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Low-dose methotrexate (MTX) is a standard therapy for rheumatoid arthritis due to its low cost and efficacy. Despite these benefits, MTX has been reported to cause chronic drug-induced liver injury, namely liver fibrosis. The hallmark of liver fibrosis is excessive scarring of liver tissue, triggered by hepatocellular injury and subsequent activation of hepatic stellate cells (HSCs). However, little is known about the precise mechanisms through which MTX causes hepatocellular damage and activates HSCs. Here, we investigated the mechanisms leading to hepatocyte injury in HepaRG and used immortalized stellate cells (hTERT-HSC) to elucidate the mechanisms leading to HSC activation by exposing mono- and co-cultures of HepaRG and hTERT-HSC to MTX. The results showed that at least two mechanisms are involved in MTX-induced toxicity in HepaRG: (i) oxidative stress through depletion of glutathione (GSH) and (ii) impairment of cellular respiration in a GSH-independent manner. Furthermore, we measured increased levels of endoplasmic reticulum (ER) stress in activated HSC following MTX treatment. In conclusion, we established a human-relevant in vitro model to gain mechanistical insights into MTX-induced hepatotoxicity, linked oxidative stress in HepaRG to a GSH-dependent and -independent pathway, and hypothesize that not only oxidative stress in hepatocytes but also ER stress in HSCs contribute to MTX-induced activation of HSCs.

Background: Drug-induced liver injury (DILI), represented by acetaminophen (APAP), is a common cause of acute liver failure in clinics. Paeoniflorin (PF) has been proven to demonstrate a significant hepatoprotective effect. However, it is still unclear whether it can be a potential agent against hepatotoxicity induced by APAP. This study aimed to explore the preventive and therapeutic effects and mechanisms of PF on APAP-induced liver injury. Methods: Different doses of PF (50, 100, and 200 mg/kg) were given to C57BL/6 male mice for five consecutive days. After 12 h of APAP (250 mg/kg i.p.) treatment, blood and liver tissues were collected and isolated for detection. Results: The results showed that the therapeutic effects of PF on APAP mice were presented in the downregulation of the content of serum indices and significantly improved hepatic tissue edema and inflammatory infiltration. Meanwhile, PF reduces the level of the mitochondrial metabolic enzyme. Ulteriorly, it was found that PF has a downregulating effect on the apoptotic reaction and could inhibit the protein expression of CYP2E1/JNK signaling, which in turn reduces the damage of APAP. Conclusion: Our findings showed that PF acted as a protective agent against APAP-induced hepatotoxicity by inhibiting JNK-related signals, suggesting a novel insight into treating APAP-induced liver injury.

Liver fibrosis, depending on the stage of the disease, could lead to organ dysfunction and cirrhosis, and no effective treatment is actually available. Emergent proof supports a link between oxidative stress, liver fibrogenesis and mitochondrial dysfunction as molecular bases of the pathology. A valid approach to protect against the disease would be to replenish the endogenous antioxidants; thus, we investigated the protective mechanisms of the S-acetyl-glutathione (SAG), a glutathione (GSH) prodrug. Preliminary in vitro analyses were conducted on primary hepatic cells. SAG pre-treatment significantly protected against cytotoxicity induced by CCl4. Additionally, CCl4 induced a marked increase in AST and ALT levels, whereas SAG significantly reduced these levels, reaching values found in the control group. For the in vivo analyses, mice were administered twice a week with eight consecutive intraperitoneal injections of 1 mL/kg CCl4 (diluted at 1:10 in olive oil) to induce oxidative imbalance and liver inflammation. SAG (30 mg/kg) was administered orally for 8 weeks. SAG significantly restored SOD activity, GSH levels and GPx activity, while it strongly reduced GSSG levels, lipid peroxidation and H2O2 and ROS levels in the liver. Additionally, CCl4 induced a decrease in anti-oxidants, including Nrf2, HO-1 and NQO-1, which were restored by treatment with SAG. The increased oxidative stress characteristic on liver disfunction causes the impairment of mitophagy and accumulation of dysfunctional and damaged mitochondria. Our results showed the protective effect of SAG administration in restoring mitophagy, as shown by the increased PINK1 and Parkin expressions in livers exposed to CCl4 intoxication. Thus, the SAG administration showed anti-inflammatory effects decreasing pro-inflammatory cytokines TNF-α, IL-6, MCP-1 and IL-1β in both serum and liver, and suppressing the TLR4/NFkB pathway. SAG attenuated reduced fibrosis, collagen deposition, hepatocellular damage and organ dysfunction. In conclusion, our results suggest that SAG administration protects the liver from CCl4 intoxication by restoring the oxidative balance, ameliorating the impairment of mitophagy and leading to reduced inflammation.

