colocalization of LC3 and Rab7 proteins. Moreover, triptolide obviously increased the levels of ferroptotic markers, including MDA, iron, prostaglandin endoperoxide synthase 2, and induced GSH and GPX4 exhaustion and oxidative stress in hepatic cells. Importantly, the inhibition of lipophagy mitigated ferroptosis and alleviated the hepatic cell damage induced by triptolide. our results demonstrated that triptolide-activated lipophagy with Rab7 serves as a pivotal factor in triggering ferroptosis and exacerbating hepatoxicity. The manipulation of lipophagy is thus a potential therapeutic strategy for ameliorating triptolide-induced hepatotoxicity.

Multiple sclerosis (MS) is an inflammatory disease that is often characterized by the development of irreversible clinical disability. Age is a strong risk factor that is strongly associated with the clinical course and progression of MS. Several lines of evidence suggest that with aging, microglia have an aging-related gene expression signature and are close to disease-associated microglia (DAM), which exhibit decreased phagocytosis but increased production of inflammatory factors. The gene expression signatures of microglia in MS overlap with those in aging, inflammation and DAM. Moreover, the clearance of damaged myelin by microglia is impaired in the aged brain. Autophagy is a cellular process that decreases in activity with age. In this review, we provide an overview of the role of autophagy and aging in MS. We describe the impact of autophagy and aging on microglial activation in MS and the molecules involved in autophagy and aging, which are related to the phagocytosis and activation of microglia. We propose that a decrease in autophagy in microglia occurs with aging, leading to a decrease in phagocytosis. Decreases in phagocytosis and increases in the production of inflammatory factors by microglia contribute to chronic inflammation in the aged brain and disease progression in MS. Thus, the modulation of autophagy in microglia serves as a potential therapeutic target for MS.

Adipose tissue thermogenesis has emerged as a prominent research focus for the treatment of metabolic diseases, particularly through mitochondrial uncoupling, which oxidizes nutrients to produce heat rather than synthesizing ATP. Uncoupling protein 1 (UCP1) has garnered significant attention as a core protein mediating non-shivering thermogenesis(NST). However, recent studies indicate that energy dissipation can also occur via UCP1-independent thermogenesis, partially driven by futile metabolic cycles. These cycles involve ATP depletion coupled with reversible energy reactions, resulting in futile energy expenditure. Unlike classical UCP1-mediated thermogenesis, futile cycling is not confined to brown and beige adipose tissue, suggesting a broader range of therapeutic targets. These findings open new avenues for targeting these pathways to enhance metabolic health. This review explores the characteristics and distinctions of the primary metabolic organs (adipose tissue, liver, and skeletal muscle) involved in the futile cycles of thermogenesis. It further elaborates on the cellular and molecular mechanisms underlying calcium, creatine, and lipid cycling, emphasizing their strengths, limitations, and roles beyond thermogenesis.

Targeting metabolic disorders has emerged as a promising therapeutic strategy in the treatment of chronic kidney disease (CKD). 18β-glycyrrhetinic acid (18β-GA) is known for its metabolic regulatory and antioxidant effects in various diseases. However, the precise effects and underlying mechanisms of 18β-GA on CKD remain unclear.

This study aims to evaluate the therapeutic efficacy of 18β-GA on CKD and to identify the molecular targets of 18β-GA with a particular emphasis on its role in metabolic regulation.

A high-fat diet-induced CKD model was established to investigate the influence of 18β-GA on lipid metabolic disorders, cellular senescence and fibrosis in the kidneys. Co-immunoprecipitation was performed to investigate the impact of 18β-GA on the interaction between transcription factor EB (TFEB) and sirtuin 1 (SIRT1). Additionally, network pharmacology and molecular docking analyses were conducted to identify the specific target proteins of 18β-GA.

18β-GA alleviated renal lipid accumulation, tubular cell senescence and renal interstitial fibrosis in CKD mice. Treatment with 18β-GA largely restored mitochondrial function and attenuated intracellular lipotoxicity and associated cellular senescence by promoting lipophagy in renal tubular cells. Mechanistically, 18β-GA acting as a partial antagonist of peroxisome proliferator-activated receptor gamma (PPARγ) enhanced lipophagy through SIRT1-mediated nuclear translocation of TFEB which induced the expression of microtubule-associated protein light chain 3 (LC3).

