Search Results (3,448)

Autophagy plays a central role in cellular homeostasis and metabolic adaptation, and its dysregulation has been implicated in metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). This study investigated the biological effects of a chemically characterised multi-component nutraceutical formulation using an integrated in vitro gut–liver–muscle axis model under lipotoxic and inflammatory conditions induced by free fatty acids (FFAs) and lipopolysaccharide (LPS). The principal bioactive constituents were quantified in both the individual extracts and the final formulation before biological testing. Caco-2, HepG2, and C2C12 cells were sequentially exposed to conditioned media to reproduce inter-organ metabolic interactions. The Supplement preserved intestinal barrier integrity by maintaining transepithelial electrical resistance and tight junction protein expression. In HepG2 cells, it preserved telomerase levels, improved markers of cellular metabolic adaptation, modulated AMPK/mTOR and SIRT1 signalling, and promoted autophagy-related responses, including increased LC3-II/I ratio, reduced p62 accumulation, and preservation of lysosomal markers. In skeletal muscle cells, exposure to conditioned medium derived from formulation-treated compartments was associated with improved cellular bioenergetics, reduced oxidative stress and inflammatory mediators, and enhanced ATP and glycogen levels under exercise-like conditions. Overall, these findings provide preliminary evidence that the chemically characterised formulation modulates interconnected pathways involved in intestinal barrier function, hepatic autophagy-related processes, and skeletal muscle metabolic adaptation under the experimental conditions employed. Full article

Background/Objectives: Chronic liver diseases (CLDs), including viral hepatitis, alcohol-related liver disease, non-alcoholic fatty liver disease, hepatic fibrosis, and hepatocellular carcinoma, account for approximately two million deaths annually and remain a global health challenge. Although phytochemicals exhibit antioxidant, anti-inflammatory, antifibrotic, and metabolic regulatory activities through modulation of Nrf2/Keap1, NF-κB/MAPK, TGF-β/Smad, and lipid metabolism pathways, their therapeutic translation is hindered by poor aqueous solubility, extensive first-pass metabolism, and low oral bioavailability. This review evaluates the potential of liposomal delivery systems to overcome these limitations and improve hepatic drug targeting. Methods: A structured narrative review was conducted using systematic literature search principles. PubMed/MEDLINE, Scopus, and Web of Science databases were searched for studies published between January 2000 and March 2025. Original research articles evaluating liposomal formulations of hepatoprotective phytochemicals were assessed with emphasis on formulation strategies, pharmacokinetics, therapeutic efficacy, targeting approaches, and translational potential. Results: Liposomal encapsulation frequently improved systemic exposure and, in several preclinical studies, increased oral bioavailability relative to free phytochemicals, although the magnitude of improvement varied substantially according to the compound, formulation, route of administration, and experimental model. Liposomal encapsulation also improved formulation stability and enabled controlled release in several studies. Surface engineering using polyethylene glycol and receptor-specific ligands, including galactose, lactobionic acid, glycyrrhetinic acid, and vitamin A, further improved circulation time and cell-specific hepatic delivery. Emerging technologies such as microfluidic manufacturing, biomimetic liposomes, and multifunctional formulations show promise for improving formulation reproducibility and therapeutic performance, although clinical evidence remains limited. Conclusions: Liposomal delivery represents a promising strategy for enhancing the pharmacokinetic performance and therapeutic efficacy of hepatoprotective phytochemicals. However, additional well-designed clinical studies, scalable manufacturing approaches, and regulatory standardization are required to facilitate successful clinical translation. Full article

With the advent of the new definition, fatty liver disorders have been reframed into metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and the mixed phenotype referred to as MetALD (MASLD and increased alcohol intake). This change reflects the real-world clinical practice, where metabolic dysfunction and alcohol frequently coexist and synergize to increase risks of steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). While conventional non-invasive tests (NITs) remain the backbone of risk stratification, lipidomics and metabolomics can capture biological information on disease mechanisms and may improve early detection and prognosis. Here, we summarize the current evidence on circulating and tissue lipidomic and metabolomic signatures across MASLD, ALD and MetALD, discuss how the new definitions affect clinical risk assessment, and highlight recent studies which partially distinguish molecular fingerprints for mixed etiology disease. Full article

Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder that can progress to non-alcoholic steatohepatitis (NASH), in which lipotoxicity, oxidative stress, apoptosis, and impaired autophagy contribute to liver injury. 14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive diterpenoid from Andrographis paniculata, has shown anti-inflammatory and antioxidant activities, but its role in NASH-associated lipotoxicity remains unclear. This study investigated the protective effects and underlying mechanisms of deAND using palmitic acid (PA)-treated AML12 hepatocytes and a choline-deficient, L-amino acid-defined, high-fat-diet (CDAHFD)-induced mouse model of NASH. In AML12 cells, PA impaired autophagic flux and reduced the expression of the mitophagy-associated proteins PINK1 and Parkin and increased p62, LC3-II, reactive oxygen species production, and apoptotic signaling. deAND treatment restored autophagic flux and increased PINK1 and Parkin expression, enhanced antioxidant defense-related proteins, including HO-1, GCLM, and GPX2, and reduced oxidative stress and apoptosis. The protective effects of deAND were attenuated by autophagy inhibitors, supporting the involvement of autophagy regulation. In CDAHFD-fed mice, deAND reduced hepatic steatosis, inflammation, fibrosis, apoptosis, and autophagy dysregulation. These findings suggest that deAND alleviates lipotoxic liver injury by restoring autophagic homeostasis and reducing oxidative stress. Full article

Background: Hyperlipidemia is a major risk factor for cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), and is closely associated with oxidative stress. Opuntia ficus-indica (OFI) cladodes are recognized as a rich source of bioactive phytochemicals; however, the molecular mechanisms underlying their metabolic benefits remain incompletely understood. Objectives: This study aimed to comprehensively evaluate the hypolipidemic and hepatoprotective potential of a polyphenol-rich O. ficus-indica cladode extract (OCE) using an integrated approach combining in vivo evaluation, untargeted metabolomics (UHPLC-Orbitrap-MS/MS), molecular docking, and ADMET prediction. Methods: Hyperlipidemic mice fed a high-fat diet (HFD) were treated with OCE, while molecular docking was performed on ten major annotated phytochemicals against twelve key proteins involved in lipid metabolism and cholesterol homeostasis, including HMGCR, FAS, PPARα, PCSK9, and NPC1L1, using simvastatin as the reference compound. Results: OCE treatment significantly improved plasma and hepatic lipid profiles, improved glucose homeostasis, and markedly reduced hepatic malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. Histopathological analysis further supported a pronounced hepatoprotective effect, with a substantial reduction in hepatic steatosis. Untargeted metabolomics enabled the annotation of 102 metabolites, putatively identifying piscidic acid as the predominant phenolic constituent together with a diverse profile of flavonoids and phenolic acids. Molecular docking supported the potential contribution of these phytochemicals to the regulation of lipid metabolism through favorable interactions with multiple therapeutic targets, while ADMET prediction suggested an overall favorable pharmacokinetic and toxicity profile despite the lower intestinal permeability predicted for glycosylated derivatives. Conclusions: Overall, these findings support O. ficus-indica cladodes as a promising source of dietary bioactive compounds with potential applications in the nutritional management and prevention of hyperlipidemia and related cardiometabolic disorders. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive inflammatory and fibrotic subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), and its treatment landscape is rapidly moving from nonspecific liver fat reduction towards mechanism-based drug positioning. Since 2024, resmetirom and semaglutide have received U.S. Food and Drug Administration accelerated approval for non-cirrhotic MASH with moderate-to-advanced fibrosis, while tirzepatide, survodutide, and fibroblast growth factor 21 analogues have shown biopsy-based phase 2 or 2b efficacy signals. This narrative review organises approved and emerging pharmacotherapies within a pathogenesis-informed three-axis framework: the weight-insulin resistance-substrate load axis, the intrahepatic lipid reprogramming axis, and the inflammation-fibrosis transition and multi-axis integration axis. We further grade evidence maturity from regulatory or phase 3 histological evidence to phase 2 biopsy-based evidence and earlier imaging- or biomarker-based signals. This framework is intended to support phenotype-sensitive treatment positioning rather than a fixed therapeutic sequence. In particular, weight-centred treatment should not be assumed to apply to all patients, including normal-weight or lean MASH. Overall, future MASH therapy will likely depend on matching drug mechanisms, fibrosis stage, cardiometabolic phenotype, and treatment goals. Full article