The role of extracellular vesicles secreted by the gut microbiota present in faeces (fEVs) is not well known in metabolic dysfunction‐associated steatotic liver disease (MASLD) and idiosyncratic drug‐induced liver injury (DILI). We identify the microbiome profiles of fEVs in these liver diseases, and analyse the effects of fEVs from MASLD, without (F≤2) or with (F≥3) significant liver fibrosis, and DILI patients on inflammation, steatosis and mitochondrial function. DILI patients showed a consistent pattern in fEVs, characterised by a decrease in Paraprevotella and an increase in AAP99, Acinetobacter, Actinobacillus, Aerococcus and Anaeroglobus. A higher presence of 16S rDNA was observed in plasma EVs from MASLD and DILI patients. HepG2 cells treated with DILI and MASLD F≥3 fEVs increased TLR4, TLR5, IL6 and CASP3 expression, and accumulation of lipid droplets. DILI fEVs enhanced the hepatotoxic impact of diclofenac on the response to microbial components (TLR4, TLR5), inflammatory response (IL1B, IL6), accumulation of lipid droplets and mitochondrial dysfunction (OPA1, DNM1L). In conclusion, bacterial EVs enter the bloodstream and could modulate the immune response. DILI and MASLD F≥3 fEVs are drivers of the pro‐inflammatory response and hepatocyte steatosis. DILI fEVs have a distinct bacterial profile that enhances the hepatotoxic potential of diclofenac. Fecal extracellular vesicles (fEVs) from DILI patients have a distinct bacterial profile. This study provides evidence that bacterial EVs enter the bloodstream. DILI and MASLD F≥3 fEVs increase the pro‐inflammatory response and hepatocyte steatosis. FEVs from DILI patients enhance the hepatotoxic potential of diclofenac.

Methotrexate (MTX)-induced hepatotoxicity is a significant clinical problem that may affect overall prognosis and disease outcome. Oxidative stress is a key player in its pathogenesis. The aim of this study was to investigate the role of ω-3 fatty acids as an adjuvant therapy in children and adolescents with acute lymphoblastic leukemia (ALL) during the maintenance phase of chemotherapy and the effect of ω-3 on MTX-induced hepatotoxicity. This randomized, double-blind, placebo-controlled trial included 70 patients with ALL who were in the maintenance phase. The participants were divided into two groups: group A received oral MTX and ω-3 fatty acids (1000 mg/d) and group B (received MTX and placebo). Both groups were followed-up for 6 mo with assessment of liver enzymes, total antioxidant capacity (TAC), uric acid, malondialdhyde, superoxide dismutase (SOD), and glutathione peroxidase. The trial was registered at ClinicalTrials.gov (NCT02373579). Baseline clinical and laboratory parameters were consistent between the two groups (P > 0.05). After 6 mo, liver enzymes and malondialdhyde increased, whereas TAC, uric acid, SOD, and glutathione peroxidase decreased in group B (MTX and placebo) compared with baseline levels or with group A ALL patients receiving ω-3 fatty acids (P < 0.001). The addition of ω-3 to MTX maintained normal liver function and oxidant–antioxidant levels among group A patients at the end of treatment compared with pretherapy levels (P > 0.05). No adverse reactions due to ω-3 supplementation were reported. ALT was inversely correlated to TAC and SOD in the MTX group. The study determined that ω-3 fatty acids ameliorated MTX-induced hepatotoxicity and could be safely used during the maintenance phase of ALL. •We determined the role of ω-3 fatty acids in patients with acute lymphoblastic leukemia (ALL) receiving methotrexate (MTX).•A randomized study divided patients with ALL into two groups and followed them for 6 mo.•MTX use alone led to significant increases in liver enzymes and oxidative stress.•MTX and ω-3 maintained oxidant–antioxidant levels.•The study found that ω-3 has protective effects against MTX-oxidative liver injury in patients with ALL.

Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced liver injury, utilizing a mouse model. Mice were intraperitoneally administered a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes after APAP administration, mice were treated with different concentrations of stachydrine (0, 2.5, 5, and 10 mg/kg). Animals were sacrificed 16 h after APAP injection for serum and liver tissue assays. APAP overdose significantly elevated the serum alanine transferase levels, hepatic pro-inflammatory cytokines, malondialdehyde activity, phospho-extracellular signal-regulated kinase (ERK), phospho-protein kinase B (AKT), and macrophage-stimulating protein expression. Stachydrine treatment significantly decreased these parameters in mice with APAP-induced liver damage. Our results suggest that stachydrine may be a promising beneficial target in the prevention of APAP-induced liver damage through attenuation of the inflammatory response, inhibition of the ERK and AKT pathways, and expression of macrophage-stimulating proteins.

Liver disease accounts for millions of deaths per year all over the world due to complications from cirrhosis and liver injury. In this study, a novel compound, dimethyl bisphenolate (DMB), was synthesized to investigate its role in ameliorating carbon tetrachloride (CCl4)-induced liver injury through the regulation of oxidative stress-related genes. The structure of DMB was confirmed based on its hydrogen spectrum and mass spectrometry. DMB significantly reduced the high levels of ALT, AST, DBIL, TBIL, ALP, and LDH in a dose-dependent manner in the sera of CCl4-treated rats. The protective effects of DMB on biochemical indicators were similar to those of silymarin. The ROS fluorescence intensity increased in CCl4-treated cells but significantly weakened in DMB-treated cells compared with the controls. DMB significantly increased the content of oxidative stress-related GSH, Nrf2, and GCLC dose-dependently but reduced MDA levels in CCl4-treated cells or the liver tissues of CCl4-treated rats. Moreover, DMB treatment decreased the expression levels of P53 and Bax but increased those of Bcl2. In summary, DMB demonstrated protective effects on CCl4-induced liver injury by regulating oxidative stress-related genes.