Our findings demonstrate that 18β-GA, functioning as a partial antagonist of PPARγ, counteracts CKD progression by activating the SIRT1-TFEB-LC3 signaling axis-mediated lipophagy and thus uncover a novel mechanism by which 18β-GA improves renal lipid metabolism disorders and exerts renoprotective effects. These results highlight the potential of 18β-GA as a promising therapeutic agent for the treatment and prevention of CKD.

Lipid droplets (LDs) store lipids in cells, provide phospholipids for membrane synthesis, and maintain the intracellular balance of energy and lipid metabolism. Undoubtedly, the crosstalk between LDs and other organelles is the foundation for performing functions. Many studies indicate that LDs promote tumor progression. LD accumulation has been observed in a variety of cancers, and high LD content is associated with malignant phenotype and poor prognosis of cancers. In this paper, we summarized the intimate crosstalk between LDs and intracellular organelles, including endoplasmic reticulum (ER), mitochondria, lysosomes and peroxisomes, and addressed the effects of LD-organelle crosstalk on cancer initiation and progression. We also integrated the changes of LD-organelle interactions in cancers to provide an insightful knowledge for cancer therapeutics.

Obesity is a global health crisis affecting individuals across all age groups, significantly increasing the risk of metabolic disorders such as type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), and cardiovascular diseases. The World Health Organization reported in 2022 that 2.5 billion adults were overweight, with 890 million classified as obese, emphasizing the urgent need for effective interventions. A critical aspect of obesity's pathophysiology is meta-inflammation-a chronic, systemic low-grade inflammatory state driven by excess adipose tissue, which disrupts metabolic homeostasis. This review examines the role of autolysosomal dysfunction in obesity-related metabolic disorders, exploring its impact across multiple metabolic organs and evaluating potential therapeutic strategies that target autophagy and lysosomal function.

Emerging research highlights the importance of autophagy in maintaining cellular homeostasis and metabolic balance. Obesity-induced lysosomal dysfunction impairs the autophagic degradation process, contributing to the accumulation of damaged organelles and toxic aggregates, exacerbating insulin resistance, lipotoxicity, and chronic inflammation. Studies have identified autophagic defects in key metabolic tissues, including adipose tissue, skeletal muscle, liver, pancreas, kidney, heart, and brain, linking autophagy dysregulation to the progression of metabolic diseases. Preclinical investigations suggest that pharmacological and nutritional interventions-such as AMPK activation, caloric restriction mimetics, and lysosomal-targeting compounds-can restore autophagic function and improve metabolic outcomes in obesity models. Autolysosomal dysfunction is a pivotal contributor to obesity-associated metabolic disorders , influencing systemic inflammation and metabolic dysfunction. Restoring autophagy and lysosomal function holds promise as a therapeutic strategy to mitigate obesity-driven pathologies. Future research should focus on translating these findings into clinical applications, optimizing targeted interventions to improve metabolic health and reduce obesity-associated complications.

N-Myc downstream regulated gene-1 (NDRG1) and the other three members of this family (NDRG2, 3, and 4) play various functional roles in the cellular stress response, differentiation, migration, and development. These proteins are involved in regulating key signaling proteins and pathways that are often dysregulated in cancer, such as EGFR, PI3K/AKT, c-Met, and the Wnt pathway. NDRG1 is the primary, well-examined member of the NDRG family, and is generally characterized as a metastasis suppressor that inhibits the first step in metastasis, the epithelial-mesenchymal transition. While NDRG1 is well-studied, emerging evidence suggests NDRG2, NDRG3, and NDRG4 also play significant roles in modulating oncogenic signaling and cellular homeostasis. NDRG family members are regulated by multiple mechanisms, including transcriptional control by hypoxia-inducible factors, p53, and Myc, as well as post-translational modifications such as phosphorylation, ubiquitination, and acetylation. Pharmacological targeting of the NDRG family is a therapeutic strategy against cancer. For instance, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) have been extensively shown to up-regulate NDRG1 expression, leading to metastasis suppression and inhibition of tumor growth in multiple cancer models. Similarly, targeting NDRG2 demonstrates its pro-apoptotic and anti-proliferative effects, particularly in glioblastoma and colorectal cancer. This review provides a comprehensive analysis of the structural features, regulatory mechanisms, and biological functions of the NDRG family and their roles in cancer and neurodegenerative diseases. Additionally, NDRG1-4 are explored as therapeutic targets in oncology, focusing on recent advances in anti-cancer agents that induce the expression of these proteins. Implications for future research and clinical applications are also discussed.

