Scheduling of oncolytic virus (OV) therapy has never been correlated with immunological/clinical response. In hepatocellular carcinoma (HCC) patients, where background liver is frequently chronically injured, repeated dosing may have deleterious implications, resulting in off-target immune-mediated damage, thereby tipping the balance between favourable clinical response and hepatotoxicity. Elucidation of the optimum dosing regime is paramount to ensure therapy, whilst limiting damage to background liver. We expand upon our experience in neoadjuvant OV therapy to compare immunological responses from single versus repeated doses of reovirus in cancer patients. The impact of OV on HCC outcomes was examined in vivo following a high-fat diet or induced liver fibrosis in the context of abnormal background liver. Furthermore, we assess the potential immune-mediated toxicity of single versus multiple virus infusions in combination with PD-1/PD-L1 blockade. Data indicate that a single dose of reovirus is equivalent or superior to repeated doses in achieving: (a) induction of an inflammatory cytokine/chemokine response; (b) peripheral blood immune cell activation; (c) migration of activated CD8+ CTLs. Repeated doses on consecutive days do not improve the amplitude of the immune response following virus infusion. Furthermore, without improving therapeutic efficacy, repeated viral dosing leads to an unwanted influx of activated T-cells into background liver, alongside elevated liver enzymes associated with aberrant liver function. A single dose of reovirus is as effective as multiple doses when combined with anti-PD-L1 therapy in limiting tumour growth and extending survival in vivo, whilst simultaneously avoiding undesirable toxicities in background liver, in the context of HCC.

Microphysiological systems to accelerate and de-risk AAV gene therapy development.

Evaluation of liver toxicity in rats exposed to silver nanoparticles - Targeted metabolomics and histology based study.

Comparative hepatoprotective effects of Benzene Sulfonamide Derivatives in a rat model of ethylene glycol-induced liver injury.

Liver toxicity is common in patients treated with immune checkpoint inhibitor (ICI) therapy. Most guidelines advocate for the admission of patients with grade 3/4 ICI mediated hepatitis. Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. An ambulatory pathway for ICI mediated hepatitis (CTCAE grade 3/4) was commenced in March 2023. Patients with ICI mediated hepatitis with normal synthetic liver function (bilirubin <30µmol/L, INR <1.5, albumin >30 g/L and grade ≤2 encephalopathy) were considered as potential candidates for acute ambulatory management. Patients received either ambulatory intravenous methylprednisolone 1 mg/kg for 2-3 days or 1 mg/kg oral prednisolone. The primary outcome measure was 30-day readmission due to progressive/refractory hepatitis. Secondary outcome measures were decision to rechallenge with ICI therapy and 30-day all-cause mortality. Eighty-nine patients treated with ICI therapy presented with grade ≥ 3 transaminase rises during the study period. Thirty-eight patients were diagnosed with ICI mediated hepatitis of whom 23 (59%) patients were managed on the ambulatory pathway.Ambulatory pathway patients had a median age of 62 years (37-78) and 10 (43.5%) were male. Median ALT was 323 u/L (range 10-49 u/L) and AST 302 u/L (range 0-33 u/L).No patients required admission due to failure of ambulatory management or worsening liver function. No patients died of any cause within 30 days. Our ambulatory care pathway has been utilised successfully to treat patients with severe ICI-mediated hepatitis. There were no observable adverse outcomes including readmissions and deaths. The adoption of this pathway for appropriate patients could potentially lead to a reduction in hospital admissions, reducing the financial burden of toxicity care, improved patient outcomes and enhancing patient experience.

