Scutellarin

Acetaminophen (APAP), one of the most commonly employed antipyretic analgesics worldwide, has paradoxically become a predominant cause of drug-induced liver injury (DILI) following overdose. The nuclear factor-erythroid 2-related factor 2 (Nrf2), a pivotal transcriptional regulator, is widely recognized as a promising therapeutic target for phytochemical-mediated amelioration of DILI. Scutellarin (Scu), a bioactive flavonoid isolated and purified from Erigeron breviscapus (Vant.) Hand.-Mazz. (Asteraceae), demonstrates pleiotropic pharmacological activities. Nevertheless, it remains to be elucidated whether Scu can activate the Nrf2 signaling pathway to exert hepatoprotective effects against APAP-induced hepatic injury.

The aim of this study was to find out how Scu protects against APAP-induced hepatotoxicity at the molecular level.

In vivo experiments were conducted using male wild-type (WT) and Nrf2-knockout (Nrf2^-/-) C57BL/6 mice. All animals were intragastrically administered APAP (400 mg/kg body weight) with or without co-administration of Scu at graded doses (90 mg/kg, 60 mg/kg or 30 mg/kg). For in vitro validation, AML12 hepatocytes were employed to investigate the protective effects of Scu against APAP-induced hepatotoxicity and its molecular mechanisms. Additionally, molecular docking was performed to characterize the potential interactions between Scu and Nrf2-related proteins.

The results demonstrated that APAP induced significant mortality and hepatotoxicity in mice, whereas Scu treatment effectively reduced mortality rates and attenuated hepatic damage. Scu administration notably ameliorated hepatic injury through simultaneous suppression of pro-inflammatory mediators, oxidative stress, apoptosis, pyroptosis, and ferroptosis, which was associated with the modulation of the TLR4-NF-κB/MAPK and NLRP3/caspase-1/GSDMD signaling cascades. Molecular docking analysis revealed that Scu exhibited high-affinity binding to specific domains of Nrf2, thereby potentiating its activation and nuclear translocation. Furthermore, Scu treatment significantly enhanced both the Nrf2-mediated antioxidant signaling pathway and the xCT/GPX4 axis. However, these cytoprotective effects were completely abolished in Nrf2^-/- mice.

This study revealed the protective effect of Scu on APAP-induced liver injury; these effects are closely linked to Nrf2 activation, suggesting that DILI may have new drugs or therapeutic strategies.

In acute liver failure due to Wilson disease (ALF-WD), early and correct diagnosis is critical. Readily available biochemical parameters, e.g., ALT:AST ratio provide acceptable diagnostic accuracy. Recently, accurate nonceruloplasmin bound copper (ANCC), reflecting bioavailable serum copper and relative-ANCC (RelANCC) were developed. We investigated the diagnostic use of ANCC and RelANCC, and the validity of current diagnostic markers in ALF-WD.

Serum samples and data were collected through the US ALF Study Group registry. Etiologies included ALF-WD (n = 23), acetaminophen (n = 11), autoimmune (n = 10), drug induced liver injury (n = 13), HBV/HDV (n = 10), and other (n = 3). Standard clinical and biochemical parameters, serum copper (s-Cu), ANCC, and RelANCC were measured. Receiver operating characteristic analysis was performed.

Both ANCC (cut-off ≥483 μg/L) and s-Cu (≥1369 μg/L) provided excellent diagnostic information for ALF-WD (area under the receiver operating curve [AUROC] 0.94 and 0.89). Low ALP (≤45 U/L), and ALT (≤52 U/L) individually provided diagnostic information for ALF-WD (AUROC's > 0.89). Combining ALT with either s-Cu or ANCC further improved diagnostic accuracy, with the ANCC-ALT score being more accurate, AUROC 0.99, sensitivity 91% and specificity 100%. Adding ALP:total bilirubin ratio, AST:ALT ratio or serum zinc to ANCC did not improve accuracy. Median RelANCC was significantly higher in patients with WD (64%) than in non-WD ALF patients (22%) ( P = 0.0001).

Standard biochemistry provides excellent diagnostic information for identifying WD in the setting of ALF. Combining ALT with specific copper measurements significantly improved diagnostic use, with ANCC outperforming s-Cu. RelANCC may also be useful for WD diagnosis. We suggest adding s-Cu to the clinical algorithm in ALF.