Pyropia haitanensis (T.J. Chang and B.F. Zheng) undergoes periodic dehydration and rehydration cycles, necessitating robust adaptive mechanisms. Despite extensive research on its physiological responses to desiccation stress, the comprehensive metabolic pathways and recovery mechanisms post-rehydration remain poorly understood. This study investigated the metabolic responses of P. haitanensis to varying degrees of desiccation stress using LC-MS and UPLC-MS/MS. Under mild dehydration, the thallus primarily accumulated sugars and proline, while moderate and severe dehydration triggered the accumulation of additional osmoprotectants like alanine betaine and trehalose to maintain turgor pressure and water retention. Concurrently, the alga activated a potent antioxidant system, including enzymes and non-enzymatic antioxidants, to counteract the increased reactive oxygen species levels and prevent oxidative damage. Hormonal regulation also plays a crucial role in stress adaptation, with salicylic acid and jasmonic acid upregulating under mild dehydration and cytokinins and gibberellin GA15 accumulating under severe stress. Rehydration triggered the recovery process, with indole acetic acid, abscisic acid, and jasmonic acid promoting rapid cell recovery. Additionally, arachidonic acid, acting as a signaling molecule, induced general stress resistance, facilitating the adaptation of the thallus to the dynamic intertidal environment. These findings reveal P. haitanensis' metabolic adaptation strategies in intertidal environments, with implications for enhancing cultivation and stress resistance in this economically important seaweed.

Neuromelanin is a unique pigment made by some human catecholamine neurons. These neurons survive with their neuromelanin content for a lifetime but can also be affected by age-related neurodegenerative conditions, as observed using new neuromelanin imaging techniques. The limited quantities of neuromelanin has made understanding its normal biology difficult, but recent rodent and primate models, as well as omics studies, have confirmed its importance for selective neuronal loss in Parkinson's disease (PD). We review the development of neuromelanin in dopamine versus noradrenaline neurons and focus on previously overlooked cellular organelles in neuromelanin formation and function. We discuss the role of neuromelanin in stimulating endogenous α-synuclein misfolding in PD which renders neuromelanin granules vulnerable, and can exacerbates other pathogenic processes.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the abnormal deposition of amyloid-beta (Aβ) peptides and neurofibrillary tangles (NFTs). Ginsenosides, the primary active constituents in ginseng, exhibit potential in combating AD. In our previous work, the ginsenoside SumI was demonstrated to have superior anti-AD activity compared to other ginsenosides when used alone. This study revealed that SumI effectively decreased the lysosomal pH, promoted autophagosome formation, increased autophagic flux, and facilitated the transport of misfolded proteins to lysosomes for degradation in Caenorhabditis elegans. SumI activated the HLH-30 transcription factor by triggering a lipid-catabolic response akin to starvation. bec-1 RNAi significantly abrogated the anti-AD effect of SumI. Our findings indicate that SumI mitigated protein aggregation by activating the autophagy-lysosome pathway in C. elegans and provide scientific evidence that ginsenoside composition could be a potential therapeutic agent for treating or preventing AD.

With the increasing production and use of lithium-based products, concerns over lithium pollution in aquatic ecosystems are increasing, whereas research on its toxicity mechanisms in aquatic organisms remains limited. The main objective of the present study was to explore the effects of environmentally relevant concentrations of lithium exposure on the life-history strategy, behavior, antioxidant system, and autophagy process of Daphnia magna. Acute (24-96 h) and chronic (21 days) exposure experiments under three lithium treatments (low: 8.34 μg/L, medium: 83.44 μg/L, and high: 834.41 μg/L) were conducted. The results indicated that exposure to medium and high lithium concentrations led to eye and tail deformities in D. magna. Furthermore, developmental and reproductive parameters such as body length, total neonates per female, and average neonates per time were negatively influenced. Lithium also interfered with energy metabolism to cause the decreasing swimming speed and the reduction in the swimming range. In addition, lithium exposure affected the expression of gsk-3β, further disrupting the dynamic balance of mitochondrial fission, fusion, and regeneration, which caused ROS accumulation and induced oxidative stress. D. magna attenuated the stress by activating the FoxO/SESN and Nrf2/Keap1 pathways, synergistically enhancing downstream antioxidant enzymes expression. Concurrently, D. magna also mitigated oxidative stress and mitochondrial damage by promoting autophagy and inhibiting apoptosis. In summary, lithium harmed the physiological and biochemical functions of D. magna through multiple mechanisms, suggesting that environmental lithium pollution may pose a potential threat to aquatic organisms.