Background/Objectives: Lifestyle modification is central to non-alcoholic fatty liver disease, now termed metabolic dysfunction-associated steatotic liver disease (NAFLD/MASLD), yet comparable health-promoting lifestyle (HPL) data for patients and family members are limited. This study compared two independent samples and examined psychosocial correlates. Methods: Two convenience samples recruited at one tertiary hospital were analyzed: 305 adults with NAFLD/MASLD and 299 adult family members of affected patients. A self-administered electronic questionnaire comprised the Health-Promoting Lifestyle Profile II (HPLP-II), the Self-Rated Abilities for Health Practices scale, autonomous-motivation items from the Treatment Self-Regulation Questionnaire, the Medical Outcomes Study Social Support Survey, and sociodemographic items. Group comparisons used parametric and non-parametric tests. HPL correlates were examined using complete-case regression, HC3 inference, and rank-based sensitivity analysis. Cross-sectional indirect-association decompositions used 5000 bootstrap resamples. Results: HPLP-II scores were 102.2 ± 17.5 in patients and 104.2 ± 17.4 in family members (p = 0.171; Mann–Whitney p = 0.166); the adjusted patient-minus-family difference was −1.14 (HC3 95% CI −3.89 to 1.60; p = 0.413). Physical activity was the lowest-scoring dimension. Self-efficacy was the most robust correlate in both samples; social support was associated in the primary models but weakened under rank transformation in family members. Group-by-correlate interactions were not significant. Exploratory indirect associations through self-efficacy were 0.355 (95% bootstrap CI 0.234–0.512) in patients and 0.163 (0.071–0.287) in family members; reverse-order models were also non-zero. Conclusions: The independent unmatched samples reported similar moderate, physically inactive lifestyles. The results identify associations, not shared-household effects or causal mechanisms; objectively characterized, dyad-matched longitudinal studies are needed. Full article

Background and aims. Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease associated with cirrhosis, hepatocellular carcinoma, and increased risks of liver-related and cardiovascular mortality. Many patients, however, remain asymptomatic until advanced stages. The gamma-glutamyl transferase to high-density lipoprotein cholesterol (GGT/HDL-C) ratio is a simple, noninvasive marker reflecting hepatic dysfunction and cardiometabolic imbalance. This study assessed its association with NAFLD and determined an optimal cutoff for identifying NAFLD. Methods. We conducted a cross-sectional analysis of 575 adults undergoing routine health examinations at the University of Medicine and Pharmacy Hospital in Ho Chi Minh City between 2021 and 2023. Participants with significant alcohol intake, viral hepatitis, or other chronic liver diseases were excluded. NAFLD was diagnosed by standardized abdominal ultrasonography based on increased hepatic echogenicity relative to the renal cortex or spleen. Associations between GGT/HDL-C and NAFLD were assessed by logistic regression (both as a continuous variable and by quartiles), and diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Statistical significance was defined as a two-tailed p-value < 0.05. Results. Individuals with NAFLD showed significantly higher BMI, prevalence of hypertension and diabetes, and elevated glucose, HbA1c, AST, ALT, GGT, cholesterol, triglycerides, and LDL-C, along with lower HDL-C. Each unit increase in the GGT/HDL-C ratio was associated with a 2% increase in the odds of NAFLD based on univariate logistic regression analysis. However, after adjustment for demographic and metabolic covariates, the GGT/HDL-C ratio was no longer independently associated with NAFLD. The highest quartile had an odds ratio of 7.05 (95% CI: 4.2–11.83) compared to the lowest. The area under the ROC curve for GGT/HDL-C was 0.72, outperforming GGT or HDL-C alone. A cutoff of 32.47 UI/mmol had 72.4% sensitivity and 63.3% specificity. Conclusions. The GGT/HDL-C ratio showed a significant unadjusted association with NAFLD and moderate discriminatory performance. However, because the association was no longer significant after full adjustment, the ratio should currently be considered a simple laboratory-based screening marker that requires further validation before routine clinical application. Full article