Deltamethrin (DM) is a common type II synthetic pyrethroid pesticide; however, increasing evidence indicates that long-term exposure can cause systemic toxicity. This toxicity is linked to inflammation due to oxidative stress and cell death, possibly involving microRNA disruption of antioxidant defenses. This study aimed to explore how a combination of chitosan and ivy leaf extract (Hedera helix) protects against liver, kidney, and reproductive toxicity caused by DM exposure. It specifically examines the role of miR-144 in antioxidant pathways. Forty-eight adult male Wistar rats were divided into eight groups. They received oral treatments for 90 days, including DM (0.6 mg/kg), chitosan (200 mg/kg), ivy leaf extract (50 mg/kg), or combinations of these. Liver and kidney functions, markers of oxidative stress (MDA, GPx, SOD), inflammatory markers (TNF-α, COX-2, MAPK14), apoptotic markers (Bax, Caspase-3, Birc5), and the expression of miR-144 were assessed, along with comprehensive histopathological and immunohistochemical evaluations. Subchronic DM exposure led to significant weight loss and multi-organ dysfunction. This was associated with a marked increase in lipid peroxidation and a decline in antioxidant defenses. Molecular analysis revealed that DM significantly increased miR-144 expression in the liver, kidney, and testis, with a strong negative correlation with SOD activity (r - 0.916 in the kidney and -0.911 in the liver). This redox imbalance was associated with an inflammatory response via MAPK14 and shifted the balance toward apoptosis. Notably, the combination of chitosan and ivy leaf extract provided greater protection than either treatment alone, with lowered miR-144 levels, restored antioxidant enzyme activity, and reduced pro-inflammatory and apoptotic signals, and a clear restoration of tissue structure toward normal. The findings suggest a superior combined protective effect. Chitosan acts by scavenging free radicals, while ivy leaf extract likely involves modulation of the miR-144-associated antioxidant pathway. This highlights the potential of using natural antioxidant combinations to counteract the long-term effects of pesticide toxicity.

Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR + /HER2 -) breast cancer (BC) is the most frequently diagnosed subtype of BC, accounting for approximately 70% of cases. The introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has significantly improved clinical outcomes and transformed the therapeutic landscape of HR + /HER2 - in both the metastatic and early settings.Hepatotoxicity associated with CDK4/6i is increasingly recognized as a clinically relevant adverse event. Most cases are asymptomatic, occur early during treatment, and resolve with dose modification or management according to the Summary of Product Characteristics (SmPC). However, variability in monitoring and management persists in clinical practice. Key issues, such as corticosteroid use, treatment continuation and reintroduction of the CDK4/6i (either the same compound or another among the three globally approved agents) after liver toxicity recovery, remain insufficiently addressed by current evidence, despite the need for routine clinical decision-making.To address these gaps, a Spanish multidisciplinary panel of hepatologists and medical oncologists developed expert consensus recommendations on liver toxicity in patients with HR + /HER2 - BC receiving CDK4/6i. This consensus provides practical guidance on the classification, monitoring and management of liver-related adverse events during CDK4/6i therapy and promotes proactive collaboration between oncology and hepatology teams to support treatment continuity and optimize patient outcomes.

In response to the growing threat of multidrug-resistant microorganisms, there is an urgent necessity for developing eco-friendly synthesis methods for the generation of nanoparticles that can serve efficiently as alternatives to commercial antibacterial agents. In spite of the achievement in this area, their toxicity remains insufficiently explored, underscoring the necessity for detailed toxicological evaluation. Herein, Ag/AgCl nanoparticles were generated via a green biosynthetic approach, where metabolites excreted by the soil-isolated bacterium Kocuria kristinae served as both reducing and stabilizing agents during nanoparticle formation. The resulting nanoparticles were stable, spherical, and had an average size of 40 ± 10 nm, as confirmed by TEM analysis. Their stability was further indicated by a high negative zeta potential of -45.8 mV. Ag/AgCl-NPs showed excellent antibacterial effectiveness against pathogenic S. aureus, P. aeruginosa, A. baumannii, and E. coli ATCC 25922, with an MIC of 7 µg mL-1, 7 µg mL-1, 10 µg mL-1, and 8 µg mL-1, respectively. Furthermore, the hepatotoxic effects of the biofabricated Ag/AgCl-NPs were evaluated histopathologically and enzymatically in mature male albino rats following intraperitoneal injection of a low dose (10 mg kg-1) and a high dose (20 mg kg-1) of Ag/AgCl-NPs. The findings indicated minor to moderate liver toxicity, characterized by steatosis, tissue degradation including necrosis, and hyperplasia of Kupffer cells, according to the dose administered. Nonetheless, liver metabolism and function may be slightly affected, as levels of liver enzymes AST and ALT were considerably reduced (p < 0.05), whereas only ALP showed a significant increase (p < 0.05) in the low-dose nanoparticle-treated group. Thus, the biofabricated Ag/AgCl-NPs can serve as effective bactericidal agents with low to moderate hepatic effects and minimal alteration in liver functioning.