Chemoresistance contributes to poor outcomes in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the mechanisms underlying chemotherapy resistance and to develop strategies that can sensitize the chemotherapy. Patient derived organoids (PDOs) drug screening and Lipidomics profiling were performed to investigate the chemoresistance mechanism. Through multi-strategy analysis, we found that SENP3 enhanced chemotherapy sensitivity in a SUMO system dependent manner. Mechanistically, chemotherapy resistance increased METTL3 expression, which regulated SENP3 mRNA stability through YTHDF2-dependent m6A methylation modifications. SENP3 interacted with HADHA and catalyzed its deSUMOylation at two lysine residues. Specifically, SUMOylation and ubiquitination exhibited crosstalk at the same modification sites on HADHA, influencing its protein stability and, consequently, regulating fatty acid oxidation (FAO) levels. The physical interaction of SENP3, HADHA, and USP10 provides a novel molecular mechanism for the abnormal activation of FAO pathway. The lipid metabolism-targeting drug could be a promising therapeutic strategy for sensitizing ICC to chemotherapy.

The liver plays a fundamental role in metabolic homeostasis, integrating systemic fuel utilization with the progression of various metabolic diseases. Hepatic stellate cells (HSCs) are a key nonparenchymal cell type in the liver, which is essential for maintaining hepatic architecture in their quiescent state. However, upon chronic liver injury or metabolic stress, HSCs become activated, leading to excessive extracellular matrix deposition and pro-fibrotic signaling, ultimately positioning them as key players in liver pathology. Emerging evidence highlights the critical roles of metabolic reprogramming and epigenetic regulation in HSCs activation. HSCs activation is driven by both intrinsic fuel metabolism reprogramming and extrinsic metabolic cues from the microenvironment, while the metabolic intermediates actively reshape the epigenetic landscape, reinforcing fibrogenic transcriptional programs. In this review, we summarize recent advances in understanding how metabolic and epigenetic alterations drive HSCs activation, thereby shaping transcriptional programs that sustain fibrosis, and discuss potential therapeutic strategies to target these interconnected pathways in human metabolic diseases.

Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum-lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD-mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.

Compound probiotics have gained increasing recognition as feed additives for improving feed conversion ratio and intestinal health of broilers. Two Lactobacillus strains (Ligilactobacillus salivarius CML391 and Limosilactobacillus reuteri CML393) and two Bacillus strains (Bacillus velezensis CML396 and Bacillus paralicheniformis CML399) were isolated from broiler intestines and combined to form a new compound probiotic (referred to as "CML compound probiotic"). The effects of CML compound probiotic on broiler growth performance, antioxidant capacity, intestinal health, cecal microbiota, and microbial-derived metabolites were assessed in this study. A total of 120 male Arbor Acres chicks were randomly divided into two groups: a control group (CON) fed a basal diet and a CML group supplemented with the compound probiotic at 10⁹ CFU/kg of diet. Dietary supplementation with CML compound probiotic promoted broiler growth performance, enhanced antioxidant capacity, and improved intestinal health. Furthermore, the CML compound probiotic modulated the cecal microbiota by increasing beneficial bacteria such as Bacteroides, Phocea and Defluviitaleaceae UCG-011, and significantly elevated the concentrations of short-chain fatty acids (SCFAs). Metabolomic analysis revealed that the CML compound probiotic influenced lipid metabolism pathways, particularly glycerophospholipid and linoleic acid metabolism. In conclusion, this study indicated that the CML compound probiotic represents a valuable strategy for optimizing broiler growth performance and intestinal health.

Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer's disease (AD), Parkisons's disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue.

Emerging evidence indicated that the excessive lipid droplets (LDs) accumulation and lipotoxicity play a significant role in the development of diabetic cardiomyopathy (DCM), yet the regulatory mechanisms governing the function of cardiac LDs are still unknown. Lipophagy has been shown to be involved in the maintenance of LDs homeostasis. The objective of this study was to explore the mechanism of lipophagy in cardiomyocytes and investigate whether berberine could mitigate DCM by modulating this pathway.