Background/Objectives: Orlistat is a gastrointestinal lipase inhibitor used for weight management. Although its established safety profile is largely characterised by fat malabsorption-related gastrointestinal events, post-marketing reports suggest a broader spectrum of adverse events. Given the increasing intersection between obesity pharmacotherapy and the management of non-alcoholic fatty liver disease/metabolic dysfunction-associated steatotic liver disease (NAFLD/MASLD), this study evaluated gastrointestinal, hepatobiliary, pancreatic, and anorectal adverse-event reporting signals associated with orlistat in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and assessed concordance with regulatory prescribing information. Methods: Quarterly FAERS files from 2004 Q1 through 2026 Q1 were analysed; some retained reports had Initial FDA Received Date (FDA_DT) values dating back to 1999. Descriptive analyses included all orlistat-associated reports, whereas disproportionality analyses were restricted to primary-suspect reports. Sixty-five prespecified Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) were screened. Reporting odds ratios (RORs), 95% confidence intervals (CIs), and proportional reporting ratios (PRRs) were calculated. A signal was defined as ROR > 2.0, lower bound of the 95% CI > 1.0, and n ≥ 3. Two-sided p values calculated using Fisher’s exact test on the corresponding 2 × 2 contingency tables were adjusted using the Benjamini–Hochberg false discovery rate procedure to address multiple testing. Signal-positive PTs were cross-referenced with prescribing information from three jurisdictions. Results: Overall, 30,454 deduplicated orlistat-associated reports were identified, including 16,684 primary-suspect reports. Thirty-eight of the 65 prespecified MedDRA PTs met the signal criteria, and all remained statistically significant after Benjamini–Hochberg false discovery rate correction (q < 0.05). The strongest signals were rectal discharge (ROR 1175.53; 95% CI 1093.44–1263.78) and steatorrhoea (ROR 1147.99; 95% CI 1058.12–1245.50); change in bowel habit also showed a high ROR (47.32; 95% CI 38.27–58.51). Unlabelled signal-positive PTs included constipation, faeces hard, cholecystitis, and irritable bowel syndrome; change in bowel habit showed jurisdiction-specific labelling discordance. Conclusions: Orlistat-associated FAERS signals included both expected fat-malabsorption-related events and additional gastrointestinal, hepatobiliary, pancreatic, and anorectal PTs, several of which were not explicitly represented in the evaluated regulatory labels. These findings reflect disproportionate reporting rather than incidence, absolute risk, or causality and require confirmation in independent clinical or epidemiological data sources. They do not, by themselves, support regulatory labelling changes. Full article