Aloe-emodin (AE), known as 1,8-dihydroxy-3-hydroxymethyl-anthraquinone, is a naturally occurring anthraquinone that has attracted attention for its diverse pharmacological applications. AE is mainly found in plant species, such as Aloe vera, Rheum palmatum, and Polygonum multiflorum. Accumulating preclinical studies suggest that AE exerts anticancer, antimicrobial, antiviral, antiparasitic, hepatoprotective, neuroprotective, cardioprotective, and anti-inflammatory properties. In particular, its anticancer effects, involving apoptosis induction, oxidative stress inhibition, mitochondrial dysfunction, and inhibition of proliferative and metastatic pathways across multiple cancer cell lines, are especially well-characterized. AE demonstrates promising preclinical results, with a range of effective in vitro doses of 0.05 to 100 µM and in vivo doses of 25-100 mg/kg in animals; however, higher micromolar concentrations have been reported to have cytotoxic and hepatotoxic effects, highlighting AE's translational potential while necessitating further safety evaluation. Simultaneously, proliferative signaling pathways, such as PI3K/Akt/mTOR and MAPK, are widely investigated; some potential signaling pathways, like PIP2 stimulation, which also activates the AKT/mTOR pathway, are still unexplored. AE combats various infectious diseases targeting gram-positive and gram-negative bacteria, influenza A, herpes simplex virus, Japanese encephalitis virus, enterovirus 71, and parasites such as Leishmania. Despite the promising pharmacological effects of AE, its clinical application is limited by poor pharmacokinetics, such as low bioavailability, rapid clearance, and inadequate intestinal absorption, along with safety risks like liver, kidney, and light-induced toxicity. Overcoming these challenges require improved delivery systems, structural modifications, and detailed toxicity profiling. Our review consolidates current pharmacological evidence, identifies research gaps, and suggests modifications and future directions for AE as a potential therapeutic agent.

Seneciphylline induces hepatotoxicity through mitochondrial apoptosis: mechanistic elucidation and in vitro-to-in vivo prediction via physiologically based pharmacokinetic modeling-facilitated reverse dosimetry.

Cuproptosis in atrazine-induced hepatotoxicity: ATOX1 as a therapeutic target for lycopene-mediated protection.

Prevalence and risk factors associated with rifampicin-induced cholestasis jaundice among tuberculosis patients in high-incidence setting: A retrospective cohort study.

The double-edged sword of Dioscorea bulbifera L.: Recent advances in its pharmacological benefits and hepatotoxicity, and the quest for detoxification strategies.

The highly hepatotoxic and carcinogenic Aspergillus-derived mycotoxin aflatoxin B1 (AFB1) stimulates hepatotoxicity and hepatocarcinogenesis by activating the nuclear factor-κB (NF-κB) signaling pathway. This review summarizes the existing information on the molecular pathways of AFB1-induced hepatocellular damage and carcinogenesis through NF-κB-mediated pathways, with an emphasis on the stepwise cascade from AFB1 bioactivation to chronic inflammation. When AFB1 is taken up by the hepatocellular membrane, it is metabolically bioactivated by cytochrome P450 (CYP450) enzymes to yield reactive intermediates (including AFB1-8,9-epoxide) capable of directly covalently altering cellular macromolecules and producing reactive oxygen species (ROS). The accumulation of AFB1-derived adducts and ROS leads to the activation of the inhibitor of κB (IκB) via IKK. This activation subsequently facilitates the phosphorylation and proteasomal degradation of IκB, allowing NF-κB to translocate into the nucleus. Long-term activation of NF-κB enhances the expression of pro-inflammatory cytokines (IL-1β, TNF-α), anti-apoptotic factors, and proliferative stimuli, creating a chronic inflammatory microenvironment that permits hepatocarcinogenesis initiation. In addition, redox-sensitive signaling cascades propagate NF-κB activation through AFB1-induced oxidative stress. This review identifies some of the main contemporary issues, such as the definition of the upstream molecular sensors that mediate IKK-IKB signaling under various conditions of exposure, mapping of downstream NF-κB effector programs, and the metabolic fate of AFB1 during prolonged pathway activation, which are still of primary concern in terms of translation. In addition, we thoroughly assessed emerging pharmacological interventions targeting the AFB1-NF-κB axis, including natural polyphenols (curcumin and resveratrol), probiotics (Lactobacillus species), antioxidants (alpha-lipoic acid), and novel candidates (phillygenin and copper-albumin complexes). These interventions exert protective effects by inhibiting NF-κB, reducing oxidative stress, and controlling apoptosis. This review offers a mechanistic basis for explaining liver toxicity caused by AFB1 and prioritizes actionable therapeutic targets and future research directions to develop novel prevention and treatment options against aflatoxin-induced hepatic pathologies.