Bioinformatics analysis identified disorders of lipid metabolism and autophagy in DCM. To carry out further research, db/db mice were utilized. Furthermore, H9C2 cells treated with palmitic acid were employed as a model to explore the molecular mechanisms involved in myocardial lipotoxicity.

The results showed that lipophagy was impaired in DCM. Mechanistically, sirtuin 3 (SIRT3) was demonstrated to regulate lipophagy in cardiomyocytes. SIRT3 was down-regulated in DCM. Conversely, activation of SIRT3 by the activator nicotinamide riboside (NR) could promote lipophagy to alleviate PA-induced lipotoxicity in H9C2 cells. Moreover, berberine administration markedly mitigated diabetes-induced cardiac dysfunction and hypertrophy in db/db mice, which dependent on SIRT3-mediated lipophagy.

Collectively, SIRT3 could moderate cardiac lipotoxicity in DCM by promoting lipophagy, suggesting that the regulation of SIRT3-mediated lipophagy may be a promising strategy for treating DCM. The findings indicate that the therapeutic potential of berberine for DCM is associated with lipophagy.

Autophagy is a conserved cellular process essential for homeostasis and development that plays a central role in the degradation and recycling of cellular components. Recent studies reveal bidirectional interactions between autophagy and steroid-hormone signaling. Steroids are signaling molecules synthesized from cholesterol that regulate key physiological and developmental processes - including autophagic activity. Conversely, other work demonstrates that autophagy regulates steroid production by controlling the availability of precursor sterol substrate. Insights from Drosophila and mammalian models provide compelling evidence for the conservation of these mechanisms across species. In this review we explore how steroid hormones modulate autophagy in diverse tissues and contexts, such as metabolism and disease, and discuss advances in our understanding of autophagy's regulatory role in steroid hormone production. We examine the implications of these interactions for health and disease and offer perspectives on the potential for harnessing this functionality for addressing cholesterol-related disorders.

Autophagy is a cellular degradation process reliant on lysosome, crucial for preserving intracellular homeostasis. The key saturated fatty acid palmitic acid (PA) has been demonstrated to exert regulatory effects on autophagic activity in mammals. However, the precise impact of PA on autophagy and its role in fish remains incompletely understood. Thus, this study aimed to investigate the regulation of PA on autophagy and explore the role of autophagy in inflammatory responses triggered by PA in the head kidney macrophages of large yellow croaker. This study indicates that PA exposure can inhibit macrophage autophagy by reducing the expression of genes related to autophagy (e.g., beclin1, ulk1, and lc3), activating the negative regulator mTORC1 signaling pathway (p70S6K and S6), and hindering autophagic flux. This effect was observed to be amplified with increasing exposure time and concentration of PA. Similarly to the in vitro results, the palm oil (PO) diet significantly reduced autophagic activity in the head kidney of the croaker in vivo. Subsequent studies demonstrated that restoring autophagy led to a notable reduction in the expression of PA and PO-induced pro-inflammatory genes (il-1β, il-6, tnf-α, and cox-2), the activation of the MAPK signaling pathway (p38 and JNK), and the NLRP3 inflammasome levels, both in vitro and in vivo. In contrast, further inhibition of autophagy produced the opposite effect in vitro. In conclusion, this study demonstrates that PA exerts a dynamic inhibitory effect on autophagy in the head kidney macrophage, which in turn promotes PA-induced inflammatory responses. These findings provide valuable insights into how PA influences autophagy and inflammatory responses in fish immune cells, contributing to the theoretical framework for improving the use of vegetable oils in aquaculture.

A maternal high-fat diet (HFD) deteriorates the long-term metabolic health of offspring. Circadian rhythms are crucial for regulating metabolism. However, the impact of maternal HFD on the circadian clock in white adipose tissue (WAT) remains unexplored. This study aimed to identify transcriptional rhythmic alterations in inguinal WAT of adult male offspring induced by maternal HFD. To this end, female mice were fed an HFD and their male offspring were raised on a standard chow diet until 16 weeks of age. Transcriptome was performed and the data was analyzed using CircaCompare. The results showed that maternal HFD before and throughout pregnancy significantly altered the circadian rhythm of inguinal WAT while slightly modifying the WAT clock in adult male offspring. Specifically, maternal HFD contributed to gaining rhythmicity of Cry2, resulted in the elevated amplitude of Nr1d2, and led to increased midline estimating statistic of rhythm (MESOR) of Clock and Nr1d2. Furthermore, maternal HFD changed the rhythmic pattern of metabolic genes, such as Pparγ, Hacd2, and Acsl1, which are significantly enriched in metabolic regulation pathways. In conclusion, a maternal HFD before and throughout pregnancy altered the circadian rhythm of inguinal WAT in adult offspring. These alterations may play a significant role in disturbing metabolic homeostasis, potentially leading to metabolic dysfunction in adult male offspring.

