To investigate the effects and targets of cordycepin (COR) in alleviating non-alcoholic fatty liver disease (NAFLD). High-fat diet was used to induce NAFLD in mice, and after COR gavage administration, changes in liver function, glucose and lipid metabolism, and ferroptosis-related signaling were detected. In vitro, palmitic acid (PA) and oleic acid (PSA) were combined to induce hepatocyte lipid injury. The effect of COR on hepatocyte ferroptosis was examined. GCH1 conditional knockout mice (GCH1-CKO) and hepatocyte models were constructed, and AAV9-GCH1 was used to construct GCH1 overexpression mouse models to verify the effect of GCH1 on NAFLD. CETSA-WB, co-immunoprecipitation, and DARTS were employed in the COR-GCH1 interaction and mechanism studies to validate the targeted binding relationship between COR and GCH1. Animal-level studies showed that COR could improve glucose and lipid metabolism and liver function damage in mouse NAFLD, inhibit ferroptosis occurrence and lipid peroxidation injury. Cell-level results showed that COR could inhibit hepatocyte ferroptosis. The ferroptosis-inhibiting effect of GCH1 is independent of GPX4 and other signals; GCH1 directly inhibits reactive oxygen free radicals and suppresses lipid metabolism peroxidation damage. COR's effects are not related to classical anti-ferroptosis signals such as GPX4 and Nrf2, but only related to GCH1. COR can target the GCH1 K155 site, stabilize protein levels by inhibiting GCH1 ubiquitination degradation, and when GCH1 is knocked out, COR's effects are antagonized. GCH1 has a protective role in NAFLD, and this effect is independent of classical GPX4 signaling. COR can target the GCH1 K155 site, inhibit GCH1 ubiquitination thereby preventing protein degradation and exerting protein stabilization. COR elevates GCH1 levels to inhibit ferroptosis. COR is a small molecule with potential for treating NAFLD.

Bisphenol A (BPA), a ubiquitous plasticizer, has been implicated in lipid metabolic imbalance, yet its contribution to nonalcoholic fatty liver disease (NAFLD) remains incompletely understood. Here, we combined NHANES data analysis, network toxicology, microarray profiling, molecular docking and dynamics simulations, and LO2 hepatocyte experiments to investigate the association between BPA exposure and NAFLD and its underlying mechanisms. Epidemiologically, urinary BPA levels were positively associated with NAFLD prevalence. In vitro, low-dose BPA induced hepatocellular triglyceride and cholesterol accumulation and impaired cell function. Mechanistic investigations highlighted inflammatory, steroidogenic, and lipid metabolic pathways. Network pharmacology and gene expression profiling pinpointed MMP9, PTGS2, MMP2, NOS3, and PLAU as key BPA-responsive genes, and experimental validation confirmed upregulation of MMP9, PTGS2, and PLAU transcripts and proteins alongside increased MMP2 protein. These findings integrate population-level, computational, and hepatocyte evidence, suggesting that matrix remodeling, inflammation, and lipid metabolism may underlie the link between BPA exposure and NAFLD.

This narrative review aims to critically summarize available data on the association between adult acromegaly and metabolic dysfunction-associated steatotic liver disease (MASLD), with a particular focus on clinical associations and treatment implications.

Cardiovascular diseases (CVDs) involve complex, interrelated pathologies such as oxidative stress, inflammation, endothelial dysfunction, platelet aggregation, and dyslipidemia, for which single-target drugs remain constrained. As a multicomponent herbal medicine, Ginkgo biloba L. (G. biloba) contains diverse bioactive constituents, primarily flavonoids (e.g., quercetin, kaempferol, isorhamnetin, ginkgetin, and isoginkgetin) and ginkgolides (e.g., ginkgolide A, B, C, and J), which are proposed to exert synergistic effects against the multifaceted pathology of CVDs. This review systematically summarizes the pharmacokinetic characteristics and pharmacodynamic mechanisms of the major bioactive components in G. biloba, highlighting distinct mechanistic axes of Nrf2-mediated antioxidant defense, platelet-activating factor (PAF) receptor antagonism, and inflammasome inhibition. These preclinical findings collectively suggest the therapeutic potential of G. biloba extracts (GbE) for atherosclerosis, stable and unstable angina, myocardial infarction, heart failure, obesity-related and diabetic cardiomyopathy, as well as diabetic nephropathy, retinopathy, and non-alcoholic fatty liver disease. However, the clinical evidence remains limited and inconsistent, and G. biloba has not been established as a standard therapy for CVDs. This review evaluates the current clinical evidence and combination therapeutic strategies, aiming to provide a reference for the design of future clinical trials.