Abstract Objectives The efficacy of cystic fibrosis transmembrane conductance regulator ( CFTR )‐modulator therapies in preventing or ameliorating cystic fibrosis liver disease (CFLD) by correcting CFTR in cholangiocytes is not well‐documented. This study aimed to assess liver function during CFTR‐modulators. Methods Patients eligible to start Elexacaftor/Tezacaftor/Ivacaftor (July 2021–December 2022), followed‐up at the Piedmont Cystic Fibrosis reference Centre of the Città della Salute e della Scienza, Turin , Italy , were enrolled through a prospective single‐center cohort study and evaluated using hematological exams and liver stiffness measurement (LSM) before treatment and at 1, 3, 6, and 12 months thereafter. The treated group was compared to a group of untreated people with cystic fibrosis (pwCF), evaluated at baseline and after 12 months. Results Sixty‐nine treated pwCF, mean age 16.0 years, 51% males, were compared to 130 non‐treated pwCF, mean age 12.14 years, 49% males. Treated pwCF were classified by LSM as normal (&lt;5 kPa) ( N = 44, 64%), mild liver fibrosis (5–7 kPa) ( N = 16, 23%), or moderate‐severe fibrosis (&gt;7 kPa) ( N = 9, 13%). A significant trend in LSM reduction was observed at Month 12 in the subgroups with LSM 5–7 kPa and LSM &gt; 7 kPa (−1.05, p = 0.016 and −1.57, p = 0.022, respectively). PwCF without fibrosis at baseline and non‐treated pwCF showed no LSM change over time. Liver enzyme levels increased at Month 12, trend mirrored in non‐treated pwCF for AST level, remaining within normal ranges. Conclusions During treatment, a significant LSM reduction was observed in pwCF with liver fibrosis at baseline, especially after Month 1. This rapid improvement could be multifactorial and may suggest a potential early response without significant liver toxicity.

Human Immunodeficiency Virus-1 (HIV-1) Reverse Transcriptase (RT) remained an epicentre of therapeutic target, yet the efficacy of current non-nucleoside reverse transcriptase inhibitors (NNRTIs) is compromised by drug-induced liver toxicity. In this study, an integrated in silico approach combining similarity-based virtual screening, molecular docking, molecular dynamics, MM-PBSA, followed by molecular descriptor analysis, was employed to identify NNRTI scaffolds with improved safety and efficacy. The similarity-based virtual screening of ZINC and ChEMBL databases, followed by ADMET filtering, highlighted candidates with reduced predicted hepatotoxicity relative to FDA-approved NNRTIs. Among them, ZINC000066352010 exhibited a highly stable binding orientation within the NNRTI binding pocket, stabilized by hydrogen bonding with Lys101 and conserved hydrophobic contacts with Tyr181, Val179, and Trp229. Molecular Dynamics simulations provided compelling validation of this binding mode, as evidenced by the lowest ligand RMSD of 0.05nm amongst the short-listed candidates, exhibited a persistent average number of hydrogen bonds of 1.95, and markedly reduced backbone fluctuations of RT relative to the apo-protein. These effects indicate enhanced conformational rigidity and long-term stability of the protein-ligand complex. The MM-PBSA provided quantitative thermodynamic support, with a binding energy of - 47.90 Kcal/mol, demonstrating stronger stabilization compared to the reference inhibitor (i.e., 9PJ). The enhanced affinity was driven predominantly by stable Van-der Waals interactions and minimized desolvation penalties. Frontier Molecular Orbital (FMO) and global reactivity descriptor analyses revealed an optimal HOMO-LUMO gap of 0.156eV and an electrophilicity index of 0.14eV, positioning it electronically within the window of FDA-approved NNRTIs, thereby indicating balanced reactivity and optimal electronic stability. Complementary electrostatic potential mapping highlighted well-defined reactive centres corroborative to the biomolecular target. Collectively, these findings positioned ZINC000066352010 as a promising NNRTI candidate with improved predicted safety and electronic stability parallel to an FDA-approved drug.