The increased global prevalence of metabolic dysfunction-associated steatohepatitis (MASLD) has been closely associated with chronic disorders of the circadian clock. Herein, we investigate the role of Clock, a core circadian gene, in the pathogenesis of MASLD. Wild-type (WT) and liver-specific Clock knockdown (Clock-KD) mice were fed a Western diet for 20 weeks to induce MASLD. A cellular MASLD model was established by treating AML12 cells with free fatty acids and the effects of Clock knockdown were examined following transfection with Clock siRNA. Increased lipid deposition and more severe steatohepatitis and fibrosis were observed in the livers of Western diet-fed but not normal chow diet-fed Clock-KD mice after 20 weeks compared to WT mice. Moreover, the Clock gene was found to be significantly downregulated in WT MASLD mice. The Clock gene was shown to regulate the expression of lipophagy-related proteins (LC3B, P62, RAB7, and PLIN2) in vivo and in vitro. Knockdown of Clock was found to inhibit lipophagy resulting in increased accumulation of lipid droplets in the mouse liver and AML12 cells. Interestingly, the CLOCK protein was shown to interact with P62. However, knockdown of the Clock gene did not promote transcription of the P62 gene but suppressed degradation of the P62 protein during lipophagy in AML12 cells. The hepatic Clock gene regulates lipophagy and affects lipid droplet deposition in liver cells, and thus plays a critical role in the development of MASLD induced by a Western diet.

Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature.

Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy.

In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Lipid metabolism encompasses the catabolism and anabolism of lipids, and is fundamental for the maintenance of cellular homeostasis, particularly within the lipid-rich CNS. Increasing evidence further underscores the importance of lipid remodelling and transfer within and between glial cells and neurons as key orchestrators of CNS lipid homeostasis. In this Review, we summarize and discuss the complex landscape of processes involved in lipid metabolism, remodelling and intercellular transfer in the CNS. Highlighted are key pathways, including those mediating lipid (and lipid droplet) biogenesis and breakdown, lipid oxidation and phospholipid metabolism, as well as cell-cell lipid transfer mediated via lipoproteins, extracellular vesicles and tunnelling nanotubes. We further explore how the dysregulation of these pathways contributes to the onset and progression of neurodegenerative diseases, and examine the homeostatic and pathogenic impacts of environment, diet and lifestyle on CNS lipid metabolism.

