Search Results (55)

Background/Objectives: This study is the first to investigate the potential mechanism of star anise extract (SAE) in protecting against cold stress-aggravated acute lung injury (CSALI) in rats. Methods: A rat CSALI model was induced via combined lipopolysaccharide challenge and cold stress exposure. The preventive effects of SAE were evaluated using cytotoxicity assays, quantification of biochemical indices and inflammatory factors, and histopathological examination. Ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC–HRMS)-based serum metabolomics was employed to systematically profile CSALI-associated metabolic alterations and decipher the potential mechanism underlying the preventive effects of SAE. Results: SAE alleviated pathological progression of CSALI, suppressed inflammatory cell migration, markedly reduced pulmonary inflammatory cell infiltration, and ameliorated lung tissue injury in CSALI rats. SAE also improved abnormal liver function indicators and lowered the levels of pro-inflammatory factors in both serum and bronchoalveolar lavage fluid (BALF). Serum metabolomics analysis identified and annotated 24 disease-altered differential metabolites and evaluated the protective effects of SAE on them. These metabolites were significantly enriched in two key metabolic pathways related to the pathogenesis of CSALI, including arachidonic acid metabolism and glycerophospholipid metabolism. Furthermore, based on metabolite changes, phospholipase A2 was hypothesized as a potential key regulatory factor that may cooperate with arachidonic metabolism to suppress the inflammatory cascade. Conclusions: These findings demonstrated that SAE exerted prominent anti-inflammatory activity and effectively protected against lung injury in CSALI rats. Full article

Thyroid hormones regulate a complex and interconnected network of metabolic signaling. Thyroid dysfunction is, at present, defined and monitored through circulating thyroid-stimulating hormone (TSH) and free thyroid hormones. However, biochemical normalization does not entirely indicate restoration of metabolic homeostasis. This discrepancy highlights a critical limitation of the current TSH-centric paradigm, which also fails to explain the heterogeneity in cardiometabolic outcomes observed among patients with similar biochemical profiles. Metabolomics, through the analysis of tissue-specific biofluids, could aid in capturing the complex metabolic perturbations that characterize this disease. In this review, we summarize metabolomic signatures typical of thyroid dysfunction, perform a critical evaluation of limitations and variability across studies, and explore the clinical and translational implications of metabolomics in thyroid pathology. In addition, five metabolic hubs influenced by thyroid hormone activity are summarized: (i) lipid and lipoprotein remodeling; (ii) mitochondrial energetics and redox balance; (iii) amino acid metabolism and protein turnover; (iv) gut–liver–thyroid axis and (v) biological impact of subclinical thyroid diseases. Taken together, these findings challenge the sufficiency of a diagnostic model based on TSH measurement and pose metabolomics as a promising tool to refine risk stratification, uncover subclinical vulnerability and guide patient-centered management of thyroid disease. Despite its promise, clinical adoption of metabolomics is hindered by a lack of standardization and complex data interpretation. To overcome these limitations, coupling metabolomics with genomics and transcriptomics may allow its translation into practical application. Full article