Environmental exposure to heavy metals poses significant threats to human health. In view of side effects and limitations of presentchelation therapy, further search for the potential agents counteracting metal toxicity is warranted. Salidroside, the main active ingredient of Rhodiola rosea, has shown potential as a natural agent for alleviating heavy metal toxicity.Our aim is to review the mechanisms by which salidroside mitigates toxicity induced by various heavy metals, providing a basis for developing protective strategies and offering a new perspective for future research. Research has shown that salidroside exerts protections against metal-induced toxicity through multiple mechanisms, including: (1) Regulating the HIF-1α/mTOR pathway to alleviate hypoxic injury; (2) Activating Nrf2/ARE antioxidant pathway; (3) Inhibiting mitochondrial pathway of apoptosis (Bcl-2/Bax/caspase-3); (4) Enhancing gap junctional intercellular communication (GJIC);(5) Down-regulating pro-inflammatory signaling through targeting MAPK and NF-κB pathways.Modulation of these signaling pathways, as well as certain other mechanisms, are involved in the protective effects of salidroside against metal toxicity in liver, brain, heart, kidneys and other organs, as evidenced from in vivo and in vitro studies. Compared with traditional chelating agents, salidroside has low toxicity and promising efficacy in alleviating cobalt, cadmium, lead, manganese, methylmercury, cisplatin, arsenic and iron toxicity. Therefore, salidroside holds promise as a new natural product for mitigating metal-induced toxicity and further studies are needed to clarify its clinical applicability.

Protective effect of green tea extract on chlorpyrifos induced toxicity in liver of male mice.

Transient prophylactic immunosuppression with abatacept or dasatinib prevents immune responses in AAV gene transfer

To investigate metabolic reprogramming-especially pyruvate metabolism-in hepatocellular carcinoma (HCC) before and after immune checkpoint inhibitor (ICI) therapy, construct a metabolism-related prognostic model, and evaluate the therapeutic potential of targeting LDHA. Integrated single-cell RNA-seq data (GEO, Mendeley) were analyzed using Seurat, AUCell, pySCENIC, CellChat, and Monocle. A prognostic model was developed from TCGA data by Cox and Lasso regression. Functional validation included in vitro CCK8 and Transwell assays in Huh7 cells and in vivo xenograft experiments combining the LDHA inhibitor (R)-GNE-140 with a PD-1 antibody. Post-ICI, HCC cells upregulated pyruvate metabolism genes (LDHA, LDHB, LDHD) but showed decreased glycolysis, lactate buildup, reduced acetylation, and suppressed TCA cycle with AMPK activation. Key transcription factors (MYC, SP5, HLF, SREBF1) were identified. CellChat revealed enhanced SPP1-CD44 and APOA1-ABCA1 signaling. Pseudotime analysis indicated terminal hepatocyte differentiation. The pyruvate metabolism-based signature predicted prognosis effectively. Combination therapy with (R)-GNE-140 and PD-1 blockade inhibited Huh7 proliferation, migration, and xenograft tumor growth without liver or renal toxicity. ICI therapy induces metabolic remodeling in HCC, marked by pyruvate metabolism dysregulation and lactate accumulation, contributing to resistance. Dual targeting of LDHA and PD-1 enhances antitumor efficacy, and the identified metabolic signature may serve as a prognostic biomarker and therapeutic target.