Renal proximal tubules are a primary site of injury in metabolic diseases. In obese patients and animal models, proximal tubular epithelial cells (PTECs) display dysregulated lipid metabolism, organelle dysfunctions, and oxidative stress that contribute to interstitial inflammation, fibrosis and ultimately end-stage renal failure. Our research group previously pointed out AMP-activated protein kinase (AMPK) decline as a driver of obesity-induced renal disease. Because PTECs display high macroautophagic/autophagic activity and rely heavily on their endo-lysosomal system, we investigated the effect of lipid stress on autophagic flux and lysosomes in these cells. Using a model of highly differentiated primary PTECs challenged with palmitate, our data placed lysosomes at the cornerstone of the lipotoxic phenotype. As soon as 6 h after palmitate exposure, cells displayed impaired lysosomal acidification subsequently leading to autophagosome accumulation and activation of lysosomal biogenesis. We also showed the inability of lysosomal quality control to restore acidic pH which finally drove PTECs dedifferentiation. When palmitate-induced AMPK activity decline was prevented by AMPK activators, lysosomal acidification and the differentiation profile of PTECs were preserved. Our work provided key insights on the importance of lysosomes in PTECs homeostasis and lipotoxicity and demonstrated the potential of AMPK in protecting the organelle from lipid stress.Abbreviation: ACAC: acetyl-CoA carboxylase; ACTB: actin beta; AICAR: 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; AMPK: AMP-activated protein kinase; APQ1: aquaporin 1 (Colton blood group); BSA: bovine serum albumin; CDH16: cadherin 16; CKD: chronic kidney disease; CTSB: cathepsin B; CTSD: cathepsin D; EPB41L5: erythrocyte membrane protein band 4.1 like 5; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EMT: epithelial-to-mesenchymal transition; FA: fatty acid; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GFP: green fluorescent protein; GUSB: glucuronidase beta; HEXB: hexosaminidase subunit beta; LAMP: lysosomal associated membrane protein; LD: lipid droplet; LGALS3: galectin 3; LLOMe: L-leucyl-L-leucine methyl ester hydrobromide; LMP: lysosomal membrane permeabilization; LRP2: LDL receptor related protein 2; LSD: lysosomal storage disorder; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1: mucolipin TRP cation channel 1; MG132: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal; MmPTECs: Mus musculus (mouse) proximal tubular epithelial cells; MTORC1: mechanistic target of rapamycin kinase complex 1; OA: oleate; PA: palmitate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PTs: proximal tubules; PTECs: proximal tubular epithelial cells; PRKAA: protein kinase AMP-activated catalytic subunit alpha; RFP: red fluorescent protein; RPS6KB: ribosomal protein S6 kinase B; SLC5A2: solute carrier family 5 member 2; SOX9: SRY-box transcription factor 9; SQSTM1: sequestosome 1; TFEB: transcription factor EB; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; VIM: vimentin.

Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdown Pdk1 expression. Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and 13C6 glucose labeling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation. 13C16 palmitate tracing of uniformly labeled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 knockdown cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation in the context of palmitic acid supplementation, suggesting that the effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover in Pdk1 knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.

Lipophagy is a selective type of autophagy where lipid droplets are targeted to the lysosome/vacuole for degradation. Even though lipophagy has been reported in various species, many questions remain unaddressed. How are the lipid droplets sequestered to the lysosome? What is the lipophagy receptor? How is this receptor regulated at a posttranslational level? A new collaborative study among several universities conducted on mouse and human hepatocytes sheds light on these questions, deciphering the lipophagy mechanism in the liver. In a recent paper, Das and colleagues identified VPS4A (vacuolar protein sorting 4 homolog A) as a selective receptor, providing new insights into the mechanistic pathway of lipophagy in mammals and its inverse association with steatotic liver diseases.

In the hypoxic tumor microenvironment, cancer cells undergo metabolic reprogramming to survive. The present study aimed to assess the effects of hypoxic conditions on the lipid metabolism of breast cancer cells to elucidate the mechanisms by which cancer cells survive in an unfavorable environment. Cell viability was assessed by trypan blue staining, MTT and Annexin V-PI assays. Intracellular lipid levels were quantified using Nile red stain with immunofluorescence (IF). Autophagy was detected using LC3 antibody, Cyto-ID stain, IF, Western blotting, and flow cytometry. Fatty acid oxidation (FAO) and ATP production were analyzed using specific assays, while gene expression was assessed by reverse transcription-polymerase chain reaction. siRNA transfection was used for gene knockdown, and Kaplan-Meier analysis was performed for survival analysis. Fatostatin and rapamycin served as an inhibitor of sterol regulatory element-binding protein 1 (SREBP1) and an autophagy inducer, respectively. Under hypoxic conditions, triple-negative breast cancer (TNBC) MDA-MB-231 cells showed markedly increased survival and proliferation rates compared with normal cells (MCF-10A) and estrogen receptor-positive cells (MCF-7), with no change in apoptosis. Under hypoxic conditions, MDA-MB-231 cells showed increased expression of lipogenesis, autophagy and FAO-related enzymes and activation of SREBP1, a key transcription factor for lipogenic genes, whereas these changes were not observed in MCF-7 cells. When SREBP1 was inhibited with chemical inhibitors and siRNA, the expression of lipogenic, autophagic and FAO-related enzymes decreased, resulting in reduced ATP production and viability in hypoxic MDA-MB-231 cells; however, this effect was restored when an autophagy inducer was added. Kaplan-Meier analysis demonstrated that higher SREBP1 expression in patients with TNBC was associated with a worse prognosis, suggesting that SREBP1-mediated reprogramming of lipid metabolism and autophagy under hypoxia is essential for TNBC cell survival. The results of the present study indicate that strategies targeting SREBP1 could be exploited to treat TNBC and improve prognosis.

