Acetaminophen (APAP) overdose is the leading cause of acute liver failure worldwide, yet existing therapy relies solely on N-acetylcysteine (NAC), whose efficacy diminishes markedly beyond an 8-10 h therapeutic window. The underlying pathology involves a self-amplifying cycle of reactive oxygen species (ROS) overproduction and macrophage-mediated inflammation, and strategies that concurrently scavenge ROS, reprogram macrophage polarization, and attenuate hepatocyte apoptosis remain lacking. Itaconate (ITA), an endogenous anti-inflammatory metabolite, suffers from poor membrane permeability and lacks intrinsic ROS-scavenging capacity. Herein, we constructed BiOCl@ITA by integrating defect-engineered bismuth oxychloride (BiOCl) with surface-loaded ITA. Oxygen vacancy engineering confers intrinsic superoxide dismutase (SOD)- and catalase (CAT)-mimicking activities under stimulus-free conditions. BiOCl@ITA showed rapid accumulation in the liver within 0.5 h after intraperitoneal administration and was efficiently internalized by both hepatocytes and macrophages in vitro. Moreover, BiOCl@ITA virtually eliminated intracellular ROS and attenuated APAP-induced hepatocyte injury, while also reprogramming LPS-stimulated macrophages from M1 toward an M2 phenotype, consistently outperforming free ITA across all endpoints. In a murine APAP-induced ALI model, BiOCl@ITA-treated mice showed near-complete thermal recovery by 24 h, accompanied by substantially reduced serum hepatic injury markers and attenuated histopathological damage. Hepatic molecular and tissue-level analyses further demonstrated restoration of antioxidant defenses, favorable regulation of BAX/BCL-2 expression, and sustained M1-to-M2 macrophage polarization in vivo. These findings demonstrate that BiOCl@ITA synergistically integrates catalytic ROS detoxification with ITA-mediated macrophage reprogramming, offering a promising therapeutic approach for APAP-induced acute liver injury.

Zilebesiran is an investigational RNA interference therapeutic that lowers blood pressure by silencing hepatic angiotensinogen, thereby offering sustained antihypertensive activity with infrequent dosing in selected ambulatory populations. This profile is attractive for long-term blood pressure control, but it also raises an unresolved clinical question: how should acute illness be managed when upstream renin-angiotensin system suppression cannot be rapidly attenuated? In this Current Opinion, we place that question in perspective using available trial data, cardiorenal physiology, and acute-care literature. Early-phase studies established that zilebesiran produces sustained angiotensinogen suppression and blood pressure reduction, while also showing that the antihypertensive response is modulated by dietary sodium intake and background renin-angiotensin-aldosterone system blockade. Phase 2 studies then confirmed antihypertensive efficacy in clinically stable outpatient populations, and KARDIA-3 extended evaluation to patients with uncontrolled hypertension and established or high cardiovascular risk receiving multiple antihypertensive agents; however, the study did not meet its prespecified multiplicity-adjusted threshold for statistical significance at month 3. The concern is not that harm has been demonstrated, but that prolonged angiotensinogen silencing may reduce short-term therapeutic flexibility during sepsis, perioperative stress, acute heart failure, marked volume depletion, or hyperkalemia-settings in which clinicians often rely on temporary adjustment of oral renin-angiotensin-aldosterone system inhibitors. Early reversal strategies are conceptually important, but current approaches appear better suited to planned de-escalation than emergency rescue. Future work should define vulnerable phenotypes, clarify whether acute-care pathways require protocol adaptation, and determine how reversibility can be operationalized as phase 3 development advances.

Leptospirosis is a globally prevalent zoonotic infection with protean manifestations, while severe disease (Weil's syndrome) is uncommon and rarely reported in the postpartum period, where it can closely mimic obstetric emergencies. We report a rare case of severe postpartum leptospirosis complicated by sudden-onset seizures and multiorgan failure. A 32-year-old woman developed generalized tonic-clonic seizures two hours after vaginal delivery, followed by septic shock, hyperpyrexia, refractory seizures, acute liver failure, acute kidney injury, coagulopathy, and stress-induced cardiomyopathy. Initial differentials included obstetric catastrophes such as eclampsia, acute fatty liver of pregnancy, and amniotic fluid embolism. Diagnosis was supported by a positive Leptospira IgM ELISA in the appropriate clinical context; however, confirmatory testing with the microscopic agglutination test (MAT) or polymerase chain reaction (PCR) could not be performed, which remains a limitation of this report. Magnetic resonance imaging (MRI) of the brain revealed features of cerebral hyperperfusion, a finding not previously reported in postpartum Weil's disease. Prompt institution of targeted antimicrobial therapy, aggressive critical care support, and multimodal monitoring resulted in gradual recovery. Cerebral oxygenation and response to therapy were continuously monitored using bilateral near-infrared spectroscopy (NIRS), representing a novel neuromonitoring strategy in this setting. This case highlights leptospirosis as an important differential in postpartum seizures with multiorgan failure in endemic regions. It expands the spectrum of postpartum Weil's disease by demonstrating cerebral hyperperfusion on MRI, novel use of NIRS monitoring, and associated stress-induced cardiomyopathy, with important implications for critical care management.