Glutathione is an abundant intracellular low-molecular-weight thiol that contributes importantly to cellular redox homeostasis. Besides its well-established role in the antioxidant defense of the cell, glutathione regulates mitochondrial function, metabolism of toxicants, protein thiol oxidation/reduction, redox signaling, and immunity. Disturbances in glutathione metabolism have been shown to play a role in various diseases; however, it has become clear that changes in glutathione metabolism are a part of a complex, multifactorial process. In this review, we summarize current knowledge of the molecular mechanisms governing glutathione synthesis, recycling, compartmentalization, and biological functions, with particular emphasis on redox signaling, the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway, and reversible protein S-glutathionylation. We further examine how disturbances in glutathione homeostasis interact with mitochondrial dysfunction, chronic inflammation, metabolic stress, and impaired cellular signaling in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, Wilson’s disease, type 2 diabetes, and nonalcoholic fatty liver disease. We also evaluate current translational interventions targeting restoration of glutathione balance through glutathione supplementation, precursor supplementation, pharmacological modulation of endogenous antioxidant mechanisms, dietary interventions, and changes in lifestyle. Despite the fact that many interventions have been promising at the mechanistic and experimental level, there are still insufficient clinical data because of the problems associated with glutathione availability, tissue specificity, disease variability, and a lack of sufficiently powered clinical trials. The conclusion of this review is that glutathione should not be viewed as a universal therapeutic target; instead, glutathione should be perceived as an important factor contributing to cellular resilience and able to help other disease-specific interventions. Future progress in glutathione-based interventions will likely depend on integrating redox biomarkers, patient stratification, and precision medicine strategies to identify individuals most likely to benefit from targeted modulation of glutathione homeostasis. Full article

Introduction. Statins’ established cardiovascular benefits are often undermined by hepatic adverse effects in obese diabetic patients with suspected non-alcoholic fatty liver disease. We evaluated whether cannabis plant treatment is a safe and effective alternative to atorvastatin in a metabolically challenged rodent model. Methods. Fourteen obese and diabetic Wistar rats received either atorvastatin for 30 days or cannabis plant extract for 30 days. Main outcome: lipid profile; secondary outcomes: renal function, glycemia and endothelial health assessed through atherogenic indices. Safety was assessed using plasma liver enzyme concentrations. Results. Baseline biochemical profiles were similar between groups. Atorvastatin increased HDL-Col more than cannabis plant (MD: 44.3; IQR [33, 57.5] mg/dL, Hedges’ g 2.713 vs. MD: 14.3; IQR [14, 17] mg/dL, Hedges’ g 5.049), and cannabis plant did not change LDL-Col. Atherogenic index of plasma and Castelli Risk Index 1 improved with both interventions, more so with atorvastatin. Liver enzymes increased with atorvastatin (ALAT, MD: 15.9; IQR [12.5, 19.5] U/L; ASAT, MD: 33; IQR [26.5, 38] U/L) but remained virtually unchanged with cannabis. Serum creatinine increased with cannabis plant, with moderate effect size (Hedges’ g 0.798), but negligibly with statins (Hedges’ g 0.122). Conclusions. Cannabis plant extract modestly improved the lipid profile and atherogenic indices, with differences often not exceeding the change in control groups. Despite apparent liver safety, the undesired renal and neurological consequences limit applicability in humans. Further studies should prioritize addiction development and renal function. Full article

Fatty liver is associated with increased all-cause mortality. Organic cation transporter 1 (OCT1) is a polyspecific hepatic uptake transporter. OCT1 mediates hepatic uptake of vitamin B1 (thiamine); thus, OCT1 deficiency may impair thiamine availability and consequently reduce glucose-derived energy. Consequently, OCT1-knockout mice exhibit significantly reduced liver fat. In 2% of Europeans and White Americans, common genetic variants markedly reduce OCT1 function. In this study, we used these naturally occurring variants to investigate the influences of reduced OCT1 function on liver fat in humans. We analyzed 2512 whole-body MRI datasets from the Study of Health in Pomerania (SHIP) and validated the findings using 31,594 datasets from the UK Biobank. In both cohorts, OCT1 deficiency was associated with lower fat content in the liver (p = 0.027 in SHIP; p = 2.9 × 10⁻⁶ in the UK Biobank), but not in other body compartments. OCT1 deficiency remained an independent predictor after adjustment for age, BMI, daily alcohol consumption, and biological sex. To investigate underlying mechanisms, we used Seahorse assays to show that OCT1-overexpressing cells exhibited increased mitochondrial metabolic activity when glucose was the sole energy source. Our findings warrant further investigation of OCT1 as a potential contributor to the pathogenesis of fatty liver. Full article