Background/Objectives: Malignant transformation of hepatocellular adenoma (HCA) represents a clinically significant yet incompletely understood process. Although the pathological and clinical characteristics of HCA have been extensively described, its spatial molecular heterogeneity and spatially organized molecular variation at the tissue level remain insufficiently characterized. This study aimed to establish a spatially integrated multi-omics workflow and to delineate spatially organized molecular variation across histologically defined regions from adenoma to carcinoma. Methods: A sequential dual-layer matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) workflow was developed to acquire small-molecule metabolomic and N-glycan spatial data from the same formalin-fixed paraffin-embedded (FFPE) tissue section. Four rare HCA specimens containing focal carcinoma transformation were included in this study. Pixel-level clustering, region-based co-localization analysis, and diffusion pseudotime modeling were applied to characterize spatial metabolic and N-glycan patterns across normal liver tissue (NL), hepatocellular adenoma (HCA), and carcinoma-transformed regions within adenoma (HCA-HCC). Results: Small-molecule MSI revealed spatial metabolic stratification within HCA, with variation observed in nucleotide-related, lipid-related, sulfur-related, and sugar nucleotide–associated metabolites. Pseudotime analysis revealed a spatial ordering of samples across NL, HCA, and HCA-HCC regions, showing differences in antioxidant-associated metabolites, lipid-related features, and bile acid-related metabolites across regions. N-glycan MSI identified independent glycosylation niches, with increasing structural complexity and enrichment of highly branched glycans in carcinoma-transformed regions. Integration of metabolomic and glycomic data suggested spatially associated patterns between metabolite features and glycan structures across regions. Conclusions: This study provides spatially resolved evidence of spatially organized patterns of molecular variation across histologically defined regions of HCA. The identified metabolic and N-glycan gradients provide insights into spatial molecular organization during malignant transformation of hepatocellular adenoma. Full article

Background and Objectives: Pro-inflammatory diet and high-fat diet (HFD) often coexist in real-world, but their combined impact on the gut–liver axis and potential nutritional countermeasures remain insufficiently studied. This study aimed to evaluate a pro-inflammatory–high-fat composite dietary pattern on the intestine and liver in the population, and to further evaluate the protective potential of astaxanthin (ATX) in complementary experimental systems. Methods: Data from the NHANES 2005–2010 were used to construct four composite exposure groups based on the dietary inflammation index (DII) and energy from fat. Survey-weighted regression analyses were performed to examine associations with systemic inflammation and liver injury. Interaction and C-reactive protein (CRP)-mediated effect analyses were conducted. Fifty SD rats were randomly divided into control group, model group induced by HFD combined with inflammatory factors, and low-, medium-, and high-dose Haematococcus pluvialis (HP) intervention groups. Serum lipids, liver enzymes, liver and colon pathology, and inflammatory and oxidative markers were measured in rats. In an in vitro organ-on-chip barrier model, the effect of ATX was observed when colonic barrier damage was induced using palmitic acid and lipopolysaccharides. Results: The high DII combined with HFD showed the largest increases in CRP, liver enzymes, and fatty liver index. A synergistic interaction was observed between DII and HFD, with CRP mediating approximately 20% of the effect. In rat model, HP-derived ATX improved the lipid profile, attenuated hepatic steatosis and oxidative damage, and reduced colonic pro-inflammatory cytokines, while restoration of tight junction proteins was limited. In colon organoid model, ATX showed limited efficacy in improving inflammation and barrier function. Conclusions: The pro-inflammatory–high-fat dietary pattern synergistically exacerbates gut–liver dysfunction. HP-derived ATX alleviates metabolic and inflammation-induced enterohepatic comorbidity, but its effect on repairing barrier structure is limited. Full article

