Exosomes have emerged as key mediators of inter-cellular communication, transporting a diverse array of cargos that can reflect the current biological state of the cell. Recent advancements in exosome biology have unveiled their crucial role in cell signaling and paracrine-mediated functions. In this article, we will highlight the concept of exofection. In this well-defined donor-recipient relationship, donor cells produce specific biomolecules encapsulated within exosomes, which are then delivered to recipient cells. This process is particularly crucial when recipient cells experience functional deficiencies due to physiological or pathological conditions. Upon receiving the exosomal cargo, recipient cells transiently express and exhibit the functional activity of the delivered molecules. The functional enhancement mediated by exofection is transient, gradually diminishing once the delivery from the donor cells declines, and the recipient cell no longer needs specific function. Utilizing studies from various fields, we highlight the diverse biological contexts in which exofection operates. For instance, mitochondria-containing EVs from brain endothelial cells restore mitochondrial function and tight junction integrity in ischemic brain tissues. In contrast, exosomes from TNF-α-preconditioned mesenchymal stromal cells regulate autophagy and inflammation in acute pancreatitis. Similarly, Th2 cell-derived EVs promote eosinophil survival during airway inflammation, and umbilical cord blood exosomes accelerate wound healing by enhancing angiogenesis and fibroblast function. The role of exosomes in complex pathophysiological contexts such as myocardial infarction, glioblastoma, and liver failure can be crucial. In each scenario, the donor cells' exosomal cargo modulates recipient cell functions, promoting tissue repair, immune regulation, or metastasis. This work expands the conceptual framework of exofection and emphasizes its potential impact on therapeutic development and understanding the pathophysiology of various diseases.

Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) represents a significant worldwide public health challenge. Toll-like receptors (TLRs) serve as essential components of the innate immune system; however, their involvement as genetic predisposition factors for HBV-ACLF remains incompletely understood. The present investigation aimed to explore the relationship between genetic variants in TLR2, TLR4, and TLR9 and the association with HBV-ACLF (compared to CHB patients). 160 individuals with HBV-ACLF, 280 subjects diagnosed with chronic hepatitis B (CHB), and 280 healthy controls were recruited for this study. Two primary laboratory techniques were utilized in this study. First, serum concentrations of TLR2, TLR4, and TLR9 were assessed using an enzyme-linked immunosorbent assay (ELISA). Second, a PCR-restriction fragment length polymorphism (PCR-RFLP) assay was adopted for the detection of specific genetic variants. HBV-ACLF patients exhibited substantially higher serum concentrations of TLR2, TLR4, and TLR9 than both CHB patients and healthy controls (all p < 0.05). Compared to the CHB control group, two specific polymorphisms emerged as significant risk factors for HBV-ACLF: TLR2 - 196 to - 174 del (D/D genotype: OR = 1.87, 95% CI 1.14-3.05, p = 0.012; D allele: OR = 1.53, 95% CI 1.16-2.03, p = 0.003) and TLR9 rs187084 (C/C genotype: OR = 2.66, 95% CI 1.22-5.78, p = 0.021; C allele: OR = 1.69, 95% CI 1.14-2.50, p = 0.011). The remaining loci showed no meaningful associations (p > 0.05) Elevated serum concentrations of TLRs are observed in individuals diagnosed with HBV-ACLF. Additionally, the TLR2 - 196 to - 174 deletion variant and the TLR9 rs187084 polymorphism demonstrate a robust association with HBV-ACLF when compared to CHB controls. These factors warrant further investigation in prospective cohorts to determine their potential value in predicting disease progression.

Objective: To investigate the feasibility and efficacy of ex vivo liver resection and autologous liver transplantation (ERAT) in the treatment of initially unresectable colorectal cancer liver metastases (CRLM). Methods: Four databases, including PubMed, Embase, Scopus and Web of Science, were systematically searched for literature on ERAT for CRLM published from database inception to May 13, 2025. Meanwhile, clinical data of CRLM patients who underwent ERAT at the Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine between 2021 and 2024 were collected. Perioperative conditions and prognosis of the patients were summarized. Results: (1) Literature review: A total of 13 patients with CRLM who underwent ERAT from 5 studies were included. Among the 9 patients with available margin status, 8 achieved R0 resection and 1 underwent R1 resection. Among cases with available complication data, postoperative complications occurred in 7 patients, including pleural effusion in 3 patients. Other complications included infectious bile leakage, small bowel perforation, and inferior vena cava obstruction or compression. One patient died on postoperative day 15 due to acute respiratory failure and renal failure secondary to hemopneumothorax. Overall survival ranged from 15 days to 76 months. Among patients with available follow-up data, tumor recurrence occurred in 3 patients, including 1 patient with confirmed bone metastasis, while the sites of recurrence in the remaining patients were not clearly reported. (2) Institutional experience: All 5 patients in our center achieved R0 resection. One patient died of acute liver failure postoperatively, and the remaining cases recovered well. Pleural effusion occurred in all patients postoperatively, but the length of hospital stay did not exceed 3 weeks in any case. One patient had early postoperative recurrence and died at 27 months, while the other 3 patients remained alive at the last follow-up(2025/9/30). Conclusions: ERAT may serve as a potential surgical option for selected patients with unresectable CRLM, and radical resection can be expected under strict patient selection criteria.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are the two primary forms of kidney disease that significantly contribute to increased mortality and progression to end-stage renal disease. To effectively treat AKI and CKD, elucidating the detailed mechanisms underlying their onset and progression is essential for the development of novel therapeutic strategies. Impaired cellular function resulting from the altered metabolism of energy-producing nutrients, such as fatty acids, glucose, and amino acids, is closely involved in the pathogenesis of both AKI and CKD. Among these nutrients, branched-chain amino acids (BCAAs), such as leucine, isoleucine, and valine, are essential amino acids in humans and animals because they cannot be synthesized de novo. BCAAs play a crucial role in protein synthesis and energy production in various metabolic tissues, including skeletal muscle, liver, brown adipose tissue, pancreas, heart, and the kidney. Maintaining an appropriate balance between BCAA catabolism and anabolism is vital for optimal cellular function. Alterations in BCAA homeostasis have emerged as key contributors to the pathophysiology of several metabolic disorders, including obesity-related insulin resistance, type 2 diabetes, heart failure, kidney disease, and sarcopenia. In the present review, we provide a comprehensive overview of BCAA metabolism, with a particular focus on the molecular mechanisms linking disrupted BCAA homeostasis in proximal tubular cells to kidney disease. We also discuss the potential of targeting BCAA metabolism as a novel therapeutic strategy to suppress kidney disease progression.