Background/Objectives: Obesity and its metabolic comorbidities, including dyslipidemia and non-alcoholic fatty liver disease (NAFLD), are a growing global health burden, and current pharmacotherapies have limited efficacy and notable adverse effects. The gut microbiome has emerged as a key regulator of host metabolism, and its dysregulation is implicated in obesity. This study investigated the therapeutic potential of Piper sarmentosum Roxb. aqueous extract (PSRW) on metabolic dysfunction and gut microbiota composition in a high-fat diet (HFD)-induced obese rat model. Methods: HFD-induced obese male Wistar rats received PSRW, simvastatin, or their combination for 12 weeks. Serum lipids (TC, TG, HDL, LDL), liver enzymes (AST, ALT), and renal markers were measured, and gut microbiota were profiled by 16S rRNA (V4) sequencing with PICRUSt2/KEGG functional prediction. The phenolic composition of the same extract was characterized by HPLC in a companion study. Results: PSRW did not cause weight loss but significantly lowered serum TC, AST, and ALT, with efficacy comparable to simvastatin and significantly lower TG than control, though not significantly different from HFD. Co-administration of PSRW and simvastatin produced a greater reduction in TC and liver enzymes than either agent alone. HFD shifted microbial community structure and enriched pro-inflammatory phyla such as Desulfobacterota; PSRW partially reversed these changes, suppressing obesogenic Lachnospiraceae genera while enriching beneficial microbes including Dwaynesavagella, and functionally reprogrammed taxa such as Kineothrix and Muribaculum from detrimental to protective associations. HFD enriched microbial glycosphingolipid biosynthesis, whereas the PSRW simvastatin combination uniquely enhanced glycine, serine, and threonine metabolism. Conclusions:P. sarmentosum extract ameliorates HFD-induced dyslipidemia and hepatotoxicity, and these effects are accompanied by remodeling of the composition and predicted functional capacity of the gut microbiome. Its ability to act in combination with statins highlights its potential as a candidate complementary therapy for hyperlipidemia and NAFLD. Full article