Improper use of acetaminophen (APAP) will induce acute liver failure. This study is designed to investigate whether early growth response-1 (EGR1) participated in the promotion on liver repair and regeneration after APAP-induced hepatotoxicity provided by natural compound chlorogenic acid (CGA). APAP induced the nuclear accumulation of EGR1 in hepatocytes regulated by extracellular-regulated protein kinase (ERK)1/2. In Egr1 knockout (KO) mice, the liver damage caused by APAP (300 mg/kg) was more severe than in wild-type (WT) mice. Results of chromatin immunoprecipitation and sequencing (ChIP-Seq) manifested that EGR1 could bind to the promoter region in Becn1 , Ccnd1 , and Sqstm1 ( p62 ) or the catalytic/modify subunit of glutamate-cysteine ligase ( Gclc / Gclm ). Autophagy formation and APAP-cysteine adduct (APAP-CYS) clearance were decreased in Egr1 KO mice administered with APAP. The EGR1 deletion reduced hepatic cyclin D1 expression at 6, 12, or 18 h post APAP administration. Meanwhile, the EGR1 deletion also decreased hepatic p62, Gclc and Gclm expression, GCL enzymatic activity, and glutathione (GSH) content and decreased nuclear factor erythroid 2-related factor 2 (Nrf2) activation and thus aggravated oxidative liver injury induced by APAP. CGA increased EGR1 nuclear accumulation; enhanced hepatic Ccnd1 , p62 , Gclc , and Gclm expression; and accelerated the liver regeneration and repair in APAP-intoxicated mice. In conclusion, EGR1 deficiency aggravated liver injury and obviously delayed liver regeneration post APAP-induced hepatotoxicity through inhibiting autophagy, enhancing liver oxidative injury, and retarding cell cycle progression, but CGA promoted the liver regeneration and repair in APAP-intoxicated mice via inducing EGR1 transcriptional activation. Graphical Abstract

This research aimed to evaluate the preventing effects of naringin, naringenin, and their combination on liver injury induced by Taxol (paclitaxel) in Wistar rats. Male Wistar rats received 2 mg/kg Taxol intraperitoneal injections twice weekly on the second and fifth days of each week for 6 weeks. During the same period as Taxol administration, rats were given naringin, naringenin, or a combination of the two (10 mg/kg b.wt) every other day. Treatment with naringin and/or naringenin reduced the abnormally high serum levels of total bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma-glutamyl transferase in Taxol-treated rats. It also significantly increased the level of serum albumin, indicating an improvement in the liver. The perturbed histological liver changes were markedly improved due to the naringin and/or naringenin treatment in Taxol-administered rats. Additionally, the treatments reduced high hepatic lipid peroxidation and increased liver glutathione content as well as the activities of superoxide dismutase and glutathione peroxidase. Furthermore, the treatments reduced the levels of alpha-fetoprotein and caspase-3, a pro-apoptotic mediator. The naringin and naringenin mixture appeared more effective in improving organ function and structural integrity. In conclusion, naringin and naringenin are suggested to employ their hepatoprotective benefits via boosting the body’s antioxidant defense system, reducing inflammation, and suppressing apoptosis. Graphical Abstract

Exosomes are small biological membrane vesicles secreted by various cells, including mesenchymal stem cells (MSCs). We previously reported that MSC-derived exosomes (MSC-Ex) can elicit hepatoprotective effects against toxicant-induced injury. However, the success of MSC-Ex-based therapy for treatment of liver diseases and the underlying mechanisms have not been well characterized. We used human umbilical cord MSC-derived exosome (hucMSC-Ex) administrated by tail vein or oral gavage at different doses and, in engrafted liver mouse models, noted antioxidant and anti-apoptotic effects and rescue from liver failure. A single systemic administration of hucMSC-Ex (16 mg/kg) effectively rescued the recipient mice from carbon tetrachloride (CCl4)-induced liver failure. Moreover, hucMSC-Ex-derived glutathione peroxidase1 (GPX1), which detoxifies CCl4 and H2O2, reduced oxidative stress and apoptosis. Knockdown of GPX1 in hucMSCs abrogated antioxidant and anti-apoptotic abilities of hucMSC-Ex and diminished the hepatoprotective effects of hucMSC-Ex in vitro and in vivo. Thus, hucMSC-Ex promote the recovery of hepatic oxidant injury through the delivery of GPX1. Yan et al. investigate the potential beneficial effect of human umbilical cord MSC-derived exosomes (hucMSC-Ex) on hepatic oxidant injury. hucMSC-Ex can elicit antioxidant and anti-apoptotic effects on CCl4- and H2O2-induced hepatic injury and GPX1 delivered by hucMSCs work as the main mechanism of protection.