Background: Persistent liver pathology despite a sustained virologic response (SVR) to hepatitis C virus (HCV) therapy is a major clinical concern. This is particularly relevant for people with HIV (PWH) with HCV coinfection, a population prone to accelerated liver disease progression. This study aimed to characterize the plasma miRNA profile in PWH with cirrhosis one year after successful completion of HCV therapy, and to explore their relationship with metabolite alterations. Methods: This cross-sectional study enrolled 47 PWH who achieved HCV clearance with antiviral therapy. Using plasma samples collected approximately one year after completion of HCV therapy, participants were stratified into two groups based on liver stiffness measurement (LSM): compensated cirrhosis (n = 32, LSM ≥ 12.5 kPa) and non-cirrhosis (n = 15, LSM < 12.5 kPa). Plasma miRNAs and metabolites were determined using small RNA sequencing and untargeted capillary electrophoresis-mass spectrometry (CE-MS), respectively. Significantly differentially expressed (SDE) miRNAs were identified using generalized linear models (GLM) with a negative binomial distribution, and their correlation with metabolite levels was quantified using Spearman’s correlation. Results: In the cirrhosis group (n = 32), we identified a distinct signature of 15 SDE miRNAs (9 upregulated, 6 downregulated) compared to the non-cirrhotic group (n = 15), showing hsa-miR-10401-3p, hsa-miR-548ak, hsa-miR-141-3p, and hsa-miR-3940-3p the largest expression changes. miRNA-gene interaction and pathway enrichment analysis suggested that these 15 SDE miRNAs potentially regulate multiple genes involved in immune response and amino acid metabolism. In addition, correlation analyses with our metabolomic data revealed significant associations between specific SDE miRNAs and amino acids and their derivatives. Specifically, the expression of upregulated miRNAs (e.g., hsa-miR-10401-3p and hsa-miR-16-5p) was positively correlated with plasma levels of L-methionine and its derivatives, while downregulated miRNAs (e.g., hsa-miR-625-5p) were inversely correlated with L-tryptophan. Conclusions: In cirrhotic PWH with history of HCV coinfection, a distinct plasma miRNA signature linked to dysregulated amino acid metabolism is found one year after completion of HCV therapy. This underscores that the HCV cure does not equate to complete hepatic recovery, highlighting the critical need for long-term monitoring in this high-risk population. Full article

The development of RNA-based drugs for MAFLD-related fibrosis is severely hampered by the poor oral bioavailability of nucleic acids. This study employed a novel, patent-protected LNP formulation to orally deliver plant-derived miR-55 and investigate its therapeutic potential, focusing on its novel mechanism of action via the CK2α/SMO interaction. In a rat model established with a methionine-choline-deficient diet, orally administered miR-55 markedly improved liver injury, lipid dysregulation, oxidative stress, and pathological collagen deposition. The anti-fibrotic efficacy was quantitatively confirmed by a significant reduction in hepatic hydroxyproline content and downregulation of key fibrogenic genes (Col1a1, Col3a1, TIMP-1, TGF-β1, CTGF) and pro-inflammatory cytokines (TNF-α, IL-6), achieving effects comparable to the full Ge Xia Zhu Yu Decoction. Mechanistically, both bioinformatic prediction and in vivo validation indicated that miR-55 is predicted to target CK2α. This targeting suppressed CK2α expression and disrupted the endogenous CK2α-SMO complex, thereby promoting the ubiquitin-mediated degradation of SMO—a previously unreported mechanism. This cascade inhibited the downstream Gli1 pathway and downregulated pro-fibrotic and pro-angiogenic factors (VEGF, PDGF), thereby providing a comprehensive mechanistic basis for the therapeutic effects. This study is the first to provide evidence that orally delivered, plant-derived miR-55 may act as a natural modulator that potentially through disrupting the CK2α/SMO interaction via a unique complex disruption-promoted degradation mechanism, attenuating Hedgehog signaling and alleviating liver fibrosis. These findings offer important insights into cross-kingdom regulation and highlight miR-55 as a potential targeted therapeutic candidate. Full article

The global prevalence of non-alcoholic fatty liver disease (NAFLD) is 25%, and its onset is closely related to fatty acid metabolism disorders. With the rise of the concept of non-drug treatment, the intervention potential of unsaturated fatty acids (especially ω-3/ω-6 fatty acids) has become a research hotspot, but the field’s development trend has not been systematically evaluated. Based on bibliometric analysis, 4509 NAFLD fatty acid-related articles in the Web of Science core collection were retrieved, and CiteSpace and VOSviewer were used to analyze the country, institution, and author cooperation networks, and keyword evolution. The annual publication volume peaked in 2022 (316 articles). China led the research output, but the United States had a significant lead in influence. The key author cluster was centered on Sanyal Arun (USA) and Li Y (China); the University of California system and the French National Institute of Health were high-impact institutions. The research topic has shifted from pathological mechanisms (“insulin resistance” and “oxidative stress”) to clinical intervention (“ω-3 fatty acids” and “double-blind trials”). The research on fatty acids in NAFLD has shifted from a stable period to a transitional period. The key words “ω-3 fatty acids”, “double-blind trials”, and “short-chain fatty acids” indicate that nutritional intervention has entered the evidence-based verification stage. Future research should explore the therapeutic potential of unsaturated fatty acids (e.g., ω-6/ω-9 fatty acids) and specialty oils, such as Torreya grandis oil, as novel dietary interventions. Full article