Drug- and metal-induced liver damage (DILI/MILI) continues to be a predominant cause of acute hepatic failure globally, with two clinically significant but mechanistically underexplored triggers being the metalloid antimony (Sb) and non-steroidal anti-inflammatory medications (NSAIDs). This review consolidates current molecular findings about the convergence of Sb(III)/Sb(V) species and NSAID reactive metabolites on a common hepatotoxic framework. Hepatic organic anion-transporting polypeptides and multidrug-resistance proteins regulate the sinusoidal uptake and canalicular efflux of both substances, while cytochrome P450 2C9/3A4/2E1-mediated bioactivation of NSAIDs and thiol-reactive Sb species produces reactive oxygen species (ROS), diminishes reduced glutathione (GSH) levels, disrupts mitochondrial membrane potential and initiates PERK-eIF2α-ATF4-CHOP-mediated endoplasmic reticulum stress. These insults target nuclear factor-kappa B, mitogen-activated protein kinase and NLRP3 inflammasome signalling, resulting in apoptotic, necroptotic, pyroptotic and ferroptotic hepatocyte death. We conduct a comprehensive assessment of the multi-target hepatoprotective effects of polyphenols (curcumin, resveratrol, quercetin), flavonoids, terpenoids, alkaloids and extracts from medicinal plants, focusing on the activation of the Nrf2/Keap1/ARE antioxidant pathway, inhibition of NF-κB and NLRP3, AMPK-SIRT1-PGC-1α-mediated mitochondrial biogenesis, PI3K/Akt cytoprotective signalling and PINK1/Parkin-dependent mitophagy. We ultimately examine translational prospects, including omics-derived hepatotoxicity biomarkers, network pharmacology, artificial intelligence-facilitated natural product discovery, nanocarrier-mediated hepatoprotective administration and precision medicine strategies for the prevention of drug-induced liver injury (DILI). The intersection of antimony- and NSAID-induced damage at a limited number of druggable targets supports the use of multi-target natural therapies as logical complements to traditional hepatoprotection. However, the strength of evidence supporting this convergence is heterogeneous: Several downstream mechanisms-particularly NLRP3 inflammasome activation, ferroptosis, pyroptosis and necroptosis in antimony-induced hepatotoxicity-are supported mainly by in vitro and animal data rather than confirmed human evidence, and are treated in this review as emerging or hypothetical rather than established. As this is a narrative rather than a systematic review, the literature search strategy, evidence-grading approach and limitations are described explicitly to aid transparent interpretation.

We report a 31-year-old woman with cirrhosis who developed bilateral pleural and pericardial effusions caused by Curvularia hawaiiensis. The patient developed worsening shock and multiorgan failure during hospitalization despite broad-spectrum antibacterial and antifungal therapy. Her course was complicated further by development of bilateral pleural effusions and pericardial effusion. Pericardiocentesis and thoracentesis were performed, with cultures initially demonstrating scant mold growth. Liposomal amphotericin B was subsequently initiated; however, the patient ultimately died following transition to comfort-focused care. Postmortem identification of both pleural and pericardial isolates revealed Curvularia hawaiiensis, a rare dematiaceous mold infrequently associated with invasive disease. This case highlights the profound immune dysfunction associated with acute-on-chronic liver failure and demonstrates the potential for rare molds to cause rapidly progressive invasive infection in cirrhotic patients. Additionally, it underscores the diagnostic and therapeutic challenges posed by delayed organism identification and limited susceptibility data for uncommon fungal pathogens. This is the first reported pericardial infection due to this human pathogen.