Nonalcoholic fatty liver disease (NAFLD) is a major metabolic liver disorder with limited pharmacological options. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora, has shown hepatometabolic effects in experimental studies, but its overall efficacy in NAFLD models remains unclear. We searched PubMed, Embase, Web of Science, the Cochrane Library, CNKI, Wanfang, VIP, and CBM from inception to January 2026 for controlled animal studies evaluating PF in diet-induced NAFLD models. Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment using SYRCLE's tool. Weighted mean differences or standardized mean differences with 95% confidence intervals were pooled using random-effects models. Ten studies were included, all using diet-induced models. PF treatment was associated with improvements in lipid metabolism, liver injury, glucose homeostasis, inflammation, and oxidative stress, including reductions in total cholesterol, triglycerides, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, body weight, fasting blood glucose, insulin resistance indices, tumor necrosis factor-α, and malondialdehyde, together with increased superoxide dismutase activity. High-density lipoprotein cholesterol showed no consistent improvement. Mechanistic findings suggested that PF may activate AMP-activated protein kinase, inhibit sterol regulatory element-binding protein-1c/fatty acid synthase-mediated lipogenesis, and modulate inflammatory and oxidative-stress pathways. However, substantial heterogeneity and incomplete reporting of randomization, allocation concealment, and blinding limited confidence in the evidence. PF showed promising preclinical effects in NAFLD, but further well-designed animal studies and clinical investigations are needed to clarify dose-response relationships, safety, and translational relevance.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern world-wide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERRα. In this study, we show that combining antimalaria drug chloroquine with rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone. Interrogation of these genes for direct transcriptional regulators identified ERRα among top candidates. Using a mouse model with genetic ERRα ablation, we demonstrate a crucial dependency on ERRα activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. In ERRα-null liver, chloroquine failed to reverse, and in some instances aggravated the upregulation of lipid metabolism genes by rapamycin, with evidence linking the impaired management of hepatic lipid overload to underling mitochondrial dysfunction. Together, these findings underscore a critical role of ERRα in reversing MASLD.

This paper aims to evaluate the feasibility of clinical application of high-pressure Schisandrae Chinensis Fructus decoction pieces(HPSCH) compared with that of traditional Schisandrae Chinensis Fructus decoction pieces(SCH), based on the efficacy of mice with nonalcoholic fatty liver disease(NAFLD) induced by a high-fat diet. The optimal preparation process of HPSCH was investigated by using schisandrin content and total extractive yield as indices. After one week of adaptive feeding, C57BL/6 mice were assigned to a normal control group, while the remaining mice were fed an HFD for eight weeks to establish the NAFLD mouse model. After being successfully modeled, the mice were divided into a blank control group, blank administration group, simple model group, fenofibrate group, SCH group, and HPSCH group. All groups were administered by intragastric administration for four weeks. Body weight changes of mice were recorded, and liver indices were calculated. The levels of blood lipid and liver function index in the serum of mice were measured. Hepatic histopathological changes were observed by using hematoxylin-eosin(HE) staining and oil red O staining. Mice's feces were collected, and the 16S rDNA high-throughput sequencing method was employed to analyze changes in the gut microbiota of mice. Untargeted lipidomic analysis of the liver was conducted by using liquid chromatography-mass spectrometry(LC-MS), and principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA) were adopted to screen and identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes(KEGG) database was used to perform relevant pathway analysis. Integrated analyses of gut microbiota and differential metabolites were performed to compare the similarities and differences in efficacy of HPSCH and SCH. The results show that both the HPSCH group and SCH group exert similar effects on biochemical indices in serum and hepatic pathological changes, lipid metabolism can be regulated, and liver injury in NAFLD mice can be improved. The two groups show similar changes in microbial abundance, trending toward the blank control group and maintaining intestinal homeostasis. Compared with those of the simple model group, the differential metabolites and metabolic pathways of both the HPSCH group and SCH group show similarity, and the differential metabolites are mainly triglycerides, diglycerides, phosphatidylcholines, phosphatidylglycerols, and so on. Metabolic pathways include glycerophospholipid metabolism, choline metabolism, retrograde endocannabinoid signaling, thermogenic lipolysis, and so on. This indicates that HPSCH and SCH share common advantages in improving hepatic function in mice and achieve comparable effects. HPSCH can improve blood lipid and liver function indices in NAFLD mice, attaining the therapeutic effect through the regulation of gut microbiota and lipid metabolism. Notably, HPSCH achieved the same efficacy as SCH at half the conventional dose, demonstrating its feasibility for clinical application. Moreover, the application of HPSCH may contribute to the conservation of medicinal resources.