Background/Objective: Cinnamaldehyde (CA) is a naturally occurring bioactive compound derived from the leaves, bark, roots, and flowers of the Chinese medicinal plant Cinnamomum cassia. It exhibits a broad spectrum of pharmacological properties, encompassing antioxidant, antibacterial, anti-diabetic, antifungal, and anticancer activities. Notably, it has shown potential therapeutic benefits in the management of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Ochratoxin A (OTA), a common contaminant found in foods such as cereals, coffee, and raisins, is also present in traditional Chinese medicinal materials, including Astragalus and liquorice. T2DM and NAFLD share intertwined pathophysiological pathways, including insulin resistance, dyslipidaemia, chronic low-grade inflammation and oxidative stress, with insulin resistance serving as the common pathological hub for both conditions. Consequently, they frequently co-occur and exacerbate each other. OTA exerts dual-targeted toxicity to the pancreas and liver, which may synergistically drive the development of the comorbidity of T2DM and NAFLD. These two processes are mutually causal and together constitute the pathological basis of metabolic comorbidity. Methods: Network toxicology employs toxicological data, gene expression, and protein–protein interaction (PPI) networks to predict the targets of toxins, while network pharmacology, based on systems biology principles, reveals how drugs exert regulatory effects through multiple targets and pathways. In this study, we employed an integrated network toxicology and network pharmacology approach to jointly decipher the potential mechanisms by which CA intervenes in OTA-induced comorbid T2DM-NAFLD. First, a network toxicology approach was employed to preliminarily screen for core toxicological targets responsible for OTA’s pathogenicity. Subsequently, network pharmacology was used to identify potential targets of CA-mediated intervention in the disease. Finally, the common overlap among the CA intervention targets, OTA toxicity targets, and disease targets was defined as the final set of potential targets for CA-mediated intervention in OTA-induced T2DM-NAFLD comorbidity. A PPI network was constructed using the STRING database, and topological analysis was performed with Cytoscape. Core targets were selected using the median values of six parameters—betweenness centrality, closeness centrality, degree centrality, eigenvector centrality, LAC (local average connectivity) score, and network centrality—as cut-off thresholds, and the top 10 key genes were further identified using the cytoHubba plugin. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database, and the results were visualized on the CNSknowall platform. Lastly, molecular docking of the core targets was performed using the CB-DOCK2 platform to validate binding affinity. Results: Based on an integrated analysis of network toxicology, network pharmacology, and molecular docking, 10 key targets were systematically identified. These may serve as potential mediators of cinnamaldehyde in the treatment of OTA-induced T2DM-NAFLD comorbidity. Among these, six targets—albumin (ALB), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), interleukin-6 (IL-6), tumor necrosis factor (TNF), actin beta (ACTB), and estrogen receptor 1 (ESR1)—possess crystal structures amenable to molecular docking. KEGG enrichment analysis revealed that CA and OTA jointly participate in key pathological processes such as the cancer pathway, the lipid and atherosclerosis pathway, the advanced glycation end-products–receptor for advanced glycation end-products (AGE-RAGE) signaling pathway, the phosphatidylinositol 3-kinase–protein kinase B (PI3K-Akt) signaling pathway, the TNF signaling pathway, and the interleukin-17 (IL-17) signaling pathway. OTA exacerbates inflammatory responses, impairs insulin signaling, promotes hepatic steatosis, and disrupts systemic metabolic homeostasis, ultimately contributing to T2DM-NAFLD comorbidity. Conversely, cinnamaldehyde counteracts these pathological processes through multiple mechanisms, including antioxidant and anti-inflammatory effects as well as regulation of glucose and lipid metabolism, thereby restoring metabolic homeostasis. Conclusions: This study has preliminarily identified the toxicological targets of OTA and the potential intervention targets of CA, offering new avenues for preventing and intervening in OTA-induced metabolic toxicity. Furthermore, it provides a theoretical basis for CA as a potential multi-target therapeutic agent and presents novel insights worthy of further investigation into the prevention of T2DM-NAFLD comorbidity. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide and poses a significant public health challenge. Allicin, a major bioactive organosulfur compound derived from garlic, has emerged as a promising candidate for MASLD prevention and management due to its antioxidant, anti-inflammatory, and metabolic regulatory properties. Despite its potential, evidence regarding allicin’s efficacy on MASLD remains limited and heterogeneous because existing studies have evaluated different garlic-derived interventions across diverse experimental settings. This review therefore distinguishes studies of purified allicin from those of raw garlic, garlic powder, aged garlic extract, black garlic, garlic essential oil, and individual garlic compounds. Preclinical studies using allicin suggest beneficial effects on hepatic steatosis, inflammation, glucose homeostasis, and lipid metabolism. Human studies, however, have evaluated raw garlic consumption or garlic powder supplementation rather than allicin alone. Findings from other garlic preparations and individual compounds are attributed only to the intervention tested, because differences in composition, stability, bioavailability, metabolism, and pharmacological activity preclude their attribution to allicin. Moreover, the available clinical trial evidence comprises five publications derived from only two randomized controlled trials conducted in Iran, both lasting 12–15 weeks. In addition, preclinical evidence most consistently supports regulation of hepatic lipid metabolism, particularly the AMP-activated protein kinase/sterol regulatory element-binding protein-1c-related signaling, as a potential mechanism underlying the anti-steatotic effects of allicin. Additional pathways may involve inflammatory signaling, oxidative stress, gut microbiota, and bile acid-related regulation, although the evidence for several of these mechanisms remains suggestive. Nevertheless, the precise molecular targets and signaling networks underlying these effects remain incompletely understood, and the relevance of allicin to aging-related MASLD is largely unexplored because previous studies have used young animals. Future studies should incorporate aged models and long-term randomized controlled trials across diverse populations to clarify the mechanisms, therapeutic potential, and safety of allicin in MASLD. Full article