Context: An adequate supply of energy is essential for the proper functioning of all life activities in living organisms. As organelles that store neutral lipids, lipid droplets (LDs) are involved in the synthesis and metabolism of lipids in cells and are also an important source of energy supply.

Methods and mechanisms: A comprehensive summary of the literature was first carried out to screen for relevant proteins affecting the morphological size of LDs. The size of milk fat globules (MFGs) is directly influenced by the morphological size of LDs, which also controls the energy storage capacity of LDs. In this review, we detail the progress of research into the role of some protein in regulating the morphological size of LDs.

Conclusion: It has been discovered that the number of protein are involved in the control of LD growth and degradation, such as Rab18-mediated local synthesis of triacylglycerol (TAG), cell death-inducing DFF45-like effector family proteins (CIDEs)-mediated atypical fusion between LDs, Stomatin protein-mediated LD fusion and autophagy-related proteins (ATGs)-mediated autophagic degradation of LDs. However, more studies are needed in the future to enrich the network of mechanisms that regulate the morphological size of LDs.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of cirrhosis and a major risk factor for hepatocellular carcinoma and liver-related death. Diabetes medications have been studied as potential treatments for NAFLD. Glucagon-like peptide-1 agonists (GLP-1RAs) have been rarely reported in the treatment of NAFLD alone as an anti-diabetic drug, and its specific mechanism of action is unknown. We investigated whether the therapeutic effect of liraglutide (LRG, a representative drug of GLP-1RAs) on hepatic steatosis is related to regulating lipid metabolism and enhancing autophagy in the hepatocytes.

We examined the effect of LRG on fat accumulation in fatty hepatocytes, and discussed its effects on enzymes related to lipid metabolism and autophagy. Meanwhile, knockdown of SIRT1 in free fatty acids(FFA)-treated cells was used to detected the influence of LRG on lipid metabolism and autophagy by regulating of AMPK/SIRT1 signaling.

Our findings showed that free fatty acids (FFA) induced hepatocyte steatosis, which was significantly reversed by LRG. Meanwhile, LRG significantly regulated the expression of hepatocyte lipogenesis and cytosolic lipolysis-related proteins (FAS, ACC1, ATGL, HSL, LAL). Furthermore, LRG enhanced FFA-induced suppression of autophagy and SIRT1 expression, reducing intracellular lipid accumulation. It is evident that LRG regulates lipid metabolism and induces autophagy in an (AMPK)-dependent manner. Moreover, SIRT1 knockdown inhibited the autophagy-inducing and lipid-lowering effects of LRG.

GLP-1RAs may lower hepatic steatosis by regulating lipid metabolism and enhancing autophagy in an AMPK/SIRT1-dependent manner, providing a new target for the treatment of NAFLD.

Previous studies demonstrated that Tspo loss causes simple steatosis (SS) in hepatocytes in vitro. However, its effect on SS in vivo remains unclear. In this study, we hypothesise that Tspo loss promotes early-stage MASLD. WT and Tspo KO rats were fed a Gubra Amylin NASH (GAN) diet for 8 weeks to induce SS. Tspo KO rats fed the GAN diet (KO GAN) exhibited increased insulin resistance, higher plasma cholesterol, and elevated hepatic triacylglycerol (TAG) levels, along with higher de novo lipogenesis (DNL) and free fatty acid (FFA) uptake, evidenced by increased fatty acid synthase (FASN) and CD36 expression. The Acyl-coenzyme A binding protein/diazepam-binding inhibitor-TSPO complex facilitated FA transport to the mitochondria, where carnitine palmitoyltransferase 1A (CPT1A) directed them for β-oxidation. TSPO interacted with CPT1A in the outer mitochondrial membrane, while its depletion increased CPT1A expression, boosting FA oxidation. Primary Tspo KO rat hepatocytes and stably overexpressed CD36 (CD36_OE) in Huh7 cells displayed impaired mitochondrial function and compromised mitochondrial membrane potential. KO GAN livers had significantly elevated AcCoA, which acetylated RAPTOR, activating mTORC1 to suppress autophagy. Overall, Tspo deficiency exacerbates the advancement of SS by enhancing CD36-mediated FFA uptake, elevating AcCoA levels, compromising mitochondrial function and impairing autophagy during the early stages of MASLD.