We report a 48-year-old male with newly diagnosed moderately differentiated hepatocellular carcinoma (HCC) presenting with diffuse pulmonary metastases with suspected lymphangitic involvement and extensive malignancy-associated thrombosis, including bilateral pulmonary emboli, portal vein thrombosis, and inferior vena cava thrombus. His hospital course was notable for rapid clinical deterioration with progression to acute hypoxic respiratory failure despite supportive management. The primary lesson of this case is that diffuse bilateral pulmonary opacities with concurrent hepatic dysfunction and systemic symptoms should prompt early evaluation for metastatic malignancy and cancer-associated thromboembolism, even when infectious etiologies are initially suspected. The synergistic contribution of lymphangitic carcinomatosis and extensive venous thrombosis to refractory hypoxic respiratory failure, combined with the inability to initiate guideline-directed systemic therapy due to clinical instability precluding variceal screening, underscores the need for early prognostic assessment and timely goals-of-care discussions in advanced HCC.

Hepatic encephalopathy (HE) is a frequent and life-threatening neurological complication of acute liver failure (ALF) encountered in the intensive care unit and remains a major determinant of short-term mortality and long-term neurological outcomes. Increasing evidence indicates that HE in ALF is primarily driven by hyperammonemia, with synergistic contributions from systemic inflammation, cerebral hemodynamic dysregulation, metabolic failure, and osmotic imbalance. These interacting mechanisms promote astrocytic swelling, disruption of the blood-brain barrier, cerebral edema, and intracranial hypertension. In patients with ALF, early recognition of cerebral involvement and systematic exclusion of alternative causes of altered mental status are essential. Given the dynamic and heterogeneous neurological manifestations of HE, reliance on isolated clinical, biochemical, or radiological parameters is insufficient. Multimodal neuromonitoring-integrating neurological examination, ammonia kinetics, cerebral hemodynamic assessment, and neuroimaging-allows more accurate assessment of cerebral injury and supports timely, targeted intervention. This review summarizes current evidence on the pathophysiology of HE in ALF with a focus on mechanisms relevant to intensive care practice. We highlight evidence-based strategies for cerebral protection, including early and sustained control of hyperammonemia with continuous renal replacement therapy, optimization of cerebral perfusion and osmotic balance, selective use of plasma exchange, and structured neurocritical care. An integrated management framework is proposed to guide prognostication and inform timely decisions regarding advanced liver support and liver transplantation in the ICU setting.

Spider bites are commonly encountered in medicine and, when recognized early, can often be effectively managed with supportive care or antivenom. However, in rare cases, particularly in individuals with poor living conditions, chronic comorbidities, or immunocompromised states, arachnid envenomation can act as a portal for rare but life-threatening complications. We introduce the case of a 59-year-old male who presented with a presumed spider bite and later developed necrotizing soft tissue infection complicated by compartment syndrome, acute mesenteric ischemia, septic shock, and multiorgan failure, including pulmonary edema, acute kidney injury, and hepatic dysfunction. This case highlights the importance of early recognition and multidisciplinary intervention in medically and socially complex patients, and underscores how structural vulnerability can both increase exposure risk and amplify clinical severity.

Acute liver failure (ALF) is characterised by massive hepatocyte death and compromised regenerative capacity, yet the metabolic-immune crosstalk underlying these pathological processes remains poorly understood. Here, we demonstrate that lactate acts as a pivotal signal that triggers neutrophil extracellular traps (NETs) formation and release. Integrated RNA-seq and scRNA-seq analyses revealed profound glycolytic reprogramming in Kupffer cells (KCs) during ALF, leading to lactate accumulation within the hepatic microenvironment. Mechanistically, neutrophils import exogenous lactate into mitochondria via monocarboxylate transporter 1 (MCT1), which subsequently activates NETosis. Macrophage depletion or administration of an MCT1 inhibitor reduced NETs formation and ameliorated liver injury. Furthermore, we demonstrate that hepatocytes internalise NETs DNA, which is sensed by endosomal Toll-like receptor 9 (TLR9). Activation of the TLR9 signalling pathway suppresses the expression of Krüppel-like factor 15 (KLF15). This downregulation diminishes AJUBA and disrupts the KLF15-AJUBA interaction, thereby increasing the phosphorylation of YAP1 and impeding hepatocyte proliferation. Notably, KLF15 overexpression bypassed TLR9-mediated inhibitory signals and rescued the NETs-induced regenerative failure in vitro. In conclusion, our study elucidates a novel KCs-neutrophil-hepatocyte crosstalk wherein lactate-driven NETosis thwarts liver regeneration via the TLR9/KLF15/AJUBA axis, thereby identifying potential therapeutic targets for the clinical management of ALF.