Investigating the hepatoprotective effects of Lonicera confusa against acetaminophen-induced acute liver injury: a systematic pharmacological approach.
Aug 2026· Natural Product Research· pp.
1-6
· 0 citations· 13 references
Medicine
TL;DR
Results suggest SYH mitigates ALI by inhibiting the pro-inflammatory TLR4/MYD88/NF-κB pathway and activating the antioxidant Keap-1/Nrf2/HO-1/NQO1 pathway.
Abstract
Acetaminophen (APAP) overdose frequently leads to acute liver injury (ALI), driven by oxidative stress and inflammation from toxic metabolites. Current treatments like N-acetylcysteine have a narrow therapeutic window, highlighting the need for novel herbal alternatives. This study investigated the hepatoprotective mechanisms of Lonicera confusa (SYH) against APAP-induced ALI using an integrated network pharmacology and molecular docking approach. We identified 33 active compounds and 55 potential targets. Protein-protein interaction analysis revealed five core targets: IL6, TNF, EGFR, CASP3, and TLR4. Enrichment analyses indicated SYH modulates key pathways related to oxidative stress and inflammation, including PI3K-AKT, NF-κB, and TNF pathways. Through molecular docking, strong binding affinities were confirmed, and apigetrin exhibited high affinity for the core targets. Subsequent in vivo validation demonstrated that apigetrin effectively alleviated APAP-induced ALI and inflammatory responses in mice. Collectively, these results suggest SYH mitigates ALI by inhibiting the pro-inflammatory TLR4/MYD88/NF-κB pathway and activating the antioxidant Keap-1/Nrf2/HO-1/NQO1 pathway.
Antitubercular Drug-Induced Hepatic Dysfunction (ATDIHD) is a
major challenge in treating tuberculosis, especially when using first-line drugs. Research shows
that oxidative stress plays a central role in liver injury. Further, it triggers inflammatory and
apoptotic pathways in liver cells. As a result, ATDIHD develops through an interplay between
these pathways. Flavonoids can protect the liver from the damaging effects of TB medication by
exerting antioxidant and anti-inflammatory effects. The study aimed to systematically evaluate
preclinical evidence on the hepatoprotective effects of flavonoids and their mechanisms in
ATDIHD.
Data were collected from PubMed, Scopus, Google Scholar, and ScienceDirect to
screen studies evaluating the protective effects of flavonoids against ATDIHD published up to
18 November 2025.
In this review, 38 studies were included. Most were preclinical, with only a few being
clinical studies. Silymarin, quercetin, naringenin, and catechin showed protection against
hepatic damage. Among these compounds, silymarin has been widely researched and supported
by both preclinical and clinical studies. Quercetin has also been found to reduce liver toxicity by
activating the Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway and blocking Nuclear
Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling.
This review demonstrates that flavonoids may reduce hepatotoxicity by modulating
oxidative stress, inflammatory responses, and apoptotic pathways, indicating their potential role
as adjuncts to antitubercular therapy. Most of the available data, however, come from different
preclinical models that use varied study designs, doses, and outcome parameters. This makes it
difficult to directly apply the findings in clinical practice.
Flavonoids show promising hepatoprotective effects in preclinical models of
antitubercular drug-induced hepatic dysfunction. Further well-designed clinical studies are
needed to confirm their effectiveness and safety as an add-on therapy.
Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), yet effective therapeutic options remain limited. Although notoginsenoside R1 (NGR1) is a major bioactive saponin isolated from Panax notoginseng with established anti-inflammatory and anti-oxidant properties, its hepatoprotective potential and underlying mechanisms in APAP-induced liver injury (AILI) have not been systematically investigated. In this study, we established an AILI mouse model and evaluated the protective effects of NGR1 through biochemical assays, histopathology, Western blotting, and immunofluorescence, complemented by integrative transcriptomic, metabolomic, and gut microbiota analyses. Mechanistic involvement of the MAPK/mTOR-autophagy pathway was further validated using L-leucine as a pharmacological activator of mTOR. NGR1 markedly attenuated AILI, as reflected by reduced serum ALT/AST levels, improved hepatic histology, and increased survival in acute liver failure. NGR1 suppressed inflammatory responses by decreasing IL-1[Formula: see text], IL-6, and TNF-[Formula: see text] levels and alleviated oxidative stress by restoring GSH and SOD while reducing MPO, ROS, and MDA accumulation. Multi-omics analysis revealed significant enrichment of MAPK/mTOR signaling, autophagy, ferroptosis, and glutathione metabolism pathways. Mechanistically, NGR1 promoted autophagic flux (increased LC3-II/I, ATG5, and ATG7 with decreased p62), inhibited ferroptosis (upregulation of GPX4 and SLC7A11 with downregulation of ACSL4), and suppressed APAP-induced activation of the MAPK/mTOR pathway. Pharmacological activation of mTOR by L-leucine partly abolished the protective effects of NGR1, reversing autophagy activation and restoring inflammatory and oxidative injury. These findings collectively demonstrate that NGR1 protects against AILI by inhibiting MAPK/mTOR signaling, restoring autophagy, and suppressing ferroptosis, highlighting NGR1 as a promising therapeutic candidate for APAP-induced hepatotoxicity.