In the last twenty years, an increasing volume of research has characterized lipids as dynamic signaling molecules that play essential roles in various physiological and pathological processes, especially concerning chronic diseases such as cardiovascular disorders, diabetes, liver disease, neurodegeneration, cancer, obesity, diabetic and chronic kidney diseases and atherosclerosis. Dysregulation of lipid synthesis and storage, lipolysis, fatty acid oxidation, lipid signaling pathways, and organelle-specific lipid modifications, including mitochondrial phospholipid remodeling and endoplasmic reticulum stress induced by saturated fatty acids, are recognized as contributors to the initiation and progression of this pathogenesis. Concurrently with the increasing comprehension of lipid metabolism, the last decade has seen progress in the understanding of genome control, especially with non-coding RNAs (ncRNAs). MicroRNAs, long non-coding RNAs, and circular RNAs, as ncRNAs, are essential modulators of gene expression at the epigenetic, transcriptional, and post-transcriptional levels that affect a number of lipid metabolism-related processes, such as fatty acid synthesis and oxidation, cholesterol homeostasis, and lipid droplet dynamics. Therapeutically, ncRNAs hold considerable promise owing to their tissue specificity and modularity, with antisense oligonucleotides and CRISPR-based editing currently under preclinical evaluation. In this context, we review recent studies exploring the interplay between ncRNAs and the regulatory networks governing lipid metabolism, and how disruptions in these networks contribute to chronic disease. This emerging paradigm underscores the role of ncRNA–lipid metabolism interactions as central nodes in metabolic and inflammatory pathways, highlighting the need for a holistic approach to therapeutic targeting. Full article

Background: Dahuang Xiaoshi Tang (DXT), an ancient Chinese herbal remedy dating back to 220 AD, as documented initially in “Treatise on Febrile and Miscellaneous Diseases,” is used to treat damp-heat jaundice with interior sthenia syndrome. In DXT, anthraquinones and alkaloids form insoluble complexes, reducing its effectiveness. A revised herbal extract, DXT-M, was developed, and its hepatoprotective properties were demonstrated in animal models using pharmacodynamic, metabolomic, network pharmacological, and toxicological approaches. Methods: The α-naphthalene isothiocyanate was utilised to establish the acute liver injury rat model. The assays of glutamate pyruvate transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, bilirubin, total bile acid, complement 3 (C3) and C4, interleukin-2 (IL-2) and IL-6, tumour necrosis factor α (TNF-α), and pathological morphology were used to evaluate the hepatoprotection of DXT in comparison to DXT-M. The ¹H-NMR-based serum and urine metabolomics were performed to identify potential biomarkers and metabolic pathways of DXT-M in treating hepatitis. The intrinsic regulatory mechanisms of DXT in liver protection, as well as the combination of network toxicology, were elucidated. Statistical analyses included RM two-way ANOVA with Geisser–Greenhouse correction and Dunnett’s post hoc test for longitudinal data, and one-way ANOVA with Dunnett’s post hoc test for group comparisons. Data were shown as mean ± SD. Results: Liver-injured animals exhibited weight loss, ruffled fur, and liver damage, accompanied by elevated liver function indicators. DXT-M effectively improved these symptoms, repaired liver damage, restored liver function, and regulated immune status by modulating complement 3. Metabonomics and other analyses indicated the CYP/GST-ROS axis is key to its hepatoprotective effects. DXT-M outperformed DXT in efficacy. Conclusions: DXT-M demonstrated significant effectiveness in restoring liver pathological damage, correcting abnormal biochemical indicators of liver function, and regulating complement factors. The pathway of CYP/GST-ROS served as the shared regulatory axis and transformation site for DXT-M’s liver protective effects. These findings suggest that DXT-M has potential as a treatment for acute liver injury, highlighting the need for further research into its underlying molecular mechanisms as well as its complete material basis. This study’s main limitation is its focus on acute models; future research should include other liver diseases and clinical observation to evaluate its full potential. Full article