Bariatric surgery is an effective treatment for obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Although most patients experience improvement in hepatic steatosis and fibrosis after surgery, severe hepatic decompensation has rarely been reported following malabsorptive procedures. Early recognition of potentially reversible causes of liver failure is essential to prevent progression to irreversible hepatic injury or liver transplantation. We report the case of a 54-year-old woman with obesity-related MASLD who underwent revisional single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) following weight regain after Roux-en-Y gastric bypass. Ten months after surgery, she developed progressive hypoalbuminemia, recurrent hyperammonemia, coagulopathy and worsening porto-systemic encephalopathy culminating in grade IV encephalopathy requiring intensive care admission and invasive mechanical ventilation. Extensive investigation excluded alternative causes of acute hepatic deterioration. Despite six weeks of intensive conservative management, including optimized nutritional rehabilitation with high-protein enteral supplementation, vitamin and micronutrient replacement, correction of electrolyte disturbances, and standard medical therapy for hepatic encephalopathy (lactulose and rifaximin), hepatic synthetic function continued to deteriorate. Following multidisciplinary discussion, surgical reversal of the malabsorptive anatomy was undertaken. Liver biopsy demonstrated advanced chronic liver disease with cholestatic changes, macrovesicular steatosis and severe secondary hepatic siderosis. Neurological improvement was observed within the first postoperative days, with complete resolution of hepatic encephalopathy and normalization of serum ammonia levels by postoperative day five, followed by progressive recovery of hepatic synthetic function. This case highlights persistent malabsorption as a reversible driver of subacute liver failure in patients with limited hepatic reserve following revisional bariatric surgery. Recognition of this rare complication is essential because timely surgical reversal may interrupt ongoing metabolic injury, restore hepatic function and prevent progression to irreversible liver failure or liver transplantation.

Emphysematous hepatitis (EH) is a rare and often fatal liver infection characterized by gas within the hepatic parenchyma without abscess formation. Diabetes mellitus and gastrointestinal malignancies are the main predisposing factors. Prompt diagnosis and aggressive treatment are essential due to its fulminant course. A 67-year-old male with uncontrolled type 2 diabetes and a long smoking history presented with abdominal pain, nausea, vomiting, dyspnea, and altered consciousness. Laboratory tests revealed elevated liver enzymes, hyperbilirubinemia, severe hyperglycemia, and increased inflammatory markers. Abdominal CT showed a gas-containing lesion in the left hepatic lobe without fluid collection. Due to rapid clinical deterioration, emergency surgical resection was performed. Despite postoperative intensive care and meropenem therapy, the patient died six hours after surgery. Cultures grew E. coli and Enterobacter hormaechei. Only 19 EH cases have been reported to date. Most patients are elderly and have diabetes. Diagnosis relies on CT imaging, which reveals intrahepatic gas without abscess. Pathogenesis may involve anaerobic bacterial fermentation and microcirculatory impairment in diabetic patients. Despite antibiotics and drainage, mortality remains high. EH should be considered in diabetic patients with sepsis and intrahepatic gas on CT. Early diagnosis and immediate intervention-including antimicrobial therapy and drainage-are critical to improving survival.

Erythropoietic protoporphyria (EPP) is a disease caused by an inborn error of heme biosynthesis. It manifests as painful photosensitivity in childhood. Liver disease occurs due to the deposition of protoporphyrin. Cholestasis due to protoporphyrin leads to a vicious cycle of worsening, which can lead to liver failure. A 29-year-old woman presented with a three-month history of intermittent low-grade fever and a one-month history of jaundice. She had a history of painful blisters over the skin in childhood that started at two years of age and progressed to multiple contractures from healed ulcers by five years of age. She also had splenomegaly on examination. Her blood tests showed pancytopenia, hyperbilirubinemia, and elevated liver enzymes. Tropical fever workup was negative. Autoimmune hepatitis was considered, as antinuclear antibodies (ANA) were positive with elevated immunoglobulin G (IgG). Skin biopsy showed features suggestive of lipoid proteinosis. However, on review with Periodic Acid-Schiff-diastase (PAS-D) staining, a close mimic, EPP was considered a possibility. Liver biopsy showed features of EPP with infiltration with refractile brown pigment showing bright-red birefringence on polarizing microscopy. Next-generation sequencing (NGS) confirmed EPP with a ferrochelatase enzyme coding gene mutation. The patient developed pneumonia during hospitalization and developed acute on chronic liver failure (ACLF) grade 3a, as defined by the European Association for the Study of the Liver (EASL), with ascites and encephalopathy. She was treated with photoprotective measures, ursodeoxycholic acid, antibiotics, and supportive care. The family was counseled regarding options for sequential hepatic and bone marrow transplants. She was managed with the best supportive care.