Shuangjiang Li, Zhipeng Liu, Guangdong Pan et al.· The American Journal of Chin...· 0 citations
To investigate the protective effects and underlying mechanisms of polydatin (PD), a natural Sirt1 agonist derived from Polygonum cuspidatum, against acetaminophen (APAP)‐induced acute liver injury (ALI), with a focus on the regulation of the NLRP3 inflammasome signaling pathway and associated inflammatory pathways.
Polydatin's hepatoprotective effects against APAP‐induced ALI were evaluated using a murine model and the AML12 cell line. Liver damage was assessed through histopathological staining and biochemical assays. The protective mechanisms of polydatin were investigated through network pharmacology and RNA sequencing. Protein levels related to inflammation are measured via Western blotting. The effect of polydatin on reactive oxygen species (ROS) was analyzed using immunofluorescence and flow cytometry. The interaction of polydatin with target proteins was analyzed through molecular docking, molecular dynamics simulations, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA).
PD significantly ameliorated APAP‐induced liver injury by restoring redox homeostasis and suppressing the release of inflammatory factors. Transcriptome sequencing revealed a time‐dependent upregulation of NLRP3, a core component of the NOD‐like receptor signaling pathway, during APAP challenge. PD inhibited the NLRP3 inflammasome signaling cascade and reduced downstream inflammatory mediators. Mechanistically, PD decreased both the expression and acetylation of C/EBPβ, thereby blocking C/EBPβ‐mediated activation of NLRP3 inflammasome signaling pathway and attenuating hepatocyte inflammation and liver damage.
This study identifies a Sirt1/C/EBPβ/NLRP3 signaling axis through which polydatin exerts its hepatoprotective effects. These findings provide a mechanistic rationale for developing PD as a preventive or therapeutic agent for APAP‐induced ALI.
Tian-yu Yang, Chen Wang, Yi Ding et al.· iNew Medicine· 0 citations
Evodiamine (EVO), a major bioactive alkaloid isolated from Tetradium ruticarpum (A.Juss.) T.G.Hartley, possesses diverse pharmacological activities; however, its potential hepatotoxicity remains insufficiently characterized. This study aimed to evaluate the hepatotoxic effects of EVO and explore the molecular events associated with its toxicity. Male mice were administered EVO (10, 20, or 40 mg/kg) for 7, 14, or 28 days. EVO exposure caused dose- and time-dependent liver injury and oxidative stress, as shown by serum biochemistry, histopathology, and oxidative stress markers. An integrated multi-omics strategy combining network toxicology, transcriptomics, and metabolomics was applied to explore the underlying mechanisms. EVO exposure induced significant liver injury and oxidative stress in a dose- and time-dependent manner. Multi-omics analyses suggested that EVO treatment was associated with alterations in pathways related to inflammation, apoptosis, and lipid metabolism, including FOXO, PPAR, and NF-κB signaling pathways. Changes in the expression of SIRT1, CASP2, and FOXO3 and disturbances in glycerophospholipid metabolism were further observed. In conclusion, EVO induces dose- and time-dependent hepatotoxicity in mice. Multi-omics analyses suggest that inflammatory responses, apoptotic processes, and metabolic disturbances may contribute to EVO-induced liver injury. These findings provide toxicological evidence regarding the safety profile of EVO and identify biological pathways associated with its hepatotoxicity.