Liver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N—acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepatotoxicity. Therefore, exploring novel liver-protecting drugs and elucidating their mechanisms of action is of great scientific significance and clinical value. Rosmarinic acid (RA), as a natural polyphenolic compound, has been proven to have significant antioxidant activity. Previous studies have shown that it has a protective effect against drug-induced liver injury. Nevertheless, the precise protective mechanism of RA in APAP-induced acute liver injury (AILI) has not been fully defined. This study was based on an AILI mouse model to systematically explore the liver-protecting effect of RA and its underlying molecular mechanisms. The research results showed that pretreatment with RA could notably mitigate liver pathological injury. It could decrease the activities of ALT and AST in the serum, suppress the liver inflammatory reaction, and reverse the decline in the levels of CAT, T-AOC, SOD, and GSH caused by APAP. Meanwhile, RA could enhance antioxidant defense capabilities by activating the Keap1/Nrf2/HO-1 signaling pathway, regulate the xCT/GPX4 axis to inhibit lipid peroxidation, and thus block the process of ferroptosis. In conclusion, this study confirmed that RA exerts a protective effect against AILI by regulating the Keap1/Nrf2/HO-1 axis to enhance antioxidant capacity and inhibit ferroptosis through the xCT/GPX4 pathway. Our research provides a theoretical basis for RA as a potential therapeutic agent for APAP-induced liver injury. Full article

Background/Objectives: Liver disease is one of the most common medical problems in the world. The pharmacological correction of these pathologies includes the use of drugs with antioxidant and hepatoprotective action, among which there are natural and synthetic sulfur-containing compounds. However, many of these drugs have side effects, and their application does not always correspond to approaches in evidence-based medicine. Therefore, today the urgent problem is the search for new effective substances with high metabolitotropic properties and high safety criteria. The aim of this work was an in-depth study of the hepatoprotective and antioxidant action of a new investigational pteridine-containing “lead-compound” (DCTP) under conditions of experimental tetrachloromethane hepatitis in rats in comparison with the reference drug “Thiotriazoline”. Methods: The hepatoprotective effect of the compound was studied using a model of acute tetrachloromethane (CCl₄) hepatitis in adult male Wistar rats. The levels of biochemical liver damage markers were estimated with spectrophotometric methods. Histological and immunohistochemical methods were used for the determination of hepatocyte damage. The statistical processing of data was performed using the nonparametric Wilcoxon–Mann–Whitney method. Results: The results of the studies showed that DCTP was superior to the reference drug Thiotriazoline in terms of its effect on the levels of AST, DC, Schiff bases, and carbonylated proteins, which are markers of oxidative (Nrf2) and inflammatory (Lipocalin-2) stress, as well as its effect on animal survival. The results were confirmed by histological examination data, which showed regeneration of the hepatocyte membrane structure; a reduction in infiltrative, destructive, and inflammatory process in the liver; a reduction in the cytolytic process; stabilization; and an increase in the functional activity of the liver due to the administration of the study drug. The pharmacological effects of the studied compound (DCTP) are probably associated with its structural similarity to tetrahydrofolic acid, which is an integral component of oxidation–reduction processes and a participant in the biosynthesis of nitrogenous bases of nucleotides and amino acids. The obtained data show the antioxidant and hepatoprotective properties of the studied “lead-compound” from the pteridinethione group (DCTP). Conclusions: It was shown that the studied substance DCTP significantly reduces acute hepatotoxic effects caused by CCl₄, as evidenced by the decrease in the level of lipid peroxidation and prooxidant markers, the normalization of liver biochemical markers, the regeneration of the liver architecture, the limitation of inflammatory effects, the decrease in Nrf2 and Lipocalin-2 markers, and the induction of liver antioxidant enzymes. Full article