Yue Pan, Yuanyuan Xiao, Qing Shen et al.· Toxicology and Applied Pharm...· 0 citations
Background Aflatoxin B1 (AFB1) is a potent hepatotoxic mycotoxin that induces severe oxidative liver damage. Kaempferol (Kae), a natural flavonoid with known antioxidant properties, has unclear protective effects against AFB1-induced hepatotoxicity. This study aimed to evaluate the hepatoprotective role of Kae and elucidate its underlying mechanism using integrated in vivo, in silico, and in vitro approaches. Methods: In vivo (AFB1-challenged mice) and in vitro (hepatocyte) models were employed, combined with network pharmacology, molecular docking, and molecular dynamics simulations. Liver injury indices, oxidative stress markers, antioxidant enzyme activities, and Keap1/Nrf2 pathway expression were assessed. Results: Kae co-treatment reversed AFB1-induced increases in liver index, serum ALT/AST, histological lesions, and reduced antioxidant capacity in mice. Network pharmacology revealed 59 common targets, with NFE2L2 (Nrf2) as a key node. In vitro, Kae pretreatment significantly lowered AFB1-elevated ROS, MDA, ALT, and AST, while restoring GSH and total antioxidant capacity. Kae reversed AFB1-induced Keap1 upregulation and Nrf2 downregulation, and increased mRNA levels of HO-1, NQO1, SOD, GPX1, and CAT. Molecular docking and simulation showed stable Kae–Keap1 binding (−9.6 kcal/mol) with critical hydrogen bonds (VAL-606) and van der Waals contacts. Conclusions: Kae directly binds Keap1, activates Nrf2 signaling, upregulates antioxidant gene expression, and mitigates AFB1-induced oxidative liver injury. These findings support Kae as a promising candidate for preventing AFB1 hepatotoxicity.
Zongmin Shu, Qingyi Zhou, Mao Zhu et al.· Nutrients· 0 citations
Drug-induced liver injury is an increasingly serious health problem, with a relatively high prevalence in China. Excessive acetaminophen (APAP) intake is a common cause of acute liver injury. Mechanistically, the toxic APAP metabolite
N
-acetyl-
p
-benzoquinone imine (NAPQI) depletes hepatic glutathione (GSH), thereby triggering oxidative stress. Yindan Pinggan Capsules (YDPG), a traditional Chinese medicine prescription, is used for clearing heat and promoting diuresis. However, their protective effects against APAP-induced liver injury (AILI) and the underlying molecular mechanisms remain unclear.
This study aimed to evaluate the protective effect of YDPG against AILI and to elucidate the underlying mechanisms.
Adult male mice were administered YDPG by oral gavage once daily for 7 days. One hour after the final YDPG administration, APAP at 300 mg/kg was injected intraperitoneally to establish a mouse model of AILI. Histopathological examination confirmed that YDPG significantly ameliorated APAP-induced hepatic necrosis and inflammation. To explore the molecular mechanisms underlying these effects, Gene Expression Omnibus data analysis, network pharmacology, and proteomics were employed. Western blot was utilized to detect the hepatic protein levels of solute carrier family 7 member 11, solute carrier family 3 member 2, glutathione peroxidase 4 (GPX4), ceruloplasmin, solute carrier family 39 member 14, acyl-CoA synthetase long-chain family member 4 (ACSL4), and lysophosphatidylcholine acyltransferase 3 (LPCAT3).
YDPG significantly downregulated the overproduction of interleukin-6 and interleukin-1β in serum. Furthermore, YDPG effectively attenuated the APAP-induced elevation of serum alanine aminotransferase and aspartate aminotransferase levels. Comprehensive proteomics analysis revealed that YDPG specifically modulated the ferroptosis pathway. Western blot and immunohistochemistry confirmed the regulatory effects of YDPG on key proteins involved in ferroptosis.
The findings of this study demonstrate that YDPG can alleviate hepatic injury and inhibit the progression of AILI in mice. These protective effects are attributed to YDPG’s ability to suppress the system Xc
−
/GSH/GPX4 axis and modulate the LPCAT3–ACSL4 pathway. Consequently, this research highlights the potential of YDPG as a therapeutic option for AILI.
Jicheng Yang, Yusheng Zhang, Ruiying Yang et al.· Science of Traditional Chine...· 0 citations