Coinfections by multiple pathogens, including viruses and bacteria, have severely impacted tilapia aquaculture globally. This study evaluated the impacts of dietary supplementation on red hybrid tilapia (Oreochromis spp.) coinfected with Tilapia lake virus (TiLV) and Aeromonas hydrophila. Fish were divided into three groups: a control group on a normal diet, and two experimental groups received diets supplemented with strategy A, an organic acid blend combined with a lyso-phospholipid-based digestive enhancer, and strategy B, an organic acid blend combined with natural immunostimulants and nutrients. Following exposure to both pathogens, the fish supplemented with strategies A and B showed lower cumulative mortality rates of 50.0% and 41.7%, respectively, compared to 76.3% in the control group. Notably, fish fed with strategy B-supplemented diet displayed a stronger immune response, with a lower expression of il-8, mx, and rsad2, and showed less pathological changes in the liver, spleen, and intestines, suggesting enhanced resistance to coinfection. In contrast, fish receiving strategy A did not exhibit significant changes in the immune-related gene expression or pathogen load, but demonstrate less pathological alterations, indicating intestinal protection. These findings highlight the potential of feed additives, particularly strategy B, to reduce the impact of virus-bacterial coinfections and improve outcomes in tilapia farming. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is currently the most common cause of chronic liver disease. Systemic inflammatory status and peripheral metabolic symptoms in the clinical picture have an impact on gut commensal bacteria. Methods: Our designed clinical trial was based on a cohort of patients with MAFLD whose diet included the daily consumption of 400 g of “Navelina” oranges for 28 days, compared with a control group of patients with the same pathologic conditions whose diet did not include the consumption of oranges and other foods containing similar nutrients/micronutrients. We used 16S metataxonomics and GC/MS analyses to identify taxa and urine/fecal VOCs, respectively. Results: A set of micronutrients from the diet were inspected, and some specific fatty acids were identified as the main contributors in terms of cluster sample separation. Metataxonomics and metabolomics profiles were obtained, and a stringent statistical approach allowed for the identification of significant taxa/VOCs, which emerged from pairwise group comparisons in both fecal and urine samples. Conclusions: In conclusion, a set of taxa/VOCs can be directly referred to as a marker of dysbiosis status and other comorbidities that, together, make up the pathologic burden associated with MAFLD. The investigated variables can be a target of therapeutic strategies. Full article

Background: High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD). Results: C57BL/6 mice (5–6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. Bacteroidetes, Firmicutes, and Proteobacteria were highly abundant in C-HFD group, while the Verrucomicrobia, Saccharibacteria (TM7), Actinobacteria, and Tenericutes were more abundant in F-HFD group. Other taxa in C-HFD group included the Bacteroides, Odoribacter, Sutterella, Firmicutes bacterium (AF12), Anaeroplasma, Roseburia, and Parabacteroides distasonis. An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (Acaca), Fatty acid synthase (Fasn), Stearoyl-CoA desaturase-1 (Scd1), Elongation of long-chain fatty acids family member 6 (Elovl6), Peroxisome proliferator-activated receptor-gamma (Pparg) and cholesterol synthesis (β-(hydroxy β-methylglutaryl-CoA reductase (Hmgcr). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (CD36), Fatty acid binding protein-1 (Fabp1) and efflux (ATP-binding cassette G1 (Abcg1), Microsomal TG transfer protein (Mttp) in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (Tnfa), C-C motif chemokine ligand 2 (Ccl2), and Interleukin-12 (Il12), as well as a tendency for liver fibrosis. Conclusion: These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance. Full article

Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP’s map